The knowledge derived from the study of inherited CRC syndromes has provided important clues regarding the molecular events that mediate tumor initiation and tumor progression in people without germline abnormalities. Among the earliest events in the colorectal tumor progression pathway (both MSI and CIN) is loss of function of the APC gene product, which appears to be consistent with its important role in predisposing persons with germline APC mutations to colorectal tumors.
Family History as a Risk Factor for CRC
Among the earliest studies of family history of CRC were those of Utah families that reported a higher number of deaths from CRC (3.9%) among the first-degree relatives of patients who had died from CRC, compared with sex-matched and age-matched controls (1.2%). This difference has since been replicated in numerous studies that have consistently found that first-degree relatives of affected cases are themselves at a twofold to threefold increased risk of CRC. Despite the various study designs (case-control, cohort), sampling frames, sample sizes, methods of data verification, analytic methods, and countries where the studies originated, the magnitude of risk is consistent.[36,37,38,39,40,41]
Population-based studies have shown a familial association for close relatives of colon cancer patients to develop CRC and other cancers. Using data from a cancer family clinic patient population, the relative and absolute risk of CRC for different family history categories was estimated (Table 1).[43,44]
A systematic review and meta-analysis of familial CRC risk was reported. Of 24 studies included in the analysis, all but one reported an increased risk of CRC if there was an affected first-degree relative. The relative risk (RR) for CRC in the pooled study was 2.25 (95% confidence interval [CI], 2.00–2.53) if there was an affected first-degree family member. In 8 of 11 studies, if the index cancer arose in the colon, the risk was slightly higher than if it arose in the rectum. The pooled analysis revealed a RR in relatives of colon and rectal cancer patients of 2.42 (95% CI, 2.20–2.65) and 1.89 (95% CI, 1.62–2.21), respectively. The analysis did not reveal a difference in RR for colon cancer based on location of the tumor (right side vs. left side).
The number of affected family members and age at cancer diagnosis correlated with the CRC risk. In studies reporting more than one first-degree relative with CRC, the RR was 3.76 (95% CI, 2.56–5.51). The highest RR was observed when the index case was diagnosed in individuals younger than 45 years, for family members of index cases diagnosed at ages 45 to 59 years, and for family members of index cases diagnosed at age 60 years or older, respectively (RR, 3.87; 95% CI, 2.40–6.22 vs. RR, 2.25; 95% CI, 1.85–2.72 vs. RR, 1.82; 95% CI, 1.47–2.25). In this meta-analysis, the familial risk of CRC associated with adenoma in a first-degree relative was analyzed. The pooled analysis demonstrated an RR for CRC of 1.99 (95% CI, 1.55–2.55) in individuals who had a first-degree relative with an adenoma. This finding has been corroborated. Other studies have reported that age at diagnosis of the adenoma influences the CRC risk, with younger age at adenoma diagnosis associated with higher RR.[46,47] As with any meta-analysis, there could be potential biases which might affect the results of the analysis, including incomplete and nonrandom ascertainment of studies included, publication bias, and heterogeneity between studies relative to design, target populations, and control selection. This study is reinforcement that there are significant associations between familial CRC risk, age at diagnosis of both CRC and adenomas, and multiplicity of affected family members.