Multiple tumor-suppressor genes on chromosome 3p contribute to head and neck squamous cell carcinoma tumorigenesis

Abstract

Head and neck squamous cell carcinoma (HNSCC) remains a significant cause of morbidity and mortality. There has been a great interest in finding specific genomic changes which contribute to HNSCC tumorigenesis, especially within the chromosome 3p area, where high frequency of LOH (loss of heterozygosity) has been reported. However, tumor-suppressor genes that may account for the frequent LOH remain to be identified. Recently, one systematic study of genomic sequencing was performed on breast and colorectal cancers and 189 candidate cancer genes (CAN-genes) were reported. Among those CAN-genes, 13 genes are located on chromosome 3p. To investigate whether any of the 13 CAN-genes on chromosome 3p is relevant to HNSCC tumorigenesis, we examined their mutational profiles in eight HNSCC cell lines and 12 tumor-normal pairs of human HNSCC in this study. Three of the 13 CAN-genes, ALS2CL, EPHA3, and CMYA1, each was found to harbor a missense mutation (1/20, 5% for each of the three genes). The mutations appeared hemizygous and SNP array analyses showed that these missense mutations are accompanied by LOH on the remaining allele. In summary, our data offer further support that ALS2CL, EPHA3, and CMYA1 are bona-fide tumor-suppressor genes and contribute to the tumorigenesis of HNSCC. Our data suggest that multiple tumor-suppressor genes are likely to be involved in accounting for the high LOH on chromosome 3p in HNSCC.

Figure 1

Presumed somatic mutations in ALS2CL, EPHA3 and CMYA1. Direct genomic sequencing was performed on 20 human HNSCC samples and cell lines. Three hemizygous alterations were discovered in ALS2CL, EPHA3 and CMYA1. These alterations are presumed somatic mutations because they were accompanied by LOH and not detected in the non-matching normal tissues or the existing NCBI SNP database.

Figure 2

LOH determined by SNP analysis in the human HNSCC samples and cell lines. SNP analysis was performed using Affymetrix 10K SNP arrays and dChip software. Blue color represents areas with LOH, yellow color indicates areas with allelic retention, while white and gray colors mean ‘not informative’.