Colorectal cancer in HNPCC: cumulative lifetime incidence, survival and tumour distribution. A report of 121 families with proven mutations

Abstract

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant condition caused by inactivating mutations of DNA mismatch repair (MMR) genes. An accurate estimation of colorectal cancer risk for mutation carriers is essential for counselling and rationalizing screening programmes. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of all relevant exons of the MMR genes. Proven and obligate mutation carriers and first-degree relatives (FDRs) with an HNPCC spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. The cumulative lifetime risk was calculated by Kaplan-Meier analysis. Three hundred and forty-one colorectal cancers in 839 proven, obligate, or assumed mutation carriers were analysed. The cumulative risk to age 70 years for all mutation carriers combined was 50.4% (95% CI 47.8-52.9). The cumulative risk in males was 54.3% (95% CI 50.7-57.8), which was significantly higher than in females (log rank p = 0.02) who had a risk of 46.3% (95% CI 42.8-49.9). These penetrance estimates from HNPCC families attending high-risk clinics have been corrected for ascertainment bias and are appropriate risks for those referred to a high-risk clinic. Current colonoscopic screening guidelines are appropriate.

A systematic review and economic evaluation of diagnostic strategies for Lynch syndrome

“…Furthermore, neither review identified more than four studies related to LS. Between them they identified only seven separate reviews, 23,49,50,59,61,81,82 of which all but one had already been identified by our review. The one study we had not identified, by Hagen and colleagues, 82 was written in German and therefore excluded from our review.…”

“…The one study we had not identified, by Hagen and colleagues, 82 was written in German and therefore excluded from our review. The only results presented by Antonanzas and colleagues were from the Barrow and colleagues (2008) 81 paper, which we excluded on the basis of population. The four studies 23,49,50,59 reported by Rogowski and colleagues 77 were all included in our review, which had a more comprehensive set of studies.…”

“…We therefore attempted to identify studies with particular relevance to the NHS. 121 recruited LS patients referred to the Manchester Regional Genetics Service and performed statistical analyses to estimate the risk of extracolonic cancers in mutation carriers (in a previous study 81 they estimated the risk of CRC). Although their methodology for risk estimation has been criticised by Bonadona and colleagues (2011), 2 their recruitment statistics are not questioned and are valuable in this setting.…”

Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome

“…The hereditary nonpolyposis colorectal cancer (HNPCC) syndrome is a major cause of hereditary colorectal cancer, predominantly within the proximal colon, with 50-80% cumulative life time risk in mutation carriers, and in addition female carriers are at a 40-60% risk of endometrial cancer and a 10-15% risk of ovarian cancer [5][6][7]. A number of other tumors types, i.e., gastric cancer, cancer of the small intestine and the upper urinary tract, skin tumors, brain tumors, and soft tissue sarcomas, have also been linked to HNPCC, albeit at lower frequencies.…”

Incidence and Clinical Characteristics of Colonic and Extra Colonic Lynch Syndrome Manifestations in Uruguayan Mismatch Repair Carriers

“…MSH2-mutation carriers show a higher incidence (48-61%) of extra colonic malignancies (gastric, pancreatic, small bowel, rectal, urological and ovarian cancer) when compared to MLHmutation carriers (11-42%) [13]. MLH1 and MSH2 mutation carriers have an overall higher cancer risk (44-79% and 38-78%) when compared with MSH6 and PMS2 mutation carriers; and the highest cumulative risk for CC at age 70 (50-65% and 40-65%, respectively), with a mean age of onset of 43-46 years old [14].…”