Abstract
Previous genetic studies on colorectal carcinomas (CRC) have identified multiple somatic mutations in four candidate pathways (TGF-β, Wnt, P53 and RTK-RAS pathways) on populations of European ancestry. However, it is under-studied whether other populations harbor different sets of hot-spot somatic mutations in these pathways and other oncogenes. In this study, to evaluate the mutational spectrum of novel somatic mutations, we assessed 41 pairs of tumor-stroma tissues from Chinese patients with CRC, including 29 colon carcinomas and 12 rectal carcinomas. We designed Illumina Custom Amplicon panel to target 43 genes, including genes in the four candidate pathways, as well as several known oncogenes for other cancers. Candidate mutations were validated by Sanger sequencing, and we further used SIFT and PolyPhen-2 to assess potentially functional mutations. We discovered 3 new somatic mutations in gene APC, TCF7L2, and PIK3CA that had never been reported in the COSMIC or NCI-60 databases. Additionally, we confirmed 6 known somatic mutations in gene SMAD4, APC, FBXW7, BRAF and PTEN in Chinese CRC patients. While most were previously reported in CRC, one mutation in PTEN was reported only in malignant endometrium cancer. Our study confirmed the existence of known somatic mutations in the four candidate pathways for CRC in Chinese patients. We also discovered a number of novel somatic mutations in these pathways, which may have implications for the pathogenesis of CRC.
Highlights
Colorectal carcinoma (CRC) is the third most commonly diagnosed cancer in males yet the second in females, and the World Health Organization GLOBOCAN database reported approximately 1.2 million new cancer cases and more than 608,000 deaths globally in 2008 [1]
Rare germline mutation of the APC gene was found in both sporadic CRC [13] and familial adenomatous polyposis [14], and other studies implied that high-penetrant germline mutations of the MSH2 and MLH1gene [15] may account for hereditary nonpolyposis colorectal cancer [16]
We identified somatic mutations from genes in four critical candidate pathways and several known oncogenes in Chinese CRC patients
Summary
Colorectal carcinoma (CRC) is the third most commonly diagnosed cancer in males yet the second in females, and the World Health Organization GLOBOCAN database reported approximately 1.2 million new cancer cases and more than 608,000 deaths globally in 2008 [1]. Earlier generation of genome-wide association studies (GWAS) identified 8q24, 11q23, 18q21, 10p14 and 8q23.3 as susceptibility loci of CRC [7,8,9], but more recently, over 20 additional loci such as rs647161 (5q31.1), rs2423279 (20p12.3) and rs10774214 (12p13.32) were discovered to be associated with CRC [10]. These results from GWAS confirmed the heritability of CRC initiation [11, 12]. Rare germline mutation of the APC gene was found in both sporadic CRC [13] and familial adenomatous polyposis [14], and other studies implied that high-penetrant germline mutations of the MSH2 and MLH1gene [15] may account for hereditary nonpolyposis colorectal cancer [16]
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