Colorectal Cancer Risks in Relatives of Young-Onset Cases: Is Risk the Same Across All First-Degree Relatives?

Abstract

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. 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. 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). 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.