Characterization of Mutator Pathway in Younger-age-onset Colorectal Adenocarcinomas

Abstract

The high-frequency microsatellite instability (MSI-H) phenotype, frequently identified in hereditary nonpolyposis colorectal cancer (HNPCC), also accounts for approximately 15% of sporadic colorectal cancers. Microsatellite instability (MSI) occurs from the mutational inactivation of the DNA mismatch repair genes, i.e. hMSH2 and hMLH1 in HNPCC, as well as from epigenetic inactivation of hMLH1 in sporadic colorectal tumors. The mutator pathway including microsatellite instability, hMLH1 promoter methylation, and hMSH2 and hMLH1 mutation patterns were identified in 21 sporadic colorectal adenocarcinoma patients younger than 30 yr excluding HNPCC. More than half of tumors showed MSI, with five MSI-H and six MSI-L (low-frequency microsatellite instability). Three of six MSI-H tumors showed the hMLH1 promoter methylation and did not express the hMLH1 protein. On the other hand, all MSI-L and all MSS (microsatellite stable) tumors expressed both hMSH2 and hMLH1 proteins. Two novel mutations, i.e. a missense mutation in hMLH1 and a splice-site alteration in hMSH2, were identified in two patients respectively. Although mutator pathway was implicated in younger-age-onset colorectal carcinogenesis, many tumors appeared to evolve from different genetic events other than hMSH2 and hMLH1 mutations frequently identified in HNPCC.

Colorectal cancer among young native Indonesians: A clinicopathological and molecular assessment on microsatellite instability

“…The distribution of MLH1 protein expression non-polyposis colorectal cancer, HNPCC). 4,5 In Indonesia, we found a different pattern, demonstrating a higher incidence of young colorectal cancer patients who have more progressive disease and do not show goodresponse in chemotherapy, which will greatly influence productivity and family's financial problem. 19 However, little is known about the biologic characteristic of colorectal cancer.…”

“…The diagnosis of HNPCC is established by using the Amsterdam I and II criteria. 4,5 In developed countries, the incidence of colorectal cancer increases sharply after the age of 50 years; whereas only 3% are found among those patients less than 40 year of age and complied with the Amsterdam / Bethesda modification criteria for HNPCC (hereditary non-polyposis colon cancer) with the following characteristics: 1) right-sided location; 2) a lower pathologic stage; 3) less tendency of metastasis; and 4) a better prognosis. 6 In Asia and Africa, colorectal cancer cases at young age are also reported with a higher incidence, 7,8 which may reach 4-5 times that of developed countries, but neither of those reports explain about biologic characteristics of colorectal cancer.…”

Incidence of colorectal cancer in young patients

“…MSI occurs from the mutational inactivation of the DNA mismatch repair genes (hMSH2 and hMLH1 in Lynch Syndrome), as well as from epigenetic inactivation of hMLH1 in sporadic CRC. Although mutator pathway (including microsatellite instability, hMLH1 promoter methylation, and hMSH2 and hMLH1 mutation patterns) has been implicated in younger-age-onset colorectal carcinogenesis, many tumors may evolve from different genetic events other than hMSH2 and hMLH1 mutations frequently identified in Lynch Syndrome 36 . Thus, it is not surprising that cancers that emerge from different mutational pathways should differ clinically.…”