Nasopharyngeal Carcinoma, Susceptibility To, 3
A number sign (#) is used with this entry because of evidence that susceptibility to nasopharyngeal carcinoma-3 (NPCA3) is conferred by heterozygous variation in the MST1R gene (600168) on chromosome 3p21.Description
Nasopharyngeal carcinoma (NPCA) is a malignant tumor that emerges from the epithelium of the nasopharynx. It has a high incidence in southern China, and evidence suggests that there may be a genetic component that underlies familial clustering. Some patients have onset before 20 years of age (summary by Dai et al., 2016)
For a general phenotypic description and a discussion of genetic heterogeneity of susceptibility to nasopharyngeal carcinoma, see NPCA1 (607107).Molecular Genetics
By whole-exome sequencing of 161 cases of NPC and 895 controls from southern China, including 39 early-onset cases, 63 patients from 52 independent families, and 59 sporadic cases, Dai et al. (2016) found a significant association between variation in the MST1R gene and development of the cancer. The variants, which were confirmed by Sanger sequencing, were filtered against the 1000 Genomes Project and Exome Sequencing Project databases. Eleven variants, including 1 frameshift and 10 missense variants located at conserved residues, were found in 13 (8.7%) patients, including 2 sibs. Seven of the 13 patients had early onset, before 20 years of age: 5 heterozygous missense variants were observed in 17.9% of the early-onset cases and in only 1.2% of controls (p = 7.94 x 10(-12)). The variants identified in the early-onset cases were A973T, E705K, V670G, A327T, and R306H (600168.0001). Functional studies of the variants were not performed. However, copy number alterations of 3p21.2 (loss of heterozygosity) were found in 9 (64%) of 14 tumors derived from individuals with germline MST1R variants. In addition, proximal promoter hypermethylation resulting in downregulation of full-length MST1R was also frequently observed. Overall, the findings suggested that variation in expression of the MST1R gene, including germline variation, may predispose to the development of nasopharyngeal carcinoma. No somatic MST1R mutations were found in over 100 NPC tumors.