Original article
Cancer Risks For Mismatch Repair Gene Mutation Carriers: A Population-Based Early Onset Case-Family Study

https://doi.org/10.1016/j.cgh.2006.01.002Get rights and content

Background & Aims: Cancer risks for mismatch repair gene mutation carriers have been derived almost exclusively using families ascertained owing to their strong cancer family history. These may be overestimates, due to analytic problems, and not generalizable. We estimated average cancer risks for mutations identified in population-based early onset colorectal cancer cases (probands) unselected for family history. Methods: Data were cancer histories and mutation status (carrier, non-carrier, or unknown) of 17 mismatch repair gene mutation carrier probands with colorectal cancer diagnosed before age 45 (8 hMLH1, 4 hMSH2, 4 hMSH6, 1 hPMS2) and their first- and second-degree relatives. We used modified segregation analysis theory, adjusting for the family being ascertained through the proband being an early onset mutation carrier. Results: Eleven carrier probands (64%) were from families meeting the Amsterdam II criteria for hereditary nonpolyposis colorectal cancer. The cumulative risk for colorectal cancer (95% confidence interval) to age 70 was 45% (29%–62%) for men and 38% (19%–51%) for women. Corresponding risks were 67% (47%–84%) and 72% (48%–85%) for any hereditary nonpolyposis colorectal cancer–related cancer. Compared with the general population, colorectal cancer incidence for men was approximately 180-fold higher before age 50, but about the same after age 50. For women, incidence was approximately 100-fold higher before age 50 and 7-fold higher thereafter. Conclusions: For carriers of the mutations in the mismatch repair genes that cause early onset colorectal cancer, colorectal cancer increases rapidly until age 50, and the incidence decreases to general population levels at older ages.

Section snippets

Subjects

Subjects were 17 early onset colorectal cases, unselected for family history, identified as being a carrier of germline mutation in a MMR gene (8 in hMLH1, 4 in hMSH2, 4 in hMSH6, and 1 in hPMS2), 19 and their adult first- and second-degree relatives. These were identified from the Victorian Colorectal Cancer Family Study, a population-based case-family study conducted between 1993 and 1997 of 131 adult men and women (probands) living in the Melbourne metropolitan area who were younger than age

Results

Table 1 shows that 9 of the 12 probands with a hMLH1 or hMSH2 germline mutation had a family history that met the Amsterdam II criteria, 2 had a family history of HNPCC-related cancers that did not meet the Amsterdam II criteria, and 1 had no family history of HNPCC-related cancers. Of 4 probands with an hMSH6 germline mutation, 2 had a family history that met the Amsterdam II criteria and 2 had no family history of HNPCC-related cancers. The proband with the hPMS2 mutation had no family

Discussion

With increasing uptake of genetic testing based on routine tumor testing for the MMR phenotype in early onset colorectal cancers, 19, 21, 22 many cases with germline MMR mutations are likely to be identified irrespective of their family cancer history. Subsequent testing of relatives will identify more carriers requiring risk assessment by genetic counselors. Which penetrance estimates should be used for these carriers who may or may not have a strong family cancer history?

We estimated that, on

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    Supported by grants from the National Health and Medical Research Council of Australia, the Victorian Health Promotion Foundation, and the National Institutes of Health, Colon Cancer Family Registry grant no. 1-U01 CA97735.

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    Copyright © 2006 American Gastroenterological Association. Published by Elsevier Ltd. All rights reserved.