Genetic variations in colorectal cancer risk and clinical outcome

Abstract

Colorectal cancer (CRC) has an apparent hereditary component, as evidenced by the well-characterized genetic syndromes and family history associated with the increased risk of this disease. However, in a large fraction of CRC cases, no known genetic syndrome or family history can be identified, suggesting the presence of "missing heritability" in CRC etiology. The genome-wide association study (GWAS) platform has led to the identification of multiple replicable common genetic variants associated with CRC risk. These newly discovered genetic variations might account for a portion of the missing heritability. Here, we summarize the recent GWASs related to newly identified genetic variants associated with CRC risk and clinical outcome. The findings from these studies suggest that there is a lack of understanding of the mechanism of many single nucleotide polymorphisms (SNPs) that are associated with CRC. In addition, the utility of SNPs as prognostic markers of CRC in clinical settings remains to be further assessed. Finally, the currently validated SNPs explain only a small fraction of total heritability in complex-trait diseases like CRC. Thus, the "missing heritability" still needs to be explored further. Future epidemiological and functional investigations of these variants will add to our understanding of CRC pathogenesis, and may ultimately lead to individualized strategies for prevention and treatment of CRC.

Colorectal cancer: a review

“…This is essential for the suppression of metastasis, and the survival rate significantly improves with high levels of KISS1. 29 It is estimated that these genetic syndromes represent about 10% of all cases of colorectal cancer; however about 25% of cases the familial history contributes to an increased risk of developing colorectal cancer in the absence of these genetic syndromes 30 . Factors such as history of ulcerous colitis, Chron's disease, personal history of polyposis, colon, rectal, ovarian, endometrium, breast cancer, and diabetes mellitus are related to a 30-50% greater risk of developing colorectal cancer, and about 75% of the malignant tumors of the colon and rectum are presented without related any of these risk factors; The relationship between hyperplastic polyposis and cancer is controversial.…”

MANAGEMENT OF ENDOCRINE DISEASE: Acromegaly and cancer: an old debate revisited

“…Although the risk of CRC increases with age, the incidence of both hereditary and sporadic forms is increasing gradually per year in individuals younger than 50 years (34). Genetic, ethnic, environmental, and especially dietary factors are important determinants of colorectal carcinogenesis (35,36). CRC most often begins as precancerous polyps, and it is assumed that a malignant transformation takes approximately 10-15 years to occur (7).…”

Allele‐specific imbalance mapping at human orthologs of mouse susceptibility to colon cancer (Scc) loci

“…To date, the identification of low‐penetrance CRC susceptibility variants has largely been accomplished by population‐based case‐control GWAS. While these studies have identified over 40 independent low‐penetrance variants from different populations, the proportion of genetic risk that they explain is modest and incomplete . Given that heritable factors are estimated to account for 12 to 35% of the risk for developing CRC, it has been proposed that the remainder of risk comes from rare variants, copy number variants, gene‐gene interactions, gene‐environment interactions and parent‐of‐origin effects—though overestimates of heritability are also a possible explanation for the missing heritability …”