Background & Aims
Colorectal cancer (CRC) risk estimates based on family history typically include only close relatives. We report familial relative risk in probands with various combinations, or constellations, of affected relatives, extending to third-degree.
A population-based resource that includes a computerized genealogy linked to statewide cancer records, was used to identify genetic relationships among CRC cases and their first-, second-, and third-degree relatives (FDRs, SDRs, and TDRs). Familial relative risks (FRRs) were estimated by comparing the observed number of affected individuals with a particular family history constellation to the expected number, based on cohort-specific CRC rates.
A total of 2,327,327 individuals included in ≥3 generation family histories were analyzed; 10,556 had a diagnosis of CRC. The FRR for CRC in individuals with ≥1 affected FDR=2.05 (95% CI 1.96–2.14), consistent with published estimates. In the absence of a positive first-degree family history, considering both affected SDRs and TDRs, only 1 constellation had an FRR estimate that was significantly > 1.0 (0 affected FDRs, 1 affected SDR, 2 affected TDRs; FRR=1.33, 95% CI 1.13–1.55). The FRR for individuals with 1 affected FDR, 1 affected SDR, and 0 affected TDRs=1.88 (95% CI 1.59–2.20), increasing to FRR=3.28 (95% CI 2.44–4.31) for probands with 1 affected FDR, 1 affected SDR, and ≥3 affected TDRs.
Increased numbers of affected FDRs influences risk much more than affected SDRs or TDRs. However, when combined with a positive first-degree family history, a positive second- and third-degree family history can significantly increase risk.