Background & Aims: During the last 15 years, several single-gene mendelian disorders have been discovered that might account for some of the familial aggregation detected in large population studies of colorectal cancer (CRC). Mutations in DNA mismatch repair (MMR) genes cause hereditary nonpolyposis colorectal cancer–Lynch syndrome, the most common of the recognized CRC-predisposition syndromes, in which one major feature is a young age for cancer onset. However, for young-onset microsatellite stable (MSS) CRC, the familial risk for CRC is unknown. Methods: Patients with CRC who were <50 years old were identified through Minnesota Cancer Surveillance System (MCSS) and Mayo Clinic, Rochester, MN. CRCs in which the DNA MMR function was deficient as evidenced by high level microsatellite instability and/or loss of expression of MMR gene product by immunostaining were excluded. A total of 278 probands (131 from MCSS; 147 from Mayo Clinic) were included. Data on 1862 relatives were collected, of whom 68 were found to have had CRC, and an additional 165 had primary cancers of other types. Results: Compared with Surveillance Epidemiology and End Results program data, relatives of young-onset CRC probands had increased risks for CRC. This relative risk (RR) was increased among first-degree relatives (RR, 1.65; 95% confidence interval [CI], 1.29–2.07) and was greater for siblings (RR, 2.67; 95% CI, 1.50–4.41) than parents (RR, 1.5; 95% CI, 1.14–1.94). Conclusions: We studied 278 probands with young-onset MSS CRC. We determined that the RR for CRC was greatest in siblings, which is consistent with an autosomal recessive inheritance pattern.
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Population
Cases were identified through a contract with the Minnesota Cancer Surveillance System (MCSS), a population-based cancer registry, and the Mayo Clinic site of the Colon CFR. The Colon CFR is a National Cancer Institute (NCI)–supported consortium established in l997 to create a multinational comprehensive collaborative infrastructure for interdisciplinary studies in the genetic epidemiology of CRC. (Detailed information about the Colon CFR can be found at http://epi.grants.cancer.gov/CFR/.) The
Summary
Compared with SEER data, relatives of young-onset CRC probands had increased risks for development of CRC; however, of the 165 other primary cancers, age-adjusted rates did not reveal increased risks for any other cancers for siblings or parents compared with SEER data. Because no CRCs were reported among the probands’ children, no analysis was feasible. As shown in Table 1, the RRs for CRC were increased among first-degree relatives (RR, 1.65; 95% CI, 1.29–2.07), and this risk was greater for
Discussion
We studied 278 probands selected solely on the basis of having developed MSS CRC at a young age of onset. Exclusion of cases with tumor MSI was aimed at excluding cases that had a high likelihood of having HNPCC-Lynch syndrome, the most common cause of hereditary CRC. We determined that the RR for CRC in this cohort was greatest in siblings (RR, 2.67; 95% CI, 1.50–4.41), which was nearly double the RR of CRC in parents (RR, 1.5; 95% CI, 1.14–1.94). However, because the CIs overlap, we can only
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Supported by the National Cancer Institute, National Institutes of Health under RFA # CA-96-001, and through cooperative agreements with members of the Colon Cancer Family Registry and P.Is. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFR; mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government or the CFR.
