Alternative titles; symbols
SNOMEDCT: 372142002; ORPHA: 1333; DO: 4905;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p12.1 | Pancreatic carcinoma, somatic | 260350 | 3 | KRAS | 190070 | |
| 12q13.13 | Pancreatic cancer, somatic | 260350 | 3 | ACVR1B | 601300 | |
| 17p13.1 | Pancreatic cancer, somatic | 260350 | 3 | TP53 | 191170 | |
| 18q21.2 | Pancreatic cancer, somatic | 260350 | 3 | SMAD4 | 600993 | |
| 19p13.3 | Pancreatic cancer, somatic | 260350 | 3 | STK11 | 602216 |
A number sign (#) is used with this entry because mutations in a number of genes are associated with pancreatic carcinoma, familial or sporadic, germline or somatic.
Pancreatic cancer shows among the highest mortality rates of any cancer, with a 5-year relative survival rate of less than 5%. By the time of initial diagnosis, metastatic disease is commonly present. Established risk factors include a family history of pancreatic cancer, a medical history of diabetes type 2, and cigarette smoking (summary by Amundadottir et al., 2009).
Genetic Heterogeneity of Pancreatic Cancer
Somatic mutations in pancreatic cancer occur in the KRAS (190070), CDKN2A (600160), MADH4 (600993), TP53 (191170), ARMET (601916), STK11 (602216), ACVR1B (601300), and RBBP8 (604124) genes.
Susceptibility loci for pancreatic cancer include PNCA1 (606856), related to mutation in the PALLD gene on chromosome 4q32 (608092); PNCA2 (613347), related to mutation in the BRCA2 gene on chromosome 13q12 (600185); PNCA3 (613348), related to mutation in the PALB2 gene on chromosome 16p12 (610355); PNCA4 (614320), related to mutation in the BRCA1 gene on chromosome 17q21 (113705); and PNCA5 (618680), related to mutation in the RABL3 gene on chromosome 3q13 (618542).
Occurrence of Pancreatic Cancer in Other Disorders
Several familial cancer syndromes increase the risk of pancreatic cancer. The best characterized include hereditary nonpolyposis colon cancer syndrome (HNPCC; see 120435); hereditary breast-ovarian cancer syndrome due to mutations in BRCA2; Peutz-Jeghers syndrome (175200); the melanoma-pancreatic cancer syndrome (606719), caused by mutations in CDKN2A (600160); von Hippel-Lindau syndrome (193300), ataxia-telangiectasia (208900) (Swift et al., 1976), and juvenile polyposis syndrome (174900).
Patients with hereditary pancreatitis (167800) resulting from gain-of-function mutations in the protease serine-1 gene (PRSS1; 276000) have a lifetime pancreatic cancer risk ratio of 57 and a cumulative incidence, to age 70 years, of 40% (Lowenfels et al., 1997).
Friedman and Fialkow (1976) observed cancer of the pancreas in 4 brothers from a sibship of 6. Diagnosis was made between ages 66 and 75 years. None had a history of pancreatitis or tumors at other sites.
Reimer et al. (1977) reported pancreatic cancer in father and son.
In a family of European Jewish ancestry, Ehrenthal et al. (1987) identified pancreatic adenocarcinoma in women of 3 successive generations. The diagnosis was histologically confirmed in each case. The youngest of the 3 women presented at age 29, her mother at age 42, and her grandmother at age 76.
Lynch et al. (1995) studied 8 families in which 2 or more first-degree relatives had pancreatic cancer. In the 8 families, 25 pancreatic cancers were found. The mean age of occurrence was 62.8 years, with a range from 45 to 90 years. Parent and child occurrence was observed in 4 of the 8 families. In one family, the progenitor had an affected brother and 5 of his 8 children developed cancer; 2 had pancreatic cancer, 2 had breast cancer (one of these also had pancreatic cancer), and 1 daughter had ovarian cancer. Of the 7 carcinomas available for pathologic review, 6 were typical ductal adenocarcinomas and the seventh was a giant cell variant of ductal carcinoma.
Caldas et al. (1994) quoted Boring et al. (1993) as indicating that pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death in either sex in the United States, with an estimated incidence in 1993 of nearly 27,700 and a mortality of 24,500.
Evans et al. (1995) described a large pedigree in which pancreatic cancer was inherited as an autosomal dominant. Diabetes and exocrine insufficiency were observed in all family members who eventually developed pancreatic cancer. The presence of diabetes, often years before the diagnosis of cancer, allowed identification of those people who had inherited the predisposing allele. The lack of attacks of abdominal pain seemingly distinguishes the affected members of this family from hereditary pancreatitis (167800) in which diabetes mellitus and pancreatic cancer occur, but the distinction is by no means clear because it was stated that 6 of the 9 persons who developed pancreatic cancer in this family also had a history clinically compatible with pancreatic insufficiency before diagnosis of cancer: weight loss, fatty and foul smelling stools, increased fecal fat, and relief with exogenous pancreatic enzyme supplementation. All 9 members of the family with pancreatic cancer were males.
Making use of pathologic, clinical, and genetic knowledge, Hruban et al. (2000) composed a progression model of pancreatic carcinoma, similar to that developed for colorectal carcinoma.
Because CD40 (109535) activation can reverse immune suppression and drive antitumor T cell responses, Beatty et al. (2011) tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable pancreatic ductal adenocarcinoma (PDA) and observed tumor regressions in some patients. They reproduced this treatment effect in a genetically engineered mouse model of PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, Beatty et al. (2011) concluded that cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, their findings demonstrated a CD40-dependent mechanism for targeting tumor stroma in the treatment of cancer.
The genome of pancreatic ductal adenocarcinoma (PDAC) frequently contains deletions of SMAD4 (600993). As loss of neighboring housekeeping genes can confer collateral lethality, Dey et al. (2017) sought to determine whether loss of the metabolic gene malic enzyme-2 (ME2; 154270) in the SMAD4 locus would create cancer-specific metabolic vulnerability upon targeting of its paralogous isoform ME3 (604626). Dey et al. (2017) showed that ME3 depletion selectively kills ME2-null PDAC cells in a manner consistent with an essential function for ME3 in ME2-null cancer cells. Mechanistically, integrated metabolomic and molecular investigation of cells deficient in mitochondrial malic enzymes revealed diminished NADPH production and consequent high levels of reactive oxygen species. These changes activate AMP-activated protein kinase (AMPK; see 602739), which in turn directly suppresses sterol regulatory element-binding protein-1 (SREBP1; 184756)-directed transcription of its direct targets, including the branched-chain amino acid transaminase-2 gene BCAT2 (113530). BCAT2 catalyses the transfer of the amino group from branched-chain amino acids to alpha-ketoglutarate, thereby regenerating glutamate, which functions in part to support de novo nucleotide synthesis. Thus, mitochondrial malic enzyme deficiency, which results in impaired NADPH production, provides a prime 'collateral lethality' therapeutic strategy for the treatment of a substantial fraction of patients diagnosed with intractable pancreatic cancer.
Starting with a systematic proteomic investigation of secreted pancreatic cancer disease mediators and underlying molecular mechanisms, Shi et al. (2019) revealed that leukemia inhibitory factor (LIF; 159540) is a key paracrine factor from activated pancreatic stellate cells acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slowed tumor progression and augmented the efficacy of chemotherapy to prolong survival of pancreatic ductal adenocarcinoma mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human pancreatic ductal adenocarcinoma, aberrant production of LIF in the pancreas was restricted to pathologic conditions and correlated with pancreatic ductal adenocarcinoma pathogenesis, and changes in the levels of circulating LIF correlated well with tumor response to therapy.
Banke et al. (2000) estimated that 10% or more of patients with pancreatic cancer inherit the risk in an autosomal dominant pattern.
McWilliams et al. (2005) analyzed family history questionnaires from 426 patients with pancreatic cancer and compared the prevalence of malignancy reported in 3,355 of their first-degree relatives to population data from the Surveillance, Epidemiology, and End Results (SEER) Project, using age- and gender-adjusted incidence rates. McWilliams et al. (2005) found an increased risk of pancreatic and liver carcinoma in the first-degree relatives of probands with pancreatic cancer (1.88- and 2.7-fold, respectively); the risk for pancreatic cancer was nearly 3-fold when the proband was diagnosed before 60 years of age, but no other malignancies were increased in this subgroup.
Berman et al. (2003) demonstrated that a wide range of digestive tract tumors, including most of those originating in the esophagus, stomach, biliary tract, and pancreas, but not in the colon, display increased hedgehog pathway activity, which is suppressible by cyclopamine, a hedgehog pathway antagonist. Cyclopamine also suppresses cell growth in vitro and causes durable regression of xenograft tumors in vivo. Unlike tumors in Gorlin syndrome (109400), pathway activity and cell growth in these digestive tract tumors are driven by endogenous expression of hedgehog ligands, as indicated by the presence of Sonic hedgehog (SHH; 600725) and Indian hedgehog (IHH; 600726) transcripts, by the pathway- and growth-inhibitory activity of a hedgehog-neutralizing antibody, and by the dramatic growth-stimulatory activity of exogenously added hedgehog ligand. Berman et al. (2003) concluded that their results identified a group of common lethal malignancies in which hedgehog pathway activity, essential for tumor growth, is activated not by mutation but by ligand expression.
Thayer et al. (2003) reported that Sonic hedgehog is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions, pancreatic intraepithelial neoplasia. The pancreata of Pdx1- (600733) Shh mice (in which Sonic hedgehog is misexpressed in the pancreatic endoderm) developed abnormal tubular structures, a phenocopy of human pancreatic intraepithelial neoplasia-1 and -2. Moreover, these pancreatic intraepithelial neoplasia-like lesions also contained mutations in Kras (190070) and overexpressed Erbb2 (164870), which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signaling remained active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signaling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. Thayer et al. (2003) concluded that their data suggested that the hedgehog pathway may have an early and critical role in the genesis of pancreatic cancer, and that maintenance of hedgehog signaling is important for aberrant proliferation and tumorigenesis.
Jones et al. (2008) performed a comprehensive genetic analysis of 24 pancreatic cancers. They determined the sequences of 23,219 transcripts, representing 20,661 protein-coding genes, in these samples. They then searched for homozygous deletions and amplifications in the tumor DNA by using microarrays containing probes for approximately 1 million SNPs. Jones et al. (2008) found that pancreatic cancers contain an average of 63 genetic alterations, the majority of which are point mutations. These alterations defined a core set of 12 cellular signaling pathways and processes that were each genetically altered in 67 to 100% of the tumors. Analysis of these tumors' transcriptomes with next-generation sequencing-by-synthesis technologies provided independent evidence for the importance of these pathways and processes. Jones et al. (2008) concluded that genetically altered core pathways and regulatory processes only become evident once the coding regions of the genome are analyzed in depth. The authors suggested that dysregulation of these core pathways and processes through mutation can explain the major features of pancreatic tumorigenesis. The 12 signaling pathways implicated in pancreatic tumorigenesis included apoptosis, DNA damage control, regulation of the G1/S phase transition, hedgehog signaling, homophilic cell adhesion, integrin signaling, C-Jun (165160) N-terminal kinase signaling, KRAS (190070) signaling, regulation of invasion, small GTPase-dependent signaling other than KRAS, TGF-beta (190180) signaling, and WNT (see 164975)/Notch (190198) signaling.
Campbell et al. (2010) used advances in DNA sequencing to annotate genomic rearrangements in 13 patients with pancreatic cancer and explore clonal relationships among metastases. Campbell et al. (2010) found that pancreatic cancer acquires rearrangements indicative of telomere dysfunction and abnormal cell-cycle control, i.e., dysregulated G1-to-S-phase transition with intact G2-M checkpoint. These initiate amplification of cancer genes and occur predominantly in early cancer development rather than the later stages of the disease. Genomic instability frequently persists after cancer dissemination, resulting in ongoing parallel and even convergent evolution among different metastases. Campbell et al. (2010) found evidence that there is genetic heterogeneity among metastasis-initiating cells, that seeding metastasis may require driver mutations beyond those required for primary tumors, and that phylogenetic trees across metastases show organ-specific branches. Campbell et al. (2010) concluded that their data attest to the richness of genetic variation in cancer, brought about by the tandem forces of genomic instability and evolutionary selection.
Yachida et al. (2010) used data generated by sequencing the genomes of 7 pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers and found that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, nonmetastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, nonmetastatic founder cell. At least 5 more years are required for the acquisition of metastatic ability, and patients die an average of 2 years thereafter. Yachida et al. (2010) concluded that their data provided novel insights into the genetic features underlying pancreatic cancer progression and defined a broad time window of opportunity for early detection to prevent deaths from metastatic disease.
Son et al. (2013) reported the identification of a noncanonical pathway of glutamine use in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumor growth. Whereas most cells use glutamate dehydrogenase (GLUD1; 138130) to convert glutamine-derived glutamate into alpha-ketoglutarate in the mitochondria to fuel the tricarboxylic acid cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (GOT1; 138180). Subsequently, this oxaloacetate is converted into malate and then pyruvate, ostensibly increasing the NADPH/NADP+ ratio which can potentially maintain the cellular redox state. Importantly, PDAC cells are strongly dependent on this series of reactions, as glutamine deprivation or genetic inhibition of any enzyme in this pathway leads to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions also results in a pronounced suppression of PDAC growth in vitro and in vivo. Furthermore, Son et al. (2013) established that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS, the signature genetic alteration in PDAC, through the transcriptional upregulation and repression of key metabolic enzymes in this pathway.
In a humanized genetically modified mouse model of PDAC, Rosenfeldt et al. (2013) showed that autophagy's role in tumor development is intrinsically connected to the status of the tumor suppressor p53 (191170). Mice with pancreases containing an activated oncogenic allele of Kras, the most common mutational event in PDAC, developed a small number of precancerous lesions that stochastically developed into PDAC over time. However, mice also lacking the essential autophagy genes Atg5 (604261) or Atg7 (608760) accumulated low-grade, premalignant pancreatic intraepithelial neoplasia lesions, but progression to high-grade pancreatic intraepithelial neoplasias and PDAC was blocked. In marked contrast, in mice containing oncogenic Kras and lacking p53, loss of autophagy no longer blocked tumor progression but actually accelerated tumor onset, with metabolic analysis revealing enhanced glucose uptake and enrichment of anabolic pathways, which can fuel tumor growth. Rosenfeldt et al. (2013) also show that treatment of mice with the autophagy inhibitor hydroxychloroquine significantly accelerates tumor formation in mice containing oncogenic Kras but lacking p53.
The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy, a conserved self-degradative process. Perera et al. (2015) showed that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family of transcription factors. In human PDA cells, the MiT/TFE proteins (MITF, 156845; TFE3, 314310; and TFEB, 600744) are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling revealed that MiT/TFE-dependent autophagy-lysosome activation is specifically required to maintain intracellular amino acid pools. Perera et al. (2015) concluded that their results identified the MiT/TFE proteins as master regulators of metabolic reprogramming in pancreatic cancer and demonstrated that transcriptional activation of clearance pathways converging on the lysosome is a novel hallmark of aggressive malignancy.
Seifert et al. (2016) reported that the principal components of the necrosome, receptor-interacting proteins RIP1 (603453) and RIP3 (605817), are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Cytoplasmic SF3B3 (605592), a subunit of the histone deacetylase complex, was expressed in PDA in a RIP1/RIP3-dependent manner, and MINCLE (609962), its cognate receptor, was upregulated in tumor-infiltrating myeloid cells. Ligation of MINCLE by SAP130 promoted oncogenesis, whereas deletion of MINCLE protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumor microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or MINCLE is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or MINCLE signaling, were reprogrammed into indispensable mediators of antitumor immunity in the absence of RIP3 or MINCLE. Seifert et al. (2016) concluded that their work described parallel networks of necroptosis-induced CXCL1 and MINCLE signaling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.
Bailey et al. (2016) performed integrated genomic analysis of 456 pancreatic ductal adenocarcinomas and identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-beta, WNT, NOTCH, ROBO/SLIT signaling (see 602430), G1/S transition, SWI-SNF (see 603111), chromatin modification, DNA repair, and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathologic characteristics. Squamous tumors are enriched for TP53 (191170) and KDM6A (300128) mutations, upregulation of the TP63-delta-N (603273) transcriptional network, and hypermethylation of pancreatic endodermal cell fate-determining genes, and have a poor prognosis. Pancreatic progenitor tumors preferentially express genes involved in early pancreatic development (FOXA2 (600288)/FOXA3 (602295); PDX1, 600733; and MNX1, 142994). ADEX tumors displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2, 604453 and RBPJL, 616104), and endocrine differentiation (NEUROD1, 601724 and NKX2-2, 604612). Immunogenic tumors contained upregulated immune networks including pathways involved in acquired immune suppression.
To study the role of glycan changes in pancreatic disease, Engle et al. (2019) inducibly expressed human fucosyltransferase-3 (FUT3; 111100) and beta-1,3-galactosyltransferase-5 (B3GALT5; 604066) in mice, reconstituting the glycan sialyl-Lewis, also known as carbohydrate antigen 19-9 (CA19-9). Notably, CA19-9 expression in mice resulted in rapid and severe pancreatitis with hyperactivation of epidermal growth factor receptor (EGFR) signaling. Mechanistically, CA19-9 modification of the matricellular protein fibulin-3 (FBLN3; 601548) increased its interaction with EGFR, and blockade of fibulin-3, EGFR ligands, or CA19-9 prevented EGFR hyperactivation in organoids. CA19-9-mediated pancreatitis was reversible and could be suppressed with CA19-9 antibodies. CA19-9 also cooperated with the Kras(G12D) oncogene (190070.0003) to produce aggressive pancreatic cancer. Engle et al. (2019) concluded that their findings implicated CA19-9 in the etiology of pancreatitis and pancreatic cancer and nominated CA19-9 as a therapeutic target.
Yao et al. (2019) developed an unbiased functional target discovery platform to query oncogeneic KRAS-dependent changes of the pancreatic ductal adenocarcinoma surfaceome, which revealed syndecan-1 (SDC1; 186355) as a protein that is upregulated at the cell surface by oncogenic KRAS. Localization of SDC1 at the cell surface, where it regulates macropinocytosis, an essential metabolic pathway that fuels pancreatic ductal adenocarcinoma cell growth, is essential for disease maintenance and progression.
Notta et al. (2016) tracked changes in DNA copy number and their associated rearrangements in tumor-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumors analyzed harbored complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors was the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set off invasive cancer growth. Notta et al. (2016) concluded that these findings challenged the pancreatic intraepithelial neoplasm (PanIN) progression model of pancreatic cancer and provided insights into the mutational processes that give rise to these aggressive tumors.
Aykut et al. (2019) showed that fungi migrate from the gut lumen to the pancreas and that this is implicated in the pathogenesis of pancreatic ductal adenocarcinoma (PDA). PDA tumors in humans and mouse models of this cancer displayed an increase in fungi of about 3,000-fold compared to normal pancreatic tissue. The composition of the mycobiome of PDA tumors was distinct from that of the gut or normal pancreas on the basis of alpha- and beta-diversity indices. Specifically, the fungal community that infiltrated PDA tumors was markedly enriched for Malassezia species in both mice and humans. Ablation of the mycobiome was protective against tumor growth in slowly progressive and invasive models of PDA, and repopulation with a Malassezia species, but not species in the genera Candida, Saccharomyces, or Aspergillus, accelerated oncogenesis. Aykut et al. (2019) also discovered that ligation of mannose-binding lectin (MBL2; 154545), which binds to glycans of the fungal wall to activate the complement cascade, was required for oncogenic progression, whereas deletion of MBL or C3 (120700) in the extratumoral compartment, or knockdown of C3AR (605246) in tumor cells, were both protective against tumor growth. In addition, reprogramming of the mycobiome did not alter the progression of PDA in Mbl-null or C3-deficient mice. Aykut et al. (2019) concluded that their work showed that pathogenic fungi promote PDA by driving the complement cascade through the activation of MBL.
Ferroptosis is a form of cell death that results from the catastrophic accumulation of lipid ROS. Oncogenic signaling elevates lipid ROS production in many tumor types and is counteracted by metabolites that are derived from the amino acid cysteine. Badgley et al. (2020) showed that the import of oxidized cysteine (cystine) via system x(C)- is a critical dependency of PDAC. PDAC cells used cysteine to synthesize glutathione and coenzyme A, which, together, downregulate ferroptosis. Studying genetically engineered mice, Badgley et al. (2020) found that the deletion of a system x(C)- subunit, Slc7a11 (607933), induced tumor-selective ferroptosis and inhibited PDAC growth. This was replicated through the administration of cyst(e)inase, a drug that depletes cysteine and cystine, demonstrating a translatable means to induce ferroptosis in PDAC.
Yamamoto et al. (2020) showed that in PDAC, major histocompatibility complex class I (MHC-I; see 142800) molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the receptor NBR1 (166945). PDAC cells displayed reduced expression of MHC-I at the cell surface and instead demonstrated localization in autophagosomes and lysosomes. Inhibition of autophagy restored surface levels of MHC-I and led to improved antigen presentation, enhanced antitumor T cell responses, and reduced tumor growth in syngeneic host mice. The antitumor effects of autophagy inhibition were reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy synergized with dual immune check-point blockade therapy and led to enhanced antitumor immune response.
Pancreatic Neuroendocrine Tumors
Heaphy et al. (2011) evaluated telomere status in pancreatic neuroendocrine tumors (PanNETs) in which ATRX (300032) and DAXX (603186) mutational status had been determined through Sanger sequencing. Telomere-specific FISH revealed that 25 of 41 (61%) PanNETs displayed large, ultrabright telomere FISH signals, a nearly universal feature of the telomerase-independent telomere maintenance mechanism termed alternative lengthening of telomeres. ATRX and DAXX gene mutations both were significantly correlated with ALT positivity (P less than 0.008 for each gene). All 19 (100%) PanNETs with ATRX or DAXX gene mutations were ALT-positive, whereas 6 of 20 cases without detectable mutations were ALT-positive. To ascertain whether ATRX and DAXX gene mutations might be more generally associated with the ALT phenotype, Heaphy et al. (2011) examined 439 tumors of other types and found a strong correlation between inactivation of ATRX or DAXX and the ALT phenotype in unrelated tumor types.
Using mass spectrometry analyses, Melo et al. (2015) identified a cell surface proteoglycan, glypican-1 (GPC1; 600395), specifically enriched on cancer cell-derived exosomes. GPC1-positive circulating exosomes were monitored and isolated using flow cytometry from the serum of patients and mice with cancer. GPC1-positive circulating exosomes were detected in the serum of patients with pancreatic cancer with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreatic disease from patients with early- and late-stage pancreatic cancer. Levels of GPC1-positive circulating exosomes correlated with tumor burden and the survival of pre- and post-surgical patients. GPC1-positive circulating exosomes from patients and from mice with spontaneous pancreatic tumors carry specific KRAS (190070) mutations, and reliably detected pancreatic intraepithelial lesions in mice despite negative signals by MRI. Melo et al. (2015) concluded that GPC1-positive circulating exosomes may serve as a potential noninvasive diagnostic and screening tool to detect early stages of pancreatic cancer to facilitate possible curative surgical therapy.
Associations Pending Confirmation
Amundadottir et al. (2009) conducted a 2-stage genomewide association study of pancreatic cancer, genotyping over 500,000 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus 1 hospital-based case-control study. The authors conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from 8 case-control studies, adjusting for study, sex, ancestry, and 5 principal components. They identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 x 10(8); multiplicative per-allele odds ratio 1.20; 95% CI 1.12-1.28). This SNP maps to the first intron of the ABO blood group gene (110300). The protective allele T for rs505922 is in complete linkage disequilibrium with the O allele of the ABO locus, consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.
Petersen et al. (2010) conducted a genomewide association study of pancreatic cancer in 3,851 affected individuals and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry, and 5 principal components, Petersen et al. (2010) identified 8 SNPs that map to 3 loci on chromosomes 13q22.1, 1q32.1, and 5p15.33. Two correlated SNPs, rs9543325 (p = 3.27 x 10(-11), per-allele odds ratio 1.26, 95% CI 1.18-1.35) and rs9564966 (p = 5.86 x 10(-8), per-allele odds ratio 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2 (604453), and the strongest signal was at rs3790844 (p = 2.45 x 10(-10), per-allele odds ratio 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (p = 3.66 x 10(-7), per-allele odds ratio 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L (612585)-TERT (187270) locus on 5p15.33, which is associated with multiple cancers. Petersen et al. (2010) concluded that their study identified common susceptibility loci for pancreatic cancer that warrant follow-up studies.
By genomewide association analysis, Zheng et al. (2016) identified a G-A SNP in exon 4 of the LINC00673 gene (617079) (rs11655237) that was associated with susceptibility to pancreatic ductal adenocarcinoma in a Han Chinese population. The A allele of rs11655237 was predicted to change the local structure of LINC00673 and to introduce a potential binding site for microRNA-1231 (MIR1231; 617040). Reporter gene assays confirmed that MIR1231 inhibited expression of LINC00673 with the A allele of rs11655237 in a dose-dependent manner, but it had no effect on LINC00673 with the G allele of rs11655237. Allele-specific targeting of LINC00673 by MIR1231 inhibited LINC00673 regulation of the PTPN11 (176876) pathway, thereby promoting tumor cell growth in individuals carrying the A allele of rs11655237.
Mutation in KRAS2
Point mutations in codon 12 of the KRAS2 gene (190070) occur in 75 to 90% of pancreatic cancers (Almoguera et al., 1988), and also occur in foci of pancreatic intraepithelial neoplasia, a putative precursor lesion of pancreatic cancer (Hruban et al., 2000). Evans et al. (1995) analyzed this gene in pancreatic tumors from patients in a large pedigree with autosomal dominant pancreatic cancer preceded by diabetes and exocrine insufficiency. The presence of diabetes, often years before the diagnosis of cancer, allowed identification of those who had inherited the predisposing allele. Pancreatic tissue from all 3 persons analyzed showed KRAS point mutations, and in all 3 the mutations were located in codon 13. The observation of several different KRAS mutations in pancreatic tumors from this family and the presence of only wildtype KRAS in normal tissue clearly showed that the mutant KRAS gene was not the germline event underlying pancreatic cancer in this family.
Mutation in CDKN2A
Although KRAS mutations are found in 85% or more of cases of pancreatic adenocarcinoma, and p53 mutations (191170) in at least of 50% of cases, little is known of the genetic changes that occur in pancreatic carcinogenesis. Caldas et al. (1994) described experiments suggesting that mutation in the p16 gene (CDKN2A; 600160), which they referred to as MTS1, is a frequent cause of pancreatic adenocarcinoma.
Liu et al. (1995) found that 50% of pancreatic cancer cell lines had deletions of both exons 1 and 2 of the CDKN2 gene; furthermore, an additional 30% of pancreatic cancer cell lines harbored point mutations or microdeletions based on DNA sequencing.
Further evidence of the role of CDKN2 in pancreatic tumorigenesis was provided by Whelan et al. (1995), who described a kindred with an increased risk of pancreatic cancers, melanomas, and possibly additional types of tumors cosegregating with a CDKN2 mutation (600160.0005).
In a population-based study, Ghiorzo et al. (2012) identified CDKN2A mutations in 13 (5.7%) of 225 Italian patients with pancreatic cancer. Six patients carried the common G101W mutation (600160.0005), which was the most common mutation. Among the 16 probands with a family history of cancer, including pancreatic cancer and melanoma, 5 (31%) were found to carry CDKN2A mutations. The mutation frequency ranged from 20% in families with 2 affected members to 50% in families with 3 affected members. The findings suggested that CDKN2A is the main susceptibility gene in Italian families with pancreatic cancer.
Mutation in BRCA2
See 613347 for information on pancreatic cancer susceptibility due to mutation in the BRCA2 gene (600185).
Mutation in PALLD
See 606856 for information on autosomal dominant pancreatic cancer due to mutation in the PALLD gene (608092).
Mutation in PALB2
See 606856 for information on pancreatic cancer susceptibility due to mutation in the PALB2 gene (610355).
Mutation in BRCA1
Al-Sukhni et al. (2008) found loss of heterozygosity at the BRCA1 locus (113705) in pancreatic tumor DNA from 5 (71%) of 7 patients with pancreatic cancer who carried a heterozygous germline BRCA1 mutation (see, e.g., 113705.0003 and 113705.0018). Pancreatic tumor DNA was available for sequencing in 4 cases, and 3 demonstrated loss of the wildtype allele. In contrast, only 1 (11%) of 9 patients with sporadic pancreatic cancer and no germline BRCA1 mutations showed LOH at the BRCA1 locus. Al-Sukhni et al. (2008) concluded that BRCA1 germline mutations likely predispose to the development of pancreatic cancer, and suggested that individuals with these mutations be considered for pancreatic cancer-screening programs.
Mutation in Axon Guidance Pathway Genes
Biankin et al. (2012) performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort of 142 patients with early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumors identified substantial heterogeneity with 2,016 nonsilent mutations and 1,628 copy number variations. Biankin et al. (2012) defined 16 significantly mutated genes, reaffirming known mutations (KRAS, 190070; TP53, 191170; CDKN2A, 600160; SMAD4, 600993; MLL3, 606833; TGFBR2, 190182; ARID1A, 603024; and SF3B1, 605590), and uncovered novel mutated genes including additional genes involved in chromatin modification (EPC1, 610999 and ARID2, 609539), DNA damage repair (ATM; 607585), and other mechanisms (ZIM2 (see 601483); MAP2K4, 601335; NALCN, 611549; SLC16A4, 603878; and MAGEA6, 300176). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signaling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. Biankin et al. (2012) also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO (see 603742) signaling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
Mutation in UPF1
Liu et al. (2014) identified mutations in the UPF1 gene (601430) in pancreatic adenosquamous carcinoma (ASC) tumors from 18 of 23 patients. Liu et al. (2014) also tested 3 other nonsense-mediated RNA decay (NMD) genes--UPF2 (605529), UPF3A (605530), and UPF3B (300298)--but did not detect mutations. The UPF1 mutations were somatic in origin, as they were not present in matched normal pancreatic tissues from the 18 patients. UPF1 mutations were also not detectable in 29 non-ASC pancreatic tumors and in 21 lung squamous cell carcinomas that were tested. Liu et al. (2014) concluded that UPF1 mutations are a unique signature of most pancreatic adenosquamous carcinomas.
Multigene Studies
Zhen et al. (2015) tested germline DNA from 727 unrelated probands with pancreatic cancer and a positive family history for mutations in BRCA1 (113705) and BRCA2 (600185) (including deletions and rearrangements), PALB2 (610355), and CDKN2A (600160). Among these probands, 521 met criteria for familial pancreatic cancer (FPC; at least 2 affected first-degree relatives). The prevalence of deleterious mutations, excluding variants of unknown significance, among FPC probands was BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; and CDKN2A, 2.5%. Four novel deleterious mutations were detected. FPC probands carried more mutations in the 4 genes (8.0%) than nonfamilial pancreatic cancer probands (3.5%; OR = 2.40, 95% CI 1.06-5.44, p = 0.03). The probability of testing positive for deleterious mutations in any of the 4 genes ranged up to 10.4%, depending on family history of cancers.
Waddell et al. (2015) performed whole-genome sequencing and copy number variation analysis of 100 pancreatic ductal adenocarcinomas. Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A, and ROBO2, 602431) and new candidate drivers of pancreatic carcinogenesis (KDM6A, 300128 and PREX2, 612139). Patterns of structural variation classified pancreatic ductal adenocarcinomas into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered, and unstable. A significant proportion harbored focal amplifications, many of which contained druggable oncogenes but at low individual patient prevalence. Genomic instability cosegregated with inactivation of DNA maintenance genes (BRCA1, BRCA2, or PALB2) and a mutational signature of DNA damage repair deficiency.
Associations Pending Confirmation
Using data from genomewide association studies (GWAS) of 9,013 affected individuals and 12,452 control individuals of European ancestry, Jermusyk et al. (2021) fine-mapped a pancreatic cancer risk locus on chromosome 16q23.1 and identified a region containing the SNP rs72802365 as a candidate locus. A 584-bp deletion variant in the region deleted exon 6 of CTRB2 (619620), resulting in a truncated 166-amino acid protein lacking the C chain of full-length CTRB2, including 1 of 3 amino acids in the catalytic triad, ser213. Functional characterization revealed that the truncated CTRB2 protein lost chymotrypsin activity, was not secreted, and accumulated intracellularly in the endoplasmic reticulum (ER). Differential expression analysis showed that ER stress pathways were upregulated in pancreatic tissue from carriers of the CTRB2 variant, leading to increased levels of ER stress and altered translational activity in pancreas. Fluorescence-tagged truncated CTRB2 protein was retained in the ER, resulting in increased expression of ER pathway-related genes in transfected pancreatic cells, leading to ER stress.
Pancreatic Neuroendocrine Tumors
Jiao et al. (2011) explored the genetic basis of pancreatic neuroendocrine tumors (PanNETs) by determining the exomic sequence of 10 nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN1 (613733), and 43% had mutations in genes encoding either of the 2 subunits of a transcription/chromatin remodeling complex consisting of DAXX (death domain-associated protein, 603186) and ATRX (300032). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. Jiao et al. (2011) also found mutations in genes in the mTOR (601231) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatments with mTOR inhibitors.
When Billy Carter, brother of President Jimmy Carter, died of pancreatic cancer in 1988, the news media reported that his sister Ruth Carter Stapleton, evangelist and faith healer, had died of pancreatic cancer at age 54 and their mother of pancreatic, bone, and breast cancer at age 85. In the New York Times of December 1, 1989, it was announced that President Carter's last surviving sib, Gloria Carter Spann, was found to be suffering from pancreatic cancer, 'the same disease that killed their father, sister and brother and contributed to the death of their mother.' The possibility of environmental causation might be raised, e.g., an agricultural insecticide or an oncogenic agent such as aflatoxin.
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