Studies on the Genetic Factors Influencing Predisposition to Cancer in High-risk Groups.

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To explore the molecular nature of "Cancer Predisposition", we have performed comprehensive analyses on the differential distribution of missense-single nucleotide polymorphism (ms-SNP) of cancer-related genes between cases and healthy controls. Since 1999, we have done case-control studies on 103 ms-SNP in 335 cancer cases and 110 healthy controls and we found that 22 SNP significantly associated with cancer-risk including lung adenocarcinoma (LAD), lung squamous cell carcinoma (LSC), head and neck cancer (HNSC), colorectal cancer (CRC) and esophageal cancer (ECC). These risk-related 22 SNP included 3 SNP previously reported (in genes ADH1B, ALDH2 and TP53) and 19 SNP thus far undescribed in the literature and distributed among 20 genes consisting of 6 DNA-repair genes, 5 tumor suppressor genes, 5 chromosome-segregation genes and 4 others. Of these 22 SNP, 16 were of high-risk (SNP-H) with odds ratio (OR) 1.87-18.0 and 6 were protective SNP (SNP-L) with OR 0.18-0.54. In respect to eac … More h cancer-type, number of the affecting SNP including common ones were follows; LAD (8 SNP-H and 4 SNP-L), LSC (7 SNP-H and 2 SNP-L), HNSC (3 SNP-H and 2 SNP-L), CRC (3 SNP-H and 3 SNP-L) and ECC (2 SNP-H). Because all analyses were performed with the same specimens, it was possible to examine individually the perfect overlapping of the genotype at risk on these 22 SNP. A cumulative odds ratio (COR) was calculated for each individual by multiplying OR of their all overlapping SNP at risk. As to the LAD risk calculated by 10 SNP, the frequency of individuals showing COR > 4.0 was 4.5% in healthy controls, whereas 39% in LAD patients (P = 5 x 10^<-9>, OR = 13.4 ). Similarly, for the LSC risk based on 7 SNP, the frequency of persons with COR > 4.0 in healthy controls was 13%, while 66% in LSC patients (P = 8.5 x 10^<-8>, OR = 12.0 ).Thus, our results demonstrated that many ms-SNP including those with novel findings are involved in the predisposition to cancer-incidence, suggesting the hereditary cancer-predisposition is determined, at least in part, by the sum effects of many ms-SNP in cancer-related genes. Our results suggested also that each individual's cancer-risk may be predicted by calculating COR in some cases. Less