Mutational analysis of OGG1, MYH, MTH1 in FAP, HNPCC and sporadic colorectal cancer patients: R154H OGG1 polymorphism is associated with sporadic colorectal cancer patients

Abstract

MYH, OGG1 and MTH1 are members of base excision repair (BER) families, and MYH germline mutations were recently identified in patients with multiple adenomas or familial adenomatous polyposis (FAP). A total of 20 APC-negative Korean FAP patients were analyzed for OGG1, MYH and MTH1 germline mutations. A total of 19 hereditary nonpolyposis colorectal cancer (HNPCC), 86 suspected HNPCC, and 246 sporadic colorectal cancer cases were investigated for OGG1 and MYH mutations. A total of 14 R154H OGG1 polymorphisms were identified in hereditary, sporadic colorectal cancers, and normal controls. For the case-control analysis of OGG1 R154H, a total of 625 hereditary or sporadic colorectal cancer patients and 527 normal controls were screened. R154H was a rare polymorphism associated with sporadic colorectal cancer patents (OR: 3.586, P= 0.053). R154H does not segregate with cancer phenotypes. Upon examining the possibility of recessive inheritance of R154H, we could not identify any complementary mutations in OGG1, MYH or MTH1. Samples with R154H were further screened for mutations of K-ras, beta-catenin, APC, p53, BRAF and the microsatellite instability (MSI) status. Eight somatic mutations were identified in these genes and G:C to T:A transversion mutations were not dominant in samples harboring R154H. This result raises the possibility that OGG1 R154H may function as a low/moderate-penetrance modifier for colorectal cancer development.

MYH, OGG1, MTH1, and APC alterations involved in the colorectal tumorigenesis of Korean patients with multiple adenomas

“…The MYH mutations in the AFAP families, which are frequently observed among Caucasians (Y165C and G382D) or other races of Indian (E466X) and Pakistani (Y90X), were not identified in our study. This finding is similar to other studies involving Korean, Japanese, and Jewish populations [15,19,25], and indicates a marked ethnic or regional segregation in MYH polyposis. However, we found two novel heterozygous MYH mutations: R170Q and A359V.…”

Overexpression of Wnt-2 in colorectal cancers

“…These findings suggest that constitutive activation of the Wnt canonical pathway contributes to human carcinogenesis [6]. However, somatic mutations in APC and β-catenin genes have been only rarely detected in Korean patients with colorectal cancer [7]. Thus, it is likely that there are other mechanisms responsible for activating the Wnt signaling pathway in the development of sporadic colorectal cancer in Korean patients.…”

Association between genetic polymorphisms of the base excision repair gene MUTYH and increased colorectal cancer risk in a Japanese population

“…(13-18) However, neither of these two variants has ever been detected in East Asians, including Japanese, (19)(20)(21)(22) suggesting that they are ethnicity-specific alleles. Based on the above findings, we hypothesized that MUTYH variants other than Y165C and G382D act as low-penetrance susceptibility alleles in Japanese CRC, similar to a situation previously reported for the APC and CHEK2 gene variants.…”

“…(8,9,11,12) The frequencies of Y165C and G382D have been investigated in several colorectal cancer (CRC) case-control studies, and monoallelic carriers of these variants were found in 0.0 -2.6% of the cases and 0.0 -2.1% of the controls and biallelic carriers of these variants were found in 0.0-0.8% of the cases and 0% of the controls, respectively. (13)(14)(15)(16)(17)(18) However, neither of these two variants has ever been detected in East Asians, including Japanese, (19)(20)(21)(22) suggesting that they are ethnicity-specific alleles. Based on the above findings, we hypothesized that MUTYH variants other than Y165C and G382D act as low-penetrance susceptibility alleles in Japanese CRC, similar to a situation previously reported for the APC and CHEK2 gene variants.…”