The Case for a Genetic Predisposition to Serrated Neoplasia in the Colorectum: Hypothesis and Review of the Literature

Abstract

In recent years, an alternative pathway of colorectal cancer development has been described in which serrated polyps replace the traditional adenoma as the precursor lesion. Importantly, serrated polyps and a subset of colorectal cancer show largely nonoverlapping mutation profiles to those found in adenomas and the majority of colorectal cancer. These genetic alterations include activating mutation of the BRAF proto-oncogene and widespread gene promoter hypermethylation (CpG island methylator phenotype or CIMP). Up to 15% of colorectal cancer is likely to develop on the basis of a strong genetic predisposition. The two most wellcharacterized syndromes, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer (Lynch syndrome), both develop via the adenoma-carcinoma pathway and together account for approximately one third of familial colorectal cancer. We have recently described 11 families in which there is evidence that the genetic predisposition to autosomal dominant colorectal cancer is linked to the serrated pathway. This condition, serrated pathway syndrome, and the related condition, hyperplastic polyposis, the presentation of which suggests a recessive mode of inheritance, represent two syndromes in which BRAF mutation and methylation co-occur within serrated precursor lesions. Further, CIMP is observed in the normal colonic mucosa of individuals with hyperplastic polyposis consistent with a field defect in epigenetic regulation. The spectrum of serrated neoplasia may also implicate the apparently sporadic and later onset subset of colorectal cancer with high levels of microsatellite instability. The tendency for these lesions to be multiple, associated with smoking, and to show frequent BRAF mutation and CIMP points to a defect that may result from interactions between the environment and a weakly penetrant genetic alteration. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1778 -84)

Ethnicity and Risk for Colorectal Cancers Showing Somatic BRAF V600E Mutation or CpG Island Methylator Phenotype

“…This suggests that although migrants' risk for the more common form of colorectal cancer converges to that of the Australian born with increasing duration of residence, the same is not true for tumors with BRAF mutation or the CIMP. Risk factors that act primarily before migration, or genetic factors (35,36), could explain the lack of convergence for these tumor types.…”

Phenotypic characterization and familial risk in hyperplastic polyposis syndrome

“…Patients typically have multiple and large hyperplastic polyps (HPs) proximal to the sigmoid colon [2,3] . Different types of serrated polyps as HPs, sessile serrated adenomas (SSAs), traditional serrated adenomas (TSAs) and mixed polyps (MPs) are associated with HPS [3][4][5][6][7] . The SSAs, TSAs and MPs are considered advanced lesions [5,8].…”

“…Carcinogenesis in serrated pathway involves a CpG island methylator phenotype (CIMP) and mutation of oncogene BRAF [8,10,11]. Although there are families with several affected members, suggesting a genetic predisposition [2,3,5] no specific genes were identified so far. The pattern of inheritance seems to be autosomal recessive [5].…”

“…Although there are families with several affected members, suggesting a genetic predisposition [2,3,5] no specific genes were identified so far. The pattern of inheritance seems to be autosomal recessive [5]. Besides genetic susceptibility, environmental factors probably determine tumor development.…”

Germline Genetics in Colorectal Cancer Susceptibility and Prognosis

“…About 30% of individuals with HPP have a family history of CRC. The inheritance pattern of HPP is not well defined, but a few characterized families show possible recessive inheritance (Young & Jass, 2006). A germline mutation in EPHB2 was identified in an individual who had more than 100 hyperplastic polyps, but EPHB2 mutations have not been observed in other HPP cases (Kokko et al, 2006).…”