Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Genetic Polymorphisms and Colorectal Cancer Risk
It is widely acknowledged that the familial clustering of colon cancer also occurs outside of the setting of well-characterized colon cancer family syndromes. Based on epidemiological studies, the risk of colon cancer in a first-degree relative of an affected individual can increase an individual's lifetime risk of colon cancer 2-fold to 4.3-fold. The relative risk (RR) and absolute risk of colorectal cancer (CRC) for different family history categories is estimated in Table 1. In addition, the lifetime risk of colon cancer also increases in first-degree relatives of individuals with colon adenomas. The magnitude of risk depends on the age at diagnosis of the index case, the degree of relatedness of the index case to the at-risk case, and the number of affected relatives. It is currently believed that many of the moderate- and low-risk cases are influenced by low-penetrance genes or gene combinations. Given the public health impact of identifying the etiology of this increased risk, an intense search for the responsible genes is under way.
Each locus would be expected to have a relatively small effect on CRC risk and would not produce the dramatic familial aggregation seen in Lynch syndrome (LS) or familial adenomatous polyposis (FAP). However, in combination with other common genetic loci and/or environmental factors, variants of this kind might significantly alter CRC risk. These types of genetic variations are often referred to as polymorphisms. Most loci that are polymorphic have no influence on disease risk or human traits (benign polymorphisms), while those that are associated with a difference in risk of disease or a human trait (however subtle) are sometimes termed disease-associated polymorphisms or functionally relevant polymorphisms. When such variation involves changes in single nucleotides of DNA they are referred to as single nucleotide polymorphisms (SNPs).
Polymorphisms underlying polygenic susceptibility to CRC are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to high-penetrance variants or alleles that are typically associated with more severe phenotypes, for example those APC or mismatch repair (MMR) gene mutations leading to an autosomal dominant inheritance pattern in a family. The definition of a moderate risk of cancer is arbitrary, but it is usually considered to be in the range of an RR of 1.5 to 2.0. Because these types of sequence variants are relatively common in the population, their contribution to total cancer risk is estimated to be much higher than the attributable risk in the population from the relatively rare syndromes such as FAP or LS. Additionally, polymorphisms in genes distinct from the MMR genes can modify phenotype (for example average age of CRC) in individuals with LS.
In general, low-penetrance variants have been identified in one of two manners. Earlier studies focused on candidates genes chosen because of biologic relevance to colon cancer pathogenesis. More recently, genome-wide association studies (GWAS) have been used much more extensively to identify potential CRC susceptibility genes. (Refer to the Genome-wide searches section of this summary for more information.)