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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Belinostat Therapy and UGT1A1 Genotype - Medical Genetics Summaries - NCBI Bookshelf</title>
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<meta name="citation_date" content="2023/07/20">
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<meta name="citation_author" content="Megan Kane">
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<meta name="citation_keywords" content="belinostat response">
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<meta name="og:description" content="Belinostat (brand name Beleodaq) is a histone deacetylase (HDAC) inhibitor, approved for the treatment of relapsed or refractory peripheral T-cell lymphomas (PTCLs) (1). Belinostat targets 3 classes of HDACs (I, II and IV), resulting in higher levels of acetylation of both histone and non-histone proteins, thus reversing the changes in protein acetylation that are frequently disrupted during oncogenesis. Belinostat is administered as an infusion at a rate of 1000 mg/m2 for 30 minutes on days 1–5 of a 21-day cycle (1).">
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id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK593302_"><span class="title" itemprop="name">Belinostat Therapy and <i>UGT1A1</i> Genotype</span></h1><p class="contribs">Kane M.</p><p class="fm-aai"><a href="#_NBK593302_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 23 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="belinostat.Introduction" itemprop="description"><h2 id="_belinostat_Introduction_">Introduction</h2><p>Belinostat (brand name Beleodaq) is a histone deacetylase (HDAC) inhibitor, approved for the treatment of relapsed or refractory peripheral T-cell lymphomas (PTCLs) (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>). Belinostat targets 3 classes of HDACs (I, II and IV), resulting in higher levels of acetylation of both histone and non-histone proteins, thus reversing the changes in protein acetylation that are frequently disrupted during oncogenesis. Belinostat is administered as an infusion at a rate of 1000 mg/m<sup>2</sup> for 30 minutes on days 1–5 of a 21-day cycle (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>).</p><p>Belinostat has a relatively short half-life and is primarily metabolized by uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1)-mediated glucuronidation, with minor contributions from other UGT and cytochrome P450 (CYP) enzymes (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>, <a class="bibr" href="#belinostat.REF.2" rid="belinostat.REF.2">2</a>). Genetic variation at the <i>UGT1A1</i> locus can result in decreased enzyme activity and thus increased exposure to belinostat. The US Food and Drug Administration (FDA)-approved drug label recommends a 25% decrease in dose for individuals who are known to be homozygous for the <i>UGT1A1*28</i> reduced function allele (<a href="/books/NBK593302/table/belinostat.T.the_fda_2023_drug/?report=objectonly" target="object" rid-ob="figobbelinostatTthefda2023drug">Table 1</a>) (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>). Additional indications for dose reduction include grade 3 or 4 adverse reactions or significant decrease in neutrophil or platelet counts following belinostat administration (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>). Some studies have suggested that other variant alleles may also lead to increased belinostat exposure, such as <i>UGT1A1*60</i>; however, no specific recommendations for dose reduction have been made for these alleles by either the FDA or other professional pharmacogenetic consortia. Belinostat should not be administered with other medications that can inhibit UGT1A1 function (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>), such as nilotinib, ketoconazole, or ripretinib.</p></div><div class="h2"></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figbelinostatTthefda2023drug"><a href="/books/NBK593302/table/belinostat.T.the_fda_2023_drug/?report=objectonly" target="object" title="Table 1: " class="img_link icnblk_img" rid-ob="figobbelinostatTthefda2023drug"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="belinostat.T.the_fda_2023_drug"><a href="/books/NBK593302/table/belinostat.T.the_fda_2023_drug/?report=objectonly" target="object" rid-ob="figobbelinostatTthefda2023drug">Table 1: </a></h4><p class="float-caption no_bottom_margin">The FDA (2023) Drug Label for Belinostat Dosage Recommendation based on <i>UGT1A1</i> Genotype </p></div></div><div id="belinostat.Drug_Belinostat"><h2 id="_belinostat_Drug_Belinostat_">Drug: Belinostat</h2><p>Belinostat is a pan histone deacetylase inhibitor (HDACi) used in the treatment of relapsed or refractory PTCLs (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>). Peripheral T-cell lymphomas encompass multiple subtypes that together represent 10–15% of all non-Hodgkin lymphomas. The PTCLs arise from the transformation of post-thymic T lymphocytes. (<a class="bibr" href="#belinostat.REF.3" rid="belinostat.REF.3">3</a>) It is estimated that approximately 70% of individuals with PTCL either relapse or are refractory to first-line therapy (<a class="bibr" href="#belinostat.REF.4" rid="belinostat.REF.4">4</a>). Classification and diagnostic criteria of the PTCL subtypes are described elsewhere (<a class="bibr" href="#belinostat.REF.3" rid="belinostat.REF.3">3</a>, <a class="bibr" href="#belinostat.REF.5" rid="belinostat.REF.5">5</a>, <a class="bibr" href="#belinostat.REF.6" rid="belinostat.REF.6">6</a>, <a class="bibr" href="#belinostat.REF.7" rid="belinostat.REF.7">7</a>), but the 5-year overall survival rates vary significantly among these subtypes varying from 80–25% (<a class="bibr" href="#belinostat.REF.4" rid="belinostat.REF.4">4</a>). The current indication and recommended use of belinostat is for refractory or relapsed PTCL; (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>, <a class="bibr" href="#belinostat.REF.5" rid="belinostat.REF.5">5</a>) however, it has been investigated as a first-line agent for PTCL with other first-line therapies (<a class="bibr" href="#belinostat.REF.8" rid="belinostat.REF.8">8</a>). Belinostat is one of several single agent options for refractory or relapsed PTCL recommended by the National Comprehensive Cancer Network (<a class="bibr" href="#belinostat.REF.5" rid="belinostat.REF.5">5</a>).</p><p>Changes in gene expression are observed in most PTCL types, either owing to altered epigenetic regulation, gene fusion events, somatic genetic variation of genes involved in epigenetic regulation, or some combination of these events (<a class="bibr" href="#belinostat.REF.9" rid="belinostat.REF.9">9</a>). The HDACs, key enzymes in the maintenance of protein acetylation, are also implicated in the pathogenesis of PTCL as well as other malignancies (<a class="bibr" href="#belinostat.REF.10" rid="belinostat.REF.10">10</a>, <a class="bibr" href="#belinostat.REF.11" rid="belinostat.REF.11">11</a>). Protein acetylation has a role in epigenetics as well as modulation of many other cellular homeostatic processes (<a class="bibr" href="#belinostat.REF.10" rid="belinostat.REF.10">10</a>).</p><p>Belinostat is referred to as a pan-HDACi as it can inhibit all 3 classes of HDAC isoforms in humans, impacting not only histone acetylation, but non-histone proteins as well (<a class="bibr" href="#belinostat.REF.10" rid="belinostat.REF.10">10</a>). A loss of acetylation on histones is associated with condensation of the chromatin structure and reduced expression of the underlying genes (<a class="bibr" href="#belinostat.REF.12" rid="belinostat.REF.12">12</a>). By inhibiting the removal of acetyl groups by HDACs, belinostat is thought to relax chromatin structure and affect the activity of non-histone nuclear proteins. This leads to expression of genes that were silenced during oncogenesis and facilitates pro-apoptotic cellular responses (<a class="bibr" href="#belinostat.REF.10" rid="belinostat.REF.10">10</a>). In Phase I clinical trials in solid and hematologic malignancies, belinostat had a robust antitumor and anti-angiogenic effect, leading to phase II trials in both PTCL and cutaneous T-cell lymphoma (CTCL) (<a class="bibr" href="#belinostat.REF.11" rid="belinostat.REF.11">11</a>, <a class="bibr" href="#belinostat.REF.13" rid="belinostat.REF.13">13</a>, <a class="bibr" href="#belinostat.REF.14" rid="belinostat.REF.14">14</a>).</p><p>Belinostat is administered intravenously at a dose of 1,000 mg/m<sup>2</sup> over 30 minutes once daily on days 1–5 of a 21-day cycle (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>). It has an elimination half-life of 1.1 hours with a limited body tissue distribution; the majority of belinostat is bound to protein in plasma (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>). Over 98% of belinostat is metabolized prior to excretion (<a class="bibr" href="#belinostat.REF.15" rid="belinostat.REF.15">15</a>, <a class="bibr" href="#belinostat.REF.16" rid="belinostat.REF.16">16</a>). Belinostat is primarily metabolized through glucuronidation by UGT1A1 with minor contributions by UGT2B7, and the resulting metabolite is the major form detected in urine (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>, <a class="bibr" href="#belinostat.REF.2" rid="belinostat.REF.2">2</a>, <a class="bibr" href="#belinostat.REF.15" rid="belinostat.REF.15">15</a>, <a class="bibr" href="#belinostat.REF.17" rid="belinostat.REF.17">17</a>). Additional metabolism of belinostat is carried out by CYP2A6, CYP2C9, and CYP3A4 to form belinostat amide and belinostat acid. However, the enzymes responsible for the formation of 2 other metabolites are currently unknown. (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>, <a class="bibr" href="#belinostat.REF.16" rid="belinostat.REF.16">16</a>) The primary route of excretion of belinostat and its metabolites is through urine, with less than 10% of a single radiolabeled dose detected in the feces over 168 hours post-transfusion (<a class="bibr" href="#belinostat.REF.15" rid="belinostat.REF.15">15</a>). Due to the significant role of UGT1A1 in the metabolism and elimination of belinostat, the FDA-approved drug label recommends a reduced dosage of 750 mg/m<sup>2</sup> for individuals with known UGT1A1 reduced function, specifically those who are homozygous for the <i>UGT1A1*28</i> allele (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>). The FDA-approved drug label also cautions against concomitant use of belinostat with strong inhibitors of UGT1A1 (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>).</p><p>Adverse reactions associated with belinostat include hematologic toxicity, hepatotoxicity, tumor lysis syndrome, gastrointestinal toxicity, and embryo-fetal toxicity if used during pregnancy. Hematologic toxicities include thrombocytopenia, leukopenia, anemia, or a combination of these symptoms. Hepatotoxicity and liver function should be monitored prior to initiation of therapy and at the start of each round. Nausea, vomiting, and diarrhea can also occur during belinostat therapy. (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>) The most frequently reported treatment-emergent adverse effects during clinical trials include nausea, fatigue, pyrexia, constipation, vomiting, and dizziness (<a class="bibr" href="#belinostat.REF.11" rid="belinostat.REF.11">11</a>, <a class="bibr" href="#belinostat.REF.14" rid="belinostat.REF.14">14</a>). Tumor lysis syndrome (TLS) is a particular concern for individuals with advanced stage disease or high tumor burden; baseline hyperuricemia and bulky disease were associated with one individual experiencing grade 4 TLS and death due to multiorgan failure during clinical trial (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>).</p><p>Some observed toxicities are indications for reduced dosage or discontinuation of belinostat. For hematologic toxicity, if the individual has a nadir absolute neutrophil count less than 0.5 x10<sup>9</sup>/L or platelet count less than 25x10<sup>9</sup>/L, the dosage should be decreased by 25% (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>). Similarly, if a non-hematologic Common Terminology Criteria for Adverse Events (CTCAE) (<a class="bibr" href="#belinostat.REF.18" rid="belinostat.REF.18">18</a>) Grade 3 or 4 adverse reaction is observed, decrease the dose by 25%; a recurrence of these adverse reactions after 2 dose reductions is an indication to discontinue belinostat (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>).</p><p>Due to the genotoxic effects of belinostat, there is a risk of fetal harm when administered to a pregnant woman. The FDA-approved label recommends that females use effective contraception for 6 months following the last dose of belinostat and males whose partners are females of reproductive potential should also use effective contraception for 3 months following his last dose of belinostat (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>). These recommendations are based on the mechanism of action of belinostat, as there are no available data on the use of this medication in pregnant women, nor were animal reproduction studies conducted with belinostat. (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>) Additionally, there are no data regarding the excretion of belinostat into breast milk, how belinostat may affect a breastfed child, nor the effect on milk production; based on the potential adverse reaction to the breastfed child, nursing mothers are advised not to breastfeed until 2 weeks after the last belinostat dose (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>).</p><p>Belinostat has not been proven to be safe or effective in pediatric individuals (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>). In clinical trial data, individuals aged 65 and above had a higher response rate to belinostat versus individuals under 65 (36% versus 16%) (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>, <a class="bibr" href="#belinostat.REF.11" rid="belinostat.REF.11">11</a>). However, no association was found between age of the individuals and rate of adverse reactions, indicating that age alone was not a risk factor for treatment-emergent adverse events (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>). Moderate to severe hepatic impairment (as indicated by total bilirubin greater than 1.5 times the upper normal limit) was an exclusionary criterion for participation in clinical trials, but less severe hepatic impairment may increase exposure to belinostat (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>, <a class="bibr" href="#belinostat.REF.11" rid="belinostat.REF.11">11</a>, <a class="bibr" href="#belinostat.REF.14" rid="belinostat.REF.14">14</a>). However, the FDA-approved label does not provide any alternative dosing recommendations for individuals with liver impairment (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>).</p><p>Aberrations in protein acetylation and gene dysregulation are common across many types of cancer. The efficacy and safety of belinostat in other types of malignancies is an active area of investigation. It has been tested in acute promyelocytic leukemia, CTCL, B-cell lymphoma, advanced solid tumors including neuroendocrine and lung cancers, testicular germ cell tumors, and others (<a class="bibr" href="#belinostat.REF.14" rid="belinostat.REF.14">14</a>, <a class="bibr" href="#belinostat.REF.19" rid="belinostat.REF.19">19</a>, <a class="bibr" href="#belinostat.REF.20" rid="belinostat.REF.20">20</a>, <a class="bibr" href="#belinostat.REF.21" rid="belinostat.REF.21">21</a>, <a class="bibr" href="#belinostat.REF.22" rid="belinostat.REF.22">22</a>, <a class="bibr" href="#belinostat.REF.23" rid="belinostat.REF.23">23</a>). Additionally, belinostat has been investigated as a potential therapy for atopic dermatitis (<a class="bibr" href="#belinostat.REF.24" rid="belinostat.REF.24">24</a>, <a class="bibr" href="#belinostat.REF.25" rid="belinostat.REF.25">25</a>). Clinical trials involving belinostat can be found at <a href="https://clinicaltrials.gov/ct2/results?cond=&term=belinostat&cntry=&state=&city=&dist=" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a>.</p></div><div id="belinostat.Gene_UGT1A1"><h2 id="_belinostat_Gene_UGT1A1_">Gene: <i>UGT1A1</i></h2><p>The UGT enzymes (uridine diphosphate-glucuronosyltransferase, or UDP-glucuronosyltransferase) are a superfamily of enzymes that metabolize a wide range of lipophilic molecules such as bilirubin, steroids, toxins, and drugs. These enzymes mediate the process of glucuronidation, which is a phase II metabolic pathway during which glucuronic acid is conjugated to specific targets to convert them to water-soluble metabolites that can then be eliminated from the body (<a class="bibr" href="#belinostat.REF.26" rid="belinostat.REF.26">26</a>).</p><p>The UGT genes are polymorphic, and genomic processes, such as variant splicing and epigenetic factors, likely contribute to their diversity. As a result, the substrates that the UGT enzymes catalyze are particularly variable (<a class="bibr" href="#belinostat.REF.27" rid="belinostat.REF.27">27</a>). In humans, the UGT superfamily consists of 22 enzymes divided into 4 families, of which UGT1A is a member (<a class="bibr" href="#belinostat.REF.28" rid="belinostat.REF.28">28</a>). The <i>UGT1A</i> gene locus is a cassette gene located on chromosome 2q37 in which common exons 2–5a and 5b are differentially spliced to unique first exons to form the 9 functional UGT1A family members (UGT1A1 and UGT1A3–UGT1A10) (<a class="bibr" href="#belinostat.REF.29" rid="belinostat.REF.29">29</a>, <a class="bibr" href="#belinostat.REF.30" rid="belinostat.REF.30">30</a>). The <i>UGT1A1</i> promoter is differentially regulated compared to other UGT1As and consists of elements sensitive to xenobiotics (for example, pregnane X receptor and constitutive androstane receptor), hydrocarbons (for example, the aryl hydrocarbon receptor (AhR)), electrophilic nucleophiles and reactive oxygen species (for example, the nuclear factor 2 receptor), endobiotics and fatty acids (such as the glucocorticoid receptor), and a critical Thymine-Adenine-Thymine-Adenine (TATA) box that consists of polymorphic tandem repeats, (TA)<sub>5–8</sub>TAA. Several Cytosine-phosphate-Guanine islands at the promoter further alter the affinity of nuclear receptors and therefore alter receptor activity.</p><p>Whereas many UGT enzymes overlap in the substrates they glucuronidate, UGT1A1 is the only enzyme that glucuronidates bilirubin, a yellow waste product produced during the catabolism of heme, a constituent of hemoglobin (<a class="bibr" href="#belinostat.REF.31" rid="belinostat.REF.31">31</a>). When old or damaged red blood cells are broken down in the spleen, their hemoglobin is broken down to heme, which is then converted into bilirubin. The UGT1A1 enzyme converts this toxic, insoluble form of bilirubin (unconjugated bilirubin) to its nontoxic form (conjugated bilirubin). Because conjugated bilirubin is water-soluble, it can be dissolved in bile and eliminated with solid waste. If bilirubin is not eliminated and instead accumulates to high levels (hyperbilirubinemia), it can cause a yellowish discoloration of the skin and eyes, a condition known as jaundice.</p><p>Over 150 genetic variants of <i>UGT1A1</i> have been reported (<a class="bibr" href="#belinostat.REF.26" rid="belinostat.REF.26">26</a>, <a class="bibr" href="#belinostat.REF.31" rid="belinostat.REF.31">31</a>, <a class="bibr" href="#belinostat.REF.32" rid="belinostat.REF.32">32</a>). Of these, the available evidence indicates that 5 polymorphic variants are of clinical importance to UGT1A1 activity (<i>UGT1A1*6</i>, <i>UGT1A1*27</i>, <i>UGT1A1*28</i>, <i>UGT1A1*36</i>, <i>UGT1A1*37</i>), and 3 of these variants impact the tandem repeat of the TATA box ([TA]<sub>5</sub>TAA – <i>UGT1A1*36</i>, [TA]<sub>7</sub>TAA – <i>UGT1A1*28</i>, [TA]<sub>8</sub>TAA – <i>UGT1A1*37</i> (<a class="bibr" href="#belinostat.REF.33" rid="belinostat.REF.33">33</a>)). The wild-type allele is called <i>UGT1A1*1,</i> which is associated with normal enzyme activity and the reference TATA box tandem repeat length ([TA]<sub>6</sub>TAA) (<a href="/books/NBK593302/table/belinostat.T.relative_enzymatic/?report=objectonly" target="object" rid-ob="figobbelinostatTrelativeenzymatic">Table 2</a>).</p><p>As with all genetic variation, specific alleles or haplotypes vary in frequency across populations based on genetic ancestry and any history of evolutionary migration or bottleneck. To characterize the range of genetic variation in different groups of people, studies have used a mix of ethnic, racial, and geographic descriptors to group individuals with presumed common ancestry and shared genetic traits. Those descriptors are used interchangeably below based on the cited literature; however, the goal is to reflect a shared genetic background arising from common ancestry.</p><p>There are multiple genetic variations in the <i>UGT1A1</i> locus that decrease UGT1A1 enzyme activity and can lead to jaundice in the absence of exogenous substances, such as belinostat. The jaundice may be mild, as seen in <a href="https://www.ncbi.nlm.nih.gov/medgen/4891" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Gilbert syndrome</a>, or severe, as seen in <a href="https://www.ncbi.nlm.nih.gov/medgen/1789261" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Crigler-Najjar syndrome</a>. (<a class="bibr" href="#belinostat.REF.34" rid="belinostat.REF.34">34</a>)</p><p>The most common variant <i>UGT1A1</i> allele is <i>UGT1A1*28</i>, which is commonly found in African Americans (0.42–0.45 allele frequency, or 17–20% frequency of homozygosity in the population), Caucasians (0.26–0.31 allele frequency, or 6–9% homozygosity), and in Western and South Asian populations (0.26–0.33 allele frequency, or 6–10% homozygosity); however, it is less common in East and South-East Asian populations (0.09–0.16 allele frequency, or 0.8–2.5% homozygosity) (<a class="bibr" href="#belinostat.REF.35" rid="belinostat.REF.35">35</a>, <a class="bibr" href="#belinostat.REF.36" rid="belinostat.REF.36">36</a>, <a class="bibr" href="#belinostat.REF.37" rid="belinostat.REF.37">37</a>). Within Caucasian and African American populations, the <i>UGT1A1*28</i> variant is a common cause of Gilbert syndrome (<a class="bibr" href="#belinostat.REF.35" rid="belinostat.REF.35">35</a>, <a class="bibr" href="#belinostat.REF.38" rid="belinostat.REF.38">38</a>). The <i>UGT1A1*28</i> ([TA]<sub>7</sub>TAA) variant contains an extra TA repeat within the TATA box promoter region (7 TA repeats compared with 6 in the wild-type allele) (<a class="bibr" href="#belinostat.REF.39" rid="belinostat.REF.39">39</a>). This extra TA repeat decreases the rate of transcription initiation of the <i>UGT1A1</i> gene, leading to decreased enzyme activity and decreased glucuronidation of bilirubin (<a class="bibr" href="#belinostat.REF.40" rid="belinostat.REF.40">40</a>). The data suggests that one copy of the <i>UGT1A1*28</i> allele results in an approximately 35% decrease in transcriptional activity, and 2 copies (<i>*28/*28</i>, homozygous) results in an approximately 70% decrease, which is the genotype that the FDA has incorporated into the belinostat dosing label (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>, <a class="bibr" href="#belinostat.REF.41" rid="belinostat.REF.41">41</a>, <a class="bibr" href="#belinostat.REF.42" rid="belinostat.REF.42">42</a>).</p><p>Another variant allele, UGT1A1*37 ([TA]<sub>8</sub>TAA), has 8 TA repeats at the TATA box site, and results in reduced promoter activity of the gene to levels lower than the UGT1A1*28 allele. In contrast, the UGT1A1*36 ([TA]<sub>5</sub>TAA) allele only has 5 repeats and is associated with increased promoter activity and a reduced risk of neonatal hyperbilirubinemia (a common and typically benign condition). Both UGT1A1*36 and UGT1A1*37 occur almost exclusively in populations of African origin, with estimated allele frequencies across African descent populations of 0.07 for <i>*36</i> (TA<sub>5</sub>) and 0.05 for <i>*37</i> (TA<sub>8</sub>) (gnomAD browser version 3.1.2, accessed 27 April 2023) (<a class="bibr" href="#belinostat.REF.43" rid="belinostat.REF.43">43</a>). By comparison, the average frequency of these alleles across all populations in gnomAD is 0.01–0.02. The allele <i>UGT1A1*80</i> demonstrates strong linkage disequilibrium with both <i>UGT1A1*28</i> and <i>*37</i> and is considered a surrogate marker for these alleles (<a class="bibr" href="#belinostat.REF.33" rid="belinostat.REF.33">33</a>).</p><p>Other promoter variants have been reported in the phenobarbital-responsive enhancer module of the <i>UGT1A</i> locus. A T to G substitution, referred to as <i>UGT1A1*60</i>, results in decreased transcription of the gene and was found more frequently in individuals with mild hyperbilirubinemia (<a class="bibr" href="#belinostat.REF.44" rid="belinostat.REF.44">44</a>), though other studies have reported no significant difference in total bilirubin concentration in individuals homozygous for <i>UGT1A1*60</i> versus wild-type homozygotes (<a class="bibr" href="#belinostat.REF.45" rid="belinostat.REF.45">45</a>). The <i>UGT1A1*60</i> allele has been observed more frequently in individuals of African descent versus European descent (‘Caucasians’) (<a class="bibr" href="#belinostat.REF.46" rid="belinostat.REF.46">46</a>). It should be noted that the <i>UGT1A1*28</i> and *<i>60</i> alleles are reported to be in linkage disequilibrium in multiple ethnic groups (<a class="bibr" href="#belinostat.REF.46" rid="belinostat.REF.46">46</a>, <a class="bibr" href="#belinostat.REF.47" rid="belinostat.REF.47">47</a>), meaning an individual who has the higher number of TA repeats in the promoter (<i>UGT1A1*28</i>) is also likely to have the T to G substitution (<i>UGT1A1*60</i>) in the phenobarbital-responsive enhancer module region as well. Thus, it can be difficult to ascertain the individual contribution of these variants to total enzyme activity in vivo. The <i>UGT1A1*60</i> allele has a reported allele frequency of 0.47 in Caucasians (individuals of European descent) and 0.85 in Americans of African descent (<a class="bibr" href="#belinostat.REF.46" rid="belinostat.REF.46">46</a>).</p><p>Another variant allele, <i>UGT1A1*6</i>, is more prevalent in East Asian populations, with an allele frequency of around 0.10–0.30 in Taiwanese, Chinese, Korean, and Japanese populations (<a class="bibr" href="#belinostat.REF.37" rid="belinostat.REF.37">37</a>, <a class="bibr" href="#belinostat.REF.41" rid="belinostat.REF.41">41</a>, <a class="bibr" href="#belinostat.REF.48" rid="belinostat.REF.48">48</a>, <a class="bibr" href="#belinostat.REF.49" rid="belinostat.REF.49">49</a>). The <i>UGT1A1*6</i> allele is less common in South Eastern and Southern Asian populations, ranging from 0.027--0.12 in Thai, Malay, Indonesian, Vietnamese, and Indian population studies (<a class="bibr" href="#belinostat.REF.37" rid="belinostat.REF.37">37</a>). This missense variant results in a glycine to arginine amino acid change at position 71 (p.Arg71Gly), and individuals who are homozygous for this allele have reduced UGT1A1 enzyme activity, which can cause Gilbert syndrome and prolonged neonatal jaundice (<a class="bibr" href="#belinostat.REF.50" rid="belinostat.REF.50">50</a>, <a class="bibr" href="#belinostat.REF.51" rid="belinostat.REF.51">51</a>, <a class="bibr" href="#belinostat.REF.52" rid="belinostat.REF.52">52</a>, <a class="bibr" href="#belinostat.REF.53" rid="belinostat.REF.53">53</a>).</p><p>The <i>UGT1A1*27</i> (p.Pro229Gln) variant allele is located in exon 1 and has a minor allele frequency between 0.00011–0.0030 in those with Asian ancestry. It is associated with Gilbert’s syndrome, post-irinotecan hyperbilirubinemia, and severe or life-threatening leukopenia or diarrhea during irinotecan therapy (<a class="bibr" href="#belinostat.REF.54" rid="belinostat.REF.54">54</a>, <a class="bibr" href="#belinostat.REF.55" rid="belinostat.REF.55">55</a>). The allele is associated with a significant decrease in UGT1A1 substrate binding and catalytic activity (<a class="bibr" href="#belinostat.REF.56" rid="belinostat.REF.56">56</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figbelinostatTrelativeenzymatic"><a href="/books/NBK593302/table/belinostat.T.relative_enzymatic/?report=objectonly" target="object" title="Table 2: " class="img_link icnblk_img" rid-ob="figobbelinostatTrelativeenzymatic"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="belinostat.T.relative_enzymatic"><a href="/books/NBK593302/table/belinostat.T.relative_enzymatic/?report=objectonly" target="object" rid-ob="figobbelinostatTrelativeenzymatic">Table 2: </a></h4><p class="float-caption no_bottom_margin">Relative Enzymatic Activity of UGT1A1 Variants </p></div></div><div id="belinostat.Phenoconversion"><h3>Phenoconversion</h3><p>Mismatch between an individual’s genotype-predicted phenotype and actual phenotype, or “phenoconversion,” results from extrinsic factors (namely, comedications or comorbidities) altering the expression or function of enzymes. Individuals harboring an intermediate metabolizer phenotype are typically more susceptible to phenoconversion as a function of compromised drug metabolism capacity, whereas poor metabolizers (PMs) are unlikely to undergo phenoconversion but are more likely to experience toxicity from low or absent drug metabolism capacity limiting clearance of toxic drug species (<a class="bibr" href="#belinostat.REF.59" rid="belinostat.REF.59">59</a>). The FDA-approved label recommends avoidance of belinostat administration with UGT1A1 inhibitors, as this may result in an increased exposure of the individual to belinostat (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>). Medications that inhibit UGT1A1 include nilotinib (<a class="bibr" href="#belinostat.REF.60" rid="belinostat.REF.60">60</a>), ketoconazole (<a class="bibr" href="#belinostat.REF.61" rid="belinostat.REF.61">61</a>), and ripretinib along with other tyrosine kinase inhibitor drugs (<a class="bibr" href="#belinostat.REF.62" rid="belinostat.REF.62">62</a>). This is highly relevant given the interest in belinostat therapy for multiple cancer types in a combination therapy approach (<a class="bibr" href="#belinostat.REF.8" rid="belinostat.REF.8">8</a>, <a class="bibr" href="#belinostat.REF.22" rid="belinostat.REF.22">22</a>). The use of belinostat may, conversely, impact enzymatic activity and alter the effect of other comedications. Belinostat can interfere with rifampin-induced changes in gene expression such as the induction of CYP3A4 expression (<a class="bibr" href="#belinostat.REF.63" rid="belinostat.REF.63">63</a>). Belinostat, however, did not significantly impact the metabolism of warfarin by CYP2C9 (<a class="bibr" href="#belinostat.REF.64" rid="belinostat.REF.64">64</a>). Belinostat itself inhibits UGT enzymes, and thus may interfere with metabolism of other UGT substrates (<a class="bibr" href="#belinostat.REF.65" rid="belinostat.REF.65">65</a>).</p></div></div><div id="belinostat.Linking_UGT1A1_Genet"><h2 id="_belinostat_Linking_UGT1A1_Genet_">Linking <i>UGT1A1</i> Genetic Variation with Treatment Response</h2><p>The primary mechanism of belinostat clearance is metabolism by UGT1A1 (<a class="bibr" href="#belinostat.REF.2" rid="belinostat.REF.2">2</a>, <a class="bibr" href="#belinostat.REF.15" rid="belinostat.REF.15">15</a>, <a class="bibr" href="#belinostat.REF.66" rid="belinostat.REF.66">66</a>). Genetic variation in the <i>UGT1A1</i> locus can lead to a decrease in enzyme activity and thus increase an individual’s exposure to belinostat, leading to a higher risk of adverse reactions. The FDA-approved drug label and initial clinical studies support a decrease in dose (750 mg/m<sup>2</sup>) for individuals who are homozygous for the <i>UGT1A1*28</i> allele to minimize toxicities (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>, <a class="bibr" href="#belinostat.REF.2" rid="belinostat.REF.2">2</a>). Given the FDA guidance to avoid belinostat and co-medication with UGT1A1 inhibitors, it is unclear why additional genetic variants with a known decrease in function are not indications for a dose decrease on the product label. Additional studies have suggested that the <i>UGT1A1*60</i> allele also results in decreased clearance of belinostat, both when it was the only detected variant but also when detected in <i>cis</i> with *<i>28</i> (<a class="bibr" href="#belinostat.REF.67" rid="belinostat.REF.67">67</a>, <a class="bibr" href="#belinostat.REF.68" rid="belinostat.REF.68">68</a>). Both <i>UGT1A1*28</i> and <i>*60</i> have been shown to be associated with increased belinostat exposure and a higher risk of thrombocytopenia and neutropenia (<a class="bibr" href="#belinostat.REF.67" rid="belinostat.REF.67">67</a>). However, it should be noted that the Clinical Pharmacogenetics Implementation Consortium (CPIC) reassessed the functional status of <i>UGT1A1*60</i> and determined it was a normal-function allele, as indicated by serum bilirubin concentrations (<a class="bibr" href="#belinostat.REF.45" rid="belinostat.REF.45">45</a>, <a class="bibr" href="#belinostat.REF.58" rid="belinostat.REF.58">58</a>). The clinical function of <i>UGT1A1</i> alleles as assigned by CPIC, initially published with guidelines for atazanavir pharmacogenetics (<a class="bibr" href="#belinostat.REF.33" rid="belinostat.REF.33">33</a>), are presented in <a href="/books/NBK593302/table/belinostat.T.relative_enzymatic/?report=objectonly" target="object" rid-ob="figobbelinostatTrelativeenzymatic">Table 2</a>.</p><p>Further clinical studies are needed to determine the role of both common and rare <i>UGT1A1</i> variants in belinostat metabolism and the risk of adverse reactions.</p></div><div id="belinostat.Genetic_Testing"><h2 id="_belinostat_Genetic_Testing_">Genetic Testing</h2><p>The NIH Genetic Testing Registry (GTR) has tests for <a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=CN282543" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">belinostat response</a> and <a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=54658%5bgeneid%5d" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UGT1A1 genetic variation</a>. Variants impacting UGT1A1 enzyme activity affect both the coding sequence as well as the promotor region of UGT1A locus. The FDA-approved label does not recommend for or against genetic testing prior to belinostat therapy, but states that knowledge of <i>UGT1A1*28</i> genotype is sufficient indication to alter prescribing. No other clinical practice guidelines for translation of other genotypes to altered dosing are currently available. Liu and colleagues recommend <i>UGT1A1</i> genotyping before administering any medication that is metabolized by UGT1A1 (<a class="bibr" href="#belinostat.REF.69" rid="belinostat.REF.69">69</a>). Indeed, germline testing for variation in <i>UGT1A1</i> along with 4 other pharmacogenes has been estimated to have impact on oncology care as significantly as somatic variant testing (<a class="bibr" href="#belinostat.REF.70" rid="belinostat.REF.70">70</a>). As a result of the demonstrated impact on UGT1A1 activity and the increased risk of adverse reactions, Goey and Figg recommend <i>UGT1A1</i> genotyping for both <i>*28</i> and <i>*60</i> variant alleles when determining belinostat dose (<a class="bibr" href="#belinostat.REF.68" rid="belinostat.REF.68">68</a>).</p><p>One pharmacogenetic study in an oncology clinical setting found that approximately 17% of individuals had a UGT1A1 PM phenotype, defined as having 2 decreased-function alleles (<i>UGT1A1*6</i> or *<i>28</i>) (<a class="bibr" href="#belinostat.REF.70" rid="belinostat.REF.70">70</a>). Genotyping for different lengths of the TA promoter alleles requires a high degree of precision, particularly given the multiple variant alleles reported for that position, thus it is important to consider the testing methodology when selecting a genetic test or reviewing testing results.</p><p>The <i>UGT1A1*28</i> allele has been reported to be in linkage disequilibrium with the *<i>80</i> allele; however, the <i>UGT1A1*80</i> variant itself is not known to influence <i>UGT1A1</i> expression (<a class="bibr" href="#belinostat.REF.71" rid="belinostat.REF.71">71</a>). Instead, <i>UGT1A1*80</i> has been suggested to serve as a proxy for *<i>28</i> variant identification in some single nucleotide polymorphism-based genotyping assays (<a class="bibr" href="#belinostat.REF.33" rid="belinostat.REF.33">33</a>, <a class="bibr" href="#belinostat.REF.70" rid="belinostat.REF.70">70</a>, <a class="bibr" href="#belinostat.REF.71" rid="belinostat.REF.71">71</a>).</p><p>Additionally, <i>UGT1A1</i> genotyping may reveal variants that are associated with Gilbert syndrome or Crigler-Najjar syndrome type 1 or type 2. More information and resources for these conditions are available through <a href="https://www.ncbi.nlm.nih.gov/medgen/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MedGen</a>. While more clinical data may be needed on belinostat metabolism, studies have shown that variants associated with Gilbert syndrome or Crigler-Najjar syndrome type 2 not only impact bilirubin metabolism, but multiple exogenous substances as well (<a class="bibr" href="#belinostat.REF.31" rid="belinostat.REF.31">31</a>, <a class="bibr" href="#belinostat.REF.33" rid="belinostat.REF.33">33</a>, <a class="bibr" href="#belinostat.REF.56" rid="belinostat.REF.56">56</a>, <a class="bibr" href="#belinostat.REF.72" rid="belinostat.REF.72">72</a>).</p></div><div id="belinostat.The_UGT1A1_Gene_Inte"><h2 id="_belinostat_The_UGT1A1_Gene_Inte_">The <i>UGT1A1</i> Gene Interactions with Medications Used for Additional Indications</h2><p>Variation in <i>UGT1A1</i> and its promoter region are associated with risks of adverse reactions for a range of medications.</p><ul><li class="half_rhythm"><div>Multiple medications used in oncology are metabolized by UGT1A1 including <a href="/books/n/bcms5968/irinotecan/?report=reader">irinotecan</a>, nilotinib, and sacituzumab govitecan; decreased UGT1A1 activity may lead to increased exposure to these medications with a higher risk of adverse reactions, adjusted dosing may be necessary based on <i>UGT1A1</i> genotype.</div></li><li class="half_rhythm"><div>The human immunodeficiency virus type 1 protease inhibitor, atazanavir, inhibits UGT1A1 activity and may lead to increased indirect plasma bilirubin concentration; UGT1A1 PMs may experience jaundice leading to discontinuation of therapy (<a class="bibr" href="#belinostat.REF.33" rid="belinostat.REF.33">33</a>)</div></li><li class="half_rhythm"><div>A medication used for acromegalia, pegvisomant, caused liver injury in individuals who were positive for <i>UGT1A1*28</i> (<a class="bibr" href="#belinostat.REF.26" rid="belinostat.REF.26">26</a>)</div></li></ul><p>Additional information on gene-drug interactions for <i>UGT1A1</i> are available from <a href="https://www.pharmgkb.org/gene/PA420" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PharmGKB</a>, <a href="https://cpicpgx.org/genes-drugs/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CPIC</a> and the <a href="https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">FDA</a> (search for “UGT1A1”).</p></div><div id="belinostat.Therapeutic_Recommen"><h2 id="_belinostat_Therapeutic_Recommen_">Therapeutic Recommendations based on Genotype</h2><p><b>This section contains excerpted</b><sup><a href="#belinostat.FN1">1</a></sup>
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<b>information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.</b></p><p>
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<b>2023 Statement from the US Food and Drug Administration (FDA):</b>
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</p><p>Patients with Reduced UGT1A1 Activity</p><p>Reduce the starting dose of Beleodaq to 750 mg/m<sup>2</sup> in patients known to be homozygous for the UGT1A1*28 allele.</p><p>[….]</p><p>Pharmacogenomics</p><p>UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism. Approximately 20% of the black population, 10% of the white population, and 2% of the Asian population are homozygous for the UGT1A1*28 allele. Additional reduced function alleles may be more prevalent in specific populations.</p><p>Because belinostat is primarily (80 -90%) metabolized by UGT1A1, the clearance of belinostat could be decreased in patients with reduced UGT1A1 activity (e.g., patients with UGT1A1*28 allele). Reduce the starting dose of Beleodaq to 750 mg/m<sup>2</sup> in patients known to be homozygous for the UGT1A1*28 allele to minimize dose limiting toxicities.</p><p><b>Please review the complete therapeutic recommendations that are located here:</b> (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>)</p></div><div id="belinostat.Nomenclature_for_sel"><h2 id="_belinostat_Nomenclature_for_sel_">Nomenclature for selected <i>UGT1A1</i> Alleles</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figbelinostatTe"><a href="/books/NBK593302/table/belinostat.Te/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobbelinostatTe"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="belinostat.Te"><a href="/books/NBK593302/table/belinostat.Te/?report=objectonly" target="object" rid-ob="figobbelinostatTe">Table</a></h4><p class="float-caption no_bottom_margin">-3279T>G </p></div></div></div><div id="belinostat.Acknowledgments"><h2 id="_belinostat_Acknowledgments_">Acknowledgments</h2><p>The author would like to thank Ben Kong, PharmD, Clinical Pharmacist, Oregon Health & Science University, Knight Cancer Institute, Portland, Oregon, USA; Natalie Reizine, MD, Assistant Professor of Medicine, University of Illinois Cancer Center, Chicago, IL, USA; and Tristan Sissung, PhD, MS, Staff Scientist, Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA for reviewing this summary.</p></div><div id="belinostat.References"><h2 id="_belinostat_References_">References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="belinostat.REF.1">BELEODAQ- belinostat injection, powder, lyophilized, for solution. East Windsor, NJ, USA: Acrotech Biopharma Inc; 2023. Available from: <a href="https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2e8ef36b-71fa-4492-a16f-577d5f7d111d" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://dailymed<wbr style="display:inline-block"></wbr>​.nlm<wbr style="display:inline-block"></wbr>​.nih.gov/dailymed/drugInfo<wbr style="display:inline-block"></wbr>​.cfm?setid=2e8ef36b-71fa-4492-a16f-577d5f7d111d</a></div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="belinostat.REF.2">Wang, L.Z., J.
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Ramirez, W.
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Yeo, M.Y.
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Chan, et al., Glucuronidation by UGT1A1 is the dominant pathway of the metabolic disposition of belinostat in liver cancer patients.
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PLoS One, 2013. 8(1): p. e54522.
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[<a href="/pmc/articles/PMC3559838/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3559838</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23382909" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23382909</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="belinostat.REF.3">Stuver, R., Z.D.
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Epstein-Peterson, W.T.
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Johnson, N.
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Khan, et al., Current Treatment of Peripheral T-cell Lymphoma.
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Oncology (Williston Park), 2022. 36(5): p. 293-305.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/35576176" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35576176</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="belinostat.REF.4">Wolska-Washer, A., P.
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Smolewski and T.
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Robak, Advances in the pharmacotherapeutic options for primary nodal peripheral T-cell lymphoma.
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Expert Opin Pharmacother, 2021. 22(9): p. 1203-1215.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/33524268" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33524268</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="belinostat.REF.5">NCCN Clinical Practice Guidelines in Oncology, T-Cell Lymphomas, 1.2023, 5 January 2023. Network, N.C.C.; [Cited 21 April 2023]. Available from: <a href="https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1483" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>​.nccn.org<wbr style="display:inline-block"></wbr>​/guidelines/guidelines-detail?category<wbr style="display:inline-block"></wbr>​=1&id=1483</a></div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="belinostat.REF.6">Swerdlow, S.H., E.
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Campo, S.A.
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Pileri, N.L.
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Harris, et al., The 2016 revision of the World Health Organization classification of lymphoid neoplasms.
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Blood, 2016. 127(20): p. 2375-90.
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[<a href="/pmc/articles/PMC4874220/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4874220</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26980727" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26980727</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="belinostat.REF.7">Campo, E., E.S.
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Jaffe, J.R.
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Cook, L.
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Quintanilla-Martinez, et al., The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee.
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Blood, 2022. 140(11): p. 1229-1253.
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[<a href="/pmc/articles/PMC9479027/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9479027</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35653592" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35653592</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="belinostat.REF.8">Johnston, P.B., A.F.
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Cashen, P.G.
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Nikolinakos, A.W.
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Beaven, et al., Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma.
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Exp Hematol Oncol, 2021. 10(1): p. 15.
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[<a href="/pmc/articles/PMC7893947/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7893947</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33602316" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33602316</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="belinostat.REF.9">Saleh, K., J.M.
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Ribrag, Updates in the Treatment of Peripheral T-Cell Lymphomas.
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Pharmaceutics, 2022. 14(10).
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Hart, et al.HGVS Recommendations for the Description of Sequence Variants: 2016 Update.Hum Mutat, 2016.37(6): p.564-9.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/26931183" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26931183</span></a>]</div></dd></dl></dl></div><h2 id="NBK593302_footnotes">Footnotes</h2><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>
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<sup>1</sup>
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</dt><dd><div id="belinostat.FN1"><p class="no_top_margin">
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<i>The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug. Certain terms, genes and genetic variants may be corrected in accordance to nomenclature standards, where necessary. We have given the full name of abbreviations, shown in square brackets, where necessary.</i></p></div></dd></dl></dl><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK593302_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Megan Kane</span>, PhD<sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup><sup>1</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup> NCBI<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="vog.hin.mln.ibcn@sgm" class="oemail">vog.hin.mln.ibcn@sgm</a></div></div><div><sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup>Corresponding author.</div><h3>Publication History</h3><p class="small">Created: <span itemprop="datePublished">July 20, 2023</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a><p class="small">All Medical Genetics Summaries content, except where otherwise noted, is licensed under a Creative Commons <a href="https://creativecommons.org/licenses/by/4.0/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">Attribution 4.0 International (CC BY 4.0)</a> license which permits copying, distribution, and adaptation of the work, provided the original work is properly cited and any changes from the original work are properly indicated. Any altered, transformed, or adapted form of the work may only be distributed under the same or similar license to this one.</p></div></div><h3>Publisher</h3><p><a href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=books" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Center for Biotechnology Information (US)</a>, Bethesda (MD)</p><h3>NLM Citation</h3><p>Kane M. Belinostat Therapy and UGT1A1 Genotype. 2023 Jul 20. In: Pratt VM, Scott SA, Pirmohamed M, et al., editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gtrbook/azathioprine/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gtrbook/brivaracetam/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobbelinostatTthefda2023drug"><div id="belinostat.T.the_fda_2023_drug" class="table"><h3><span class="label">Table 1: </span></h3><div class="caption"><p>The FDA (2023) Drug Label for Belinostat Dosage Recommendation based on <i>UGT1A1</i> Genotype</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK593302/table/belinostat.T.the_fda_2023_drug/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__belinostat.T.the_fda_2023_drug_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_belinostat.T.the_fda_2023_drug_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Genotype</th><th id="hd_h_belinostat.T.the_fda_2023_drug_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Recommendation</th></tr></thead><tbody><tr><td headers="hd_h_belinostat.T.the_fda_2023_drug_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*28/*28</i>
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</td><td headers="hd_h_belinostat.T.the_fda_2023_drug_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Reduce the starting dose of belinostat to 750 mg/m<sup>2</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">This table is adapted from (<a class="bibr" href="#belinostat.REF.1" rid="belinostat.REF.1">1</a>).</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobbelinostatTrelativeenzymatic"><div id="belinostat.T.relative_enzymatic" class="table"><h3><span class="label">Table 2: </span></h3><div class="caption"><p>Relative Enzymatic Activity of UGT1A1 Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK593302/table/belinostat.T.relative_enzymatic/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__belinostat.T.relative_enzymatic_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_belinostat.T.relative_enzymatic_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Allele name</th><th id="hd_h_belinostat.T.relative_enzymatic_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Variant</th><th id="hd_h_belinostat.T.relative_enzymatic_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Relative activity</th><th id="hd_h_belinostat.T.relative_enzymatic_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Potential impact on drug metabolism</th><th id="hd_h_belinostat.T.relative_enzymatic_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CPIC functional status<sup>e</sup></th></tr></thead><tbody><tr><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*1</i>
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</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">None (promoter [TA]<sub>6</sub>TAA)</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">100%<sup>a</sup></td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Normal</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Normal function</td></tr><tr><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*6</i>
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</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">p.Arg71Gly</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">70%<sup>b</sup></td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Slower</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Decreased function</td></tr><tr><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*27</i>
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</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">p.Pro229Gln</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<p>50% <sup>c</sup></p>
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</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Slower</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Decreased function</td></tr><tr><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*28</i>
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</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Promoter (TA)<sub>7</sub>TAA</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">65%<sup>a</sup></td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Slower</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Decreased function</td></tr><tr><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*36</i>
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</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Promoter (TA)<sub>5</sub>TAA</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">130%<sup>a</sup></td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Faster</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Increased function</td></tr><tr><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*37</i>
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</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Promoter (TA)<sub>8</sub>TAA</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">50%<sup>a</sup></td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Slower</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Decreased function</td></tr><tr><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*60</i>
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</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">c.-3279T>G</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">60%<sup>d</sup></td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Slower</td><td headers="hd_h_belinostat.T.relative_enzymatic_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Normal function<sup>f</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">CPIC – Clinical Pharmacogenetics Implementation Consortium</p></div></dd></dl><dl class="bkr_refwrap"><dt>
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<sup>a</sup>
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</dt><dd><div id="belinostat.TF.2.1"><p class="no_margin">Activity level from (<a class="bibr" href="#belinostat.REF.35" rid="belinostat.REF.35">35</a>)</p></div></dd></dl><dl class="bkr_refwrap"><dt>
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<sup>b</sup>
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</dt><dd><div id="belinostat.TF.2.2"><p class="no_margin">Activity level from (<a class="bibr" href="#belinostat.REF.51" rid="belinostat.REF.51">51</a>)</p></div></dd></dl><dl class="bkr_refwrap"><dt>
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<sup>c</sup>
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</dt><dd><div id="belinostat.TF.2.3"><p class="no_margin">Activity level from (<a class="bibr" href="#belinostat.REF.56" rid="belinostat.REF.56">56</a>)</p></div></dd></dl><dl class="bkr_refwrap"><dt>
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<sup>d</sup>
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</dt><dd><div id="belinostat.TF.2.4"><p class="no_margin">Activity level from (<a class="bibr" href="#belinostat.REF.44" rid="belinostat.REF.44">44</a>)</p></div></dd></dl><dl class="bkr_refwrap"><dt>
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<sup>e</sup>
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</dt><dd><div id="belinostat.TF.2.5"><p class="no_margin">Functional status from (<a class="bibr" href="#belinostat.REF.57" rid="belinostat.REF.57">57</a>)</p></div></dd></dl><dl class="bkr_refwrap"><dt>
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<sup>f</sup>
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</dt><dd><div id="belinostat.TF.2.6"><p class="no_margin">Functional status from (<a class="bibr" href="#belinostat.REF.58" rid="belinostat.REF.58">58</a>)</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobbelinostatTe"><div id="belinostat.Te" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK593302/table/belinostat.Te/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__belinostat.Te_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_belinostat.Te_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_belinostat.Te_1_1_1_1" style="text-align:left;vertical-align:top;">Common allele name</th><th id="hd_h_belinostat.Te_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_belinostat.Te_1_1_1_2" style="text-align:left;vertical-align:top;">Alternative names</th><th id="hd_h_belinostat.Te_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:top;">HGVS reference sequence</th><th id="hd_h_belinostat.Te_1_1_1_4" rowspan="2" scope="col" colspan="1" headers="hd_h_belinostat.Te_1_1_1_4" style="text-align:left;vertical-align:top;">dbSNP reference identifier for allele location</th></tr><tr><th headers="hd_h_belinostat.Te_1_1_1_3" id="hd_h_belinostat.Te_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:top;">Coding</th><th headers="hd_h_belinostat.Te_1_1_1_3" id="hd_h_belinostat.Te_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Protein</th></tr></thead><tbody><tr><td headers="hd_h_belinostat.Te_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*1</i>
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</td><td headers="hd_h_belinostat.Te_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">(TA)<sub>6</sub>TAA</td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="/nuccore/45827762" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">NM_000463.2</a>:c.-53_-52TA[7]</td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not applicable—variant occurs in a non-coding (TATA box promoter) region</td><td headers="hd_h_belinostat.Te_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs3064744" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs3064744</a>
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</td></tr><tr><td headers="hd_h_belinostat.Te_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*6</i>
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</td><td headers="hd_h_belinostat.Te_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">211G>A<br />Gly71Arg</td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="/clinvar/variation/12280/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000463.2:c.211G>A</a><br />(<a href="/nuccore/1519244464" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">NM_001072.4</a>:c.862-6536G>A)</td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/clinvar/variation/12280/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000454.1:p.Gly71Arg</a>
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</td><td headers="hd_h_belinostat.Te_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs4148323" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs4148323</a>
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</td></tr><tr><td headers="hd_h_belinostat.Te_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*27</i>
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</td><td headers="hd_h_belinostat.Te_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Pro229Gln</td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/variation/12274/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000463.3:c.686C>A</a>
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</td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/variation/12274/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000454.1:p.Pro229Gln</a>
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</td><td headers="hd_h_belinostat.Te_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs35350960" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs35350960</a>
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</td></tr><tr><td headers="hd_h_belinostat.Te_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*28</i>
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</td><td headers="hd_h_belinostat.Te_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">(TA)<sub>7</sub>TAA</td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/variation/12275/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_001072.4:c.862-6800AT[8]</a>
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</td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not applicable—variant occurs in a non-coding (TATA box promoter) region</td><td headers="hd_h_belinostat.Te_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs3064744" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs3064744</a>
|
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</td></tr><tr><td headers="hd_h_belinostat.Te_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*36</i>
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</td><td headers="hd_h_belinostat.Te_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">(TA)<sub>5</sub>TAA</td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/variation/549830/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_001072.4:c.862-6800AT[6]</a>
|
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</td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not applicable—variant occurs in a non-coding (TATA box promoter) region</td><td headers="hd_h_belinostat.Te_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs3064744" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs3064744</a>
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</td></tr><tr><td headers="hd_h_belinostat.Te_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*37</i>
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</td><td headers="hd_h_belinostat.Te_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">(TA)<sub>8</sub>TAA</td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/variation/549829/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_001072.4:c.862-6800AT[9]</a>
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</td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not applicable—variant occurs in a non-coding (TATA box promoter) region</td><td headers="hd_h_belinostat.Te_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs3064744" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs3064744</a>
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</td></tr><tr><td headers="hd_h_belinostat.Te_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*60</i>
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</td><td headers="hd_h_belinostat.Te_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-3263T>G<br /><p>-3279T>G</p></td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000012288.18" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_001072.4:c.862-10021T>G</a>
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</td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not applicable—variant occurs in a non-coding region</td><td headers="hd_h_belinostat.Te_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/snp/rs4124874" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs4124874</a>
|
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</td></tr><tr><td headers="hd_h_belinostat.Te_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<i>UGT1A1*80</i>
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</td><td headers="hd_h_belinostat.Te_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">c.-364C>T</td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="/nuccore/45827763" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">NM_007120.2</a>:c.868-7110C>T</td><td headers="hd_h_belinostat.Te_1_1_1_3 hd_h_belinostat.Te_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Not applicable—variant occurs in a non-coding region</td><td headers="hd_h_belinostat.Te_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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|
<a href="https://www.ncbi.nlm.nih.gov/snp/rs887829" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">rs887829</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Pharmacogenetic Allele Nomenclature: International Workgroup Recommendations for Test Result Reporting (<a class="bibr" href="#belinostat.REF.73" rid="belinostat.REF.73">73</a>).</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">UGT Allele nomenclature and definitions are available from (<a class="bibr" href="#belinostat.REF.32" rid="belinostat.REF.32">32</a>)</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Guidelines for the description and nomenclature of gene variations are available from the Human Genome Variation Society (HGVS (<a class="bibr" href="#belinostat.REF.74" rid="belinostat.REF.74">74</a>)). dbSNP - database of single nucleotide polymorphisms</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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