Associations between family history of colorectal cancer and genetic alterations in tumors

Abstract

A family history of colorectal cancer has been consistently associated with an increased risk of developing colon cancer. However, there is limited information on the association between family history of colorectal cancer and genetic alterations that occur in colon tumors. In this study, we evaluate the association among genetic alterations of Ki-ras and p53, microsatellite instability and having a family history of colorectal cancer in a study of incident colon cancer cases (n ‫؍‬ 1993) and population-based controls (n ‫؍‬ 2,410). Although there was a slight nonsignificant increase in risk of having an unstable tumor among those with a family history of colorectal cancer, this increase in risk disappeared after excluding those people with a known mutation in either of the mismatch repair genes hMLH1 or hMSH2. A family history of colorectal cancer was not associated with Ki-ras mutations overall, although those with a G to T mutation of the second base of codon 12 were more likely to have a family history of colorectal cancer than were those without this specific type of Ki-ras mutation. Cases with p53 mutations were less likely to have a family history of colorectal cancer than were cases without a p53 mutation. We believe that, given the general lack of association between having a family history of colorectal cancer and genetic alterations in tumors, these alterations are acquired through disease pathways that involve exposure from diet, lifestyle or other environmental factors.

Explaining the Familial Colorectal Cancer Risk Associated with Mismatch Repair (MMR)-Deficient and MMR-Stable Tumors

“…In our study, the familial risk of colorectal cancer was markedly higher in relatives of probands with tumors displaying MMR deficiency than those with MS cancers, a finding concordant with most, but not all, previously published studies (38). Furthermore, f62% of the overall excess risk of colorectal cancer in relatives was associated with MSI status in the proband.…”

“…Other studies have reported lower estimates for the prevalence of MMR mutations in unselected colorectal cancer cases (38). There are a restricted number of founder mutations in Finland that may account for the higher frequency of mutations detected in this ethnic group than that reported in analyses of some highly out-bred populations.…”

Associations of Ki-ras Proto-oncogene Mutation and p53 Gene Overexpression in Sporadic Colorectal Adenomas with Demographic and Clinicopathologic Characteristics

“…Our study excluded individuals with two or more family members with a history of CRC, which complicates the evaluation of this relationship. Two previous studies in CRC found an inverse association between family history of CRC and p53 mutation (73) or overexpression (74) compared with p53-negative tumors. These results in CRC provide supportive evidence that our finding of an inverse relationship between family history and p53 overexpression in colorectal adenomas was not due to chance.…”

p27kip1 in Intestinal Tumorigenesis and Chemoprevention in the Mouse

“…21,22). It is important that both the type of control diet and the western-style diet had such a pronounced effect on tumor formation and pathology initiated by genetic factors, because there is overwhelming evidence in human populations that diet can significantly affect risk for tumor development in different genetic populations (34)(35)(36). Therefore, not only is it imperative that diet be considered in the explanation of the large variations in risk for tumor formation at different organ sites in developed and undeveloped countries, but as a practical matter, our data show that use of diets that reflect the human diet of different populations is fundamental to the successful development of mouse genetic models that efficiently and accurately reflect tumorigenesis in the human.…”