Gastroenterology

Gastroenterology

Volume 129, Issue 2, August 2005, Pages 415-421
Gastroenterology

Clinical-alimentary tract
Cancer Risk in Hereditary Nonpolyposis Colorectal Cancer Syndrome: Later Age of Onset

https://doi.org/10.1053/j.gastro.2005.05.011Get rights and content

Background & Aims: Mutations in the mismatch repair genes cause hereditary nonpolyposis colorectal cancer (HNPCC) syndrome and convey high lifetime cancer risks for colorectal (CRC) and endometrial cancer. Currently, cancer risks for individuals with HNPCC are based on data from clinically ascertained families. The purpose of this study was to re-examine the penetrance in HNPCC using a comprehensive dataset from a geographically defined region. Methods: A combined dataset of 70 HNPCC families ascertained by traditional high-risk criteria and by molecular screening comprising 88 probands and 373 mutation-positive family members was used. Statistical methods were modified survival analysis techniques. Results: In mutation-positive relatives (excluding probands), the median age at diagnosis of CRC was 61.2 years (confidence interval [CI], 56.3–68.0 y). The lifetime risk for CRC was 68.7% (CI, 58.6%–78.9%) for men and 52.2% (CI, 37.6%–66.9%) for women. Considering only probands, the median age at diagnosis of CRC was 44.0 years (CI, 41.0–46.3 y). Median age of onset of EC was 62.0 years (CI, 55.9 y to an upper limit too high to calculate) with a lifetime cancer risk of 54% (CI, 41.9%–66.1%). Conclusions: A markedly later age of onset for CRC at 61 y than previously reported (∼44 y) is suggested, resulting mainly from a more rigorous method of analysis in which all gene-positive individuals (both affected and unaffected with cancer) are considered. Lifetime cancer risks may be lower for CRC and endometrial cancer than presently assumed. If confirmed, these data suggest a need to alter counseling practices, and to consider HNPCC in older individuals than before.

Section snippets

Cohort 1

Cohort 1 consisted of members from 45 HNPCC families in whom a germline mutation of MLH1 (N = 42) or MSH2 (N = 3) had been detected. The probands presented with CRC. They were accrued over a period of 15 years between 1980 and 1994 by 2 surgeons based on clinical data and family history. The patients came from a defined geographic area in southern and southeastern Finland. Their mutation status was determined by molecular genetic testing beginning in 1994. Of note, the ascertainment of most of

Age of Onset and LTR

The median age of diagnosis of CRC was 54.0 years among men and 70.0 years among women in the combined dataset (see Table 1 for 95% confidence intervals). For both sexes combined, the median age of diagnosis of CRC was 61.2 years. The mean age at diagnosis of CRC was 55.1 for men and 60.3 for women. These ages are approximately 10–15 years higher than the previous estimates of age at onset for CRC among HNPCC patients reported in the literature (see Discussion section). Men had an LTR estimate

Discussion

In our dataset, the age of onset of CRC in mutation-positive family members of the probands was remarkably much higher (55–60 y) than the age of onset found in probands from the same families (44–48 y). The age of onset in probands from these cohorts was the same as has been reported for HNPCC in previously published estimates (44–45 y). These findings can be explained in 3 ways. First, in Mendelian disorders probands potentially represent extreme examples of positive ascertainment bias, and

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  • Cited by (0)

    Supported by grants CA67941 and P30 CA16058 from the National Cancer Institute.

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