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SNOMEDCT: 449248000; ORPHA: 150; DO: 9261;
Cytogenetic location: 4p15.1-q12 Genomic coordinates (GRCh38) : 4:27,700,001-58,500,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p15.1-q12 | {Nasopharyngeal carcinoma 1} | 607107 | 2 |
Nasopharyngeal carcinoma (NPC, NPCA) is a multifactorial malignancy associated with both genetic and environmental factors. The cancer arises from the epithelium of the nasopharynx. The Epstein-Barr virus has been implicated (Tse et al., 2009).
Genetic Heterogeneity of Susceptibility to Nasopharyngeal Carcinoma
NPCA1 maps to chromosome 4p. NPCA2 (161550) maps to chromosome 6p21. NPCA3 (617075) is associated with variation in the MST1R gene (600168) on chromosome 3p21.
Somatic mutations have been found in the TP53 gene (191170) in nasopharyngeal carcinoma tumors.
The high frequency of NPC in southeast Asian individuals, especially persons of Cantonese Chinese ancestry, suggests a strong genetic factor predisposing to the development of the disorder. In areas with high incidence, NPC clusters in families, which suggests that both geography and genetics may influence disease risk (Feng et al., 2002).
Gajwani et al. (1980) described nasopharyngeal carcinoma in 4 sibs, 2 of them dizygotic twins. They came from a sibship of 11, all born in the U.S. of Poland-born nonconsanguineous parents.
Fischer et al. (1984) described 2 affected brothers with an affected male first cousin, all born in Australia of Greek extraction. The brothers were nonsmokers and used little alcohol.
In a genomewide search carried out in 32 families at high risk of NPC in Guangdong Province, China, Feng et al. (2002) found parametric linkage to marker D4S405 on chromosome 4, with a lod score of 3.06 and a heterogeneity lod (hlod) score of 3.21. Fine mapping with additional markers resulted in a lod score of 3.54 and hlod of 3.67 for the region 4p15.1-q12. Multipoint nonparametric linkage analysis gave lod scores of 3.54 and 4.2 at D4S405 and D4S3002, (positioned at 4.5 cM away from D4S405), respectively. When Epstein-Barr virus antibody titer was included as a covariate, the lod score reached 4.70 and 5.36 for the 2 markers, respectively. Feng et al. (2002) interpreted the evidence as indicating the presence of a major susceptibility locus for NPC on chromosome 4 in a subset of families.
Liang et al. (2004) identified a single-nucleotide polymorphism (SNP) in the COX7B2 gene (H26Q; see 609811) on 4p12 in 2 affected members of a Chinese family (pedigree 31) with nasopharyngeal carcinoma linked to chromosome 4p14-p11. Further analysis showed that the 6 related patients who shared a common disease haplotype all carried the H26Q substitution. However, 1 affected family member did not have the SNP and 5 unaffected family members did have the SNP. In addition, the H26Q substitution was not identified in patients from 7 additional families linked to NPCA1 locus or in 136 unrelated sporadic cases. Liang et al. (2004) suggested that the H26Q SNP may contribute to disease susceptibility in their family.
In 4 affected individuals and 2 controls from the 2 largest Chinese NPCA pedigrees that had previously shown strong linkage to chromosome 4 (pedigrees '31' and '34' in Feng et al., 2002), Jiang et al. (2006) analyzed 78 candidate genes and 6 predicted genes and identified a -32A polymorphism (rs17585937) in the LOC344967 gene (611963) on chromosome 4p14-p11 that cosegregated with the disease phenotype. Analysis of all family members from the 32 pedigrees previously studied revealed that all affected individuals in the 3 largest and most strongly linked pedigrees ('31,' '34,' and '62') carried the -32A SNP; the variant was also present in 10 of 18 unaffected family members. In the remaining 29 pedigrees, about one-third of cases shared the -32A variant. Jiang et al. (2006) found that the expression of LOC344967 was significantly upregulated at both mRNA and protein levels in 2 NPCA cell lines with the -32G/A genotype compared to 2 NPCA cell lines with the -32G/G genotype. They concluded that the -32A variant in the LOC344967 gene may be related to NPCA susceptibility in the families studied.
Associations Pending Confirmation
He et al. (2005) screened all exons, relevant exon-intron boundaries, and the approximately 2-kb promoter region of the palate, lung, and nasal epithelium carcinoma-associated protein gene (PLUNC; 607412) on chromosome 20q11 and identified 8 SNPs. Three haplotype-tagged SNPs were genotyped in a case-control Chinese population composed of 239 unrelated patients with nasopharyngeal carcinoma and 286 healthy controls. Two promoter SNPs, -2128T-C and -1888T-C, showed significant associations with susceptibility to NPC (OR = 2.8, p less than 0.0006, and OR = 3.3, p less than 0.0001, respectively). The distribution of haplotypes constructed based on the -2128T-C and -1888T-C polymorphisms was significantly different between NPC patients and controls: individuals with the C/C haplotype had significantly increased susceptibility to NPC (OR = 1.86, p = 0.00016). He et al. (2005) concluded that genetic variation in PLUNC may influence susceptibility to NPC in the Chinese population.
To identify genetic susceptibility loci for nasopharyngeal carcinoma, Bei et al. (2010) performed a genomewide association study using 464,328 autosomal SNPs in 1,583 NPC affected individuals and 1,894 controls of southern Chinese descent. The top 49 SNPs from the genomewide association study were genotyped in 3,507 cases and 3,063 controls of southern Chinese descent from Guangdong and Guangxi. The 7 supportive SNPs were further confirmed by transmission disequilibrium test analysis in 279 trios from Guangdong. Bei et al. (2010) identified 3 new susceptibility loci, TNFRSF19 (606122) on 13q12 (rs9510787, p combined = 1.53 x 10(-9), OR = 1.20), MDS1-EVI1 (see 600049) on 3q26 (rs6774494, p combined = 1.34 x 10(-8), OR = 0.84), and the CDKN2A-CDKN2B (600160, 600431) gene cluster on 9q21 (rs1412829, p combined = 4.84 x 10(-7), OR = 0.78). Furthermore, Bei et al. (2010) confirmed the role of HLA by revealing independent associations at rs2860580 (p combined = 4.88 x 10(-67), OR = 5.8), rs2894207 (p combined = 3.42 x 10(-33), OR = 0.61), and rs28421666 (p combined = 2.49 x 10(-18), OR = 0.67).
Somatic Mutations
Sun et al. (1992) identified a somatic mutation in the p53 gene (R280T; 191170.0024) in tumor tissue from a Chinese patient with nasopharyngeal carcinoma. Chakrani et al. (1995) studied 41 primary tumors of the undifferentiated nasopharyngeal cancer type from Hong Kong and the Guangxi province of southeastern China. Four somatic point mutations in the TP53 gene were found clustered in exon 5 within the DNA stretch from codon 175 to 177.
Using whole-exome and targeted deep sequencing as well as SNP array analysis, Lin et al. (2014) determined the mutational landscape of 128 patients with NPC. These approaches revealed a distinct mutational signature and 9 significantly mutated genes, many of which had not been previously implicated in NPC. Notably, integrated analysis showed enrichment of genetic lesions affecting several important cellular processes and pathways, including chromatin modification, ERBB (see 131550)-PI3K (see 601232) signaling, and autophagy machinery. Further functional studies suggested the biologic relevance of these lesions to the NPC malignant phenotype. The 9 significantly mutated genes were BAP1 (603089), MLL2 (602113), TSHZ3 (614119), TP53, PIK3CA (171834), ERBB2 (164870), ERBB3 (190151) KRAS (190070), and NRAS (164790). The ARID1A (603024) gene, which encodes a component of the SWI/SNF complex, was frequently deleted in NPC.
Nasopharyngeal carcinoma is most prominent in southeast Asia regions, including China, Hong Kong, and Taiwan, where the annual incidence rate is approximately 25-fold higher than in the Western world (Tse et al., 2009).
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