Cancer risk in mutation carriers of DNA-mismatch-repair genes

Abstract

Excessive incidence of various cancers is a challenging feature of the hereditary-non-polyposis-colorectal-cancer (HNPCC) syndrome. This study estimated the cancer incidences in HNPCC compared with the general population. Individuals in a cohort of 1763 members of 50 genetically diagnosed families were categorized according to their genetic status as mutation carriers, non-carriers, or individuals at 50 or 25% risk of being a carrier. Incidences of cancers in these groups were compared with those in the Finnish population overall. In 360 mutation carriers, standardized incidence ratios (SIR) were significantly increased for colorectal [68; 95% confidence intervals (CI), 56 to 81], endometrial (62; 95% CI, 44 to 86), ovarian (13; 95% CI, 5.3 to 25), gastric (6.9; 95% CI, 3.6 to 12), biliary tract (9.1; 95% CI, 1.1 to 33), uro-epithelial (7.6; 95% CI, 2.5 to 18) and kidney (4.7; 95% CI, 1 to 14) cancers and for central-nervous-system tumours (4.5; 95% CI, 1.2 to 12). The SIR increased with increasing likelihood of being a mutation carrier. The cumulative cancer incidences were 82, 60, 13 and 12% for colorectal, endometrial, gastric and ovarian cancers respectively. For other tumours associated with increased risk, corresponding incidences were below 4%. Interestingly, the incidence of endometrial cancer (60%) exceeded that for colorectal cancer in women (54%). The tumour spectrum associated with germline mutations of DNA-mismatch-repair genes involves 8 or more organ sites, suggesting a need to develop methods to screen for extra-colonic cancer also.

Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features

“…Although the incidence of mismatch repair protein abnormalities and high levels of microsatellite instability suggesting a diagnosis of Lynch syndrome is relatively low (17%) in colorectal carcinoma patients r40 years of age, it is still much higher than the reported 3-5% incidence of Lynch syndrome in colorectal carcinoma identified in all age groups. Thus, routine analysis for mismatch repair protein abnormalities and microsatellite instability in young patients with colorectal carcinoma should be performed, as these Lynch syndrome patients and their family members are at risk for synchronous or metachronous Lynch syndrome-related tumors 25 and would benefit from close surveillance and genetic counseling.…”

Low-dose metronomic cyclophosphamide treatment mediates ischemia-dependent K-ras mutation in colorectal carcinoma xenografts

“…Antiangiogenic treatment and K-ras mutation S Shahrzad et al hereditary nonpolyposis colorectal cancer are at increased risk for several types of cancer, with the highest life-time risks for CRC (80%), endometrial cancer (40-60%), ovarian cancer (10-15%), cancer of the small intestine and upper urothelial cancer (Aarnio et al, 1999). In addition, somatic MMR defects occur in a subset of certain sporadic tumor types, for example, in 15-20% of gastrointestinal and endometrial cancer, which are mostly caused by somatic hypermethylation of the MLH1 promoter (Kane et al, 1997;Esteller et al, 1998).…”

Familial colorectal adenocarcinoma from the Swedish family-cancer database

“…7,8 HNPCC accounts for some 3% of CRCs in Finland and the families have an excess of other cancers, particularly at the endometrium, urinary tract, stomach and biliary system. [11][12][13][14] Family clustering of CRC occurs even when the cases are not part of a defined hereditary syndrome. The history of CRC in first-degree relatives elevates a person's lifetime risk of CRC about 2-fold.…”