The genetic susceptibility to colorectal cancer (CRC) has been estimated to be around 35% and yet high-penetrance germline mutations found so far explain less than 5% of all cases. Much of the remaining variations could be due to the co-inheritance of multiple low penetrant variants. The identification of all the susceptibility alleles could have public health relevance in the near future. To test the hypothesis that what are considered polymorphisms in human CRC genes could constitute low-risk alleles, we selected eight common SNPs for a pilot association study in 1785 cases and 1722 controls. One SNP, rs3219489:G>C (MUTYH Q324H) seemed to confer an increased risk of rectal cancer in homozygous status (OR=1.52; CI=1.06-2.17). When the analysis was restricted to our 'super-controls', healthy individuals with no family history for cancer, also rs1799977:A>G (MLH1 I219V) was associated with an increased risk in both colon and rectum patients with an odds ratio of 1.28 (CI=1.02-1.60) and 1.34 (CI=1.05-1.72), respectively (under the dominant model); while 2 SNPs, rs1800932:A>G (MSH6 P92P) and rs459552:T>A (APC D1822V) seemed to confer a protective effect. The latter, in particular showed an odds ratio of 0.76 (CI=0.60-0.97) among colon patients and 0.73 (CI=0.56-0.95) among rectal patients. In conclusion, our study suggests that common variants in human CRC genes could constitute low-risk alleles.
Hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatosis polyposis (FAP) are well-known high-risk cancer syndromes. Hereditary colorectal cancer (HCRC) with at least three relatives with colorectal cancer and a dominant pattern of inheritance but with no specifications for age at onset and two close relatives with colorectal cancer (TCR) are other forms of familial clustering known to carry an increased risk of the disease. The frequency of the total burden of familial colorectal cancer is not well known. We therefore investigated the family history of 400/411 (97%) eligible patients with recently diagnosed colorectal cancer in Västmanland county, Sweden, during a 3-year period. Records or death certificates confirmed the diagnoses of relatives. Five patients (1.2%, 95% CI 0.15-2.2) were diagnosed as having HNPCC, eight (1.9%, 95% CI 0.6-3.2) as having HCRC and thirty-four (8.3%, 95% CI 5.6-11.0) were identified as having TCR. In total, 47 patients (11.4%, 95% CI 8.3-14.5) were found to have a contributing familial background. The implication is thus that every ninth patient with colorectal cancer represents a highly or intermediately increased risk of the disease among relatives. We conclude that the low frequency of individuals identified by family history alone makes the establishment of surveillance programs feasible.