Genotypic and Phenotypic Characteristics of Hereditary Colorectal Cancer

Abstract

The genomic causes and clinical manifestations of hereditary colorectal cancer (HCRC) might be stratified into 2 groups, namely, familial (FCRC) and a limited sense of HCRC, respectively. Otherwise, FCRC is canonically classified into 2 major categories; Lynch syndrome (LS) or associated spectra and inherited polyposis syndrome. By contrast, despite an increasing body of genotypic and phenotypic traits, some FCRC cannot be clearly differentiated as definitively single type, and the situation has become more complex as additional causative genes have been discovered. This review provides an overview of HCRC, including 6 LS or associated spectra and 8 inherited polyposis syndromes, according to molecular pathogenesis. Variants and newly-identified FCRC are particularly emphasized, including MUTYH (or MYH)-associated polyposis, Muir-Torre syndrome, constitutional mismatch repair deficiency, EPCAM-associated LS, polymerase proofreading-associated polyposis, RNF43- or NTHL1-associated serrated polyposis syndrome, PTEN hamartoma tumor syndrome, and hereditary mixed polyposis syndrome. We also comment on the clinical utility of multigene panel tests, focusing on comprehensive cancer panels that include HCRC. Finally, HCRC surveillance strategies are recommended, based on revised or notable concepts underpinned by competent validation and clinical implications, and favoring major guidelines. As hereditary syndromes are mainly attributable to genomic constitutions of distinctive ancestral groups, an integrative national HCRC registry and guideline is an urgent priority.

The Molecular Genetics of Colorectal Cancer, Hereditary Colorectal Cancer Syndromes, and Early-Onset Colorectal Cancer

“…75 However, there are also non–colorectal-related germline mutations that predispose to EOCRC, including variants in BRCA1, BRCA2, TP53, and EGFR. 64 Up to 29% of EOCRC tumors are MSI-H, compared with 15% of all CRC, and this accounts for patients with and without Lynch syndrome. Early-onset tumors are more likely to be hypermethylated and less likely to have sporadic BRAF or APC mutations.…”

“…PTEN mutations confer a risk of CRC with early age of onset, with a rate of 13% reported in one study of patients with Cowden syndrome. 47,64 It is unknown whether CRC develops from the hamartomatous or adenomatous polyps associated with the syndrome. Screening with colonoscopy is recommended starting at the age of 35 years and repeated every 1 to 2 years.…”

“…Patients with Cowden syndrome have a 95% likelihood of having colorectal polyps, ranging from few to hundreds. 64 These patients may have a variety of polyp types, including hamartomatous (most common), juvenile polyps, adenomas, and others. Cowden syndrome is also associated with macrocephaly (30% of patients), trichilemmomas (benign hair follicle tumors), and benign and malignant tumors of the breast, thyroid, uterus, and skin.…”

A Previously Unrecognized Molecular Landscape of Lynch Syndrome in the Mexican Population

“…Lynch syndrome (LS) is the most common hereditary syndrome of colorectal cancer. It is also associated with predisposition to several extracolonic neoplasms, with endometrial carcinoma being the most common, and an increased risk of cancer of the ovary, small intestine, stomach, urinary tract, pancreas, and brain [ 1 ]. It is an autosomal dominant syndrome caused by germline mutations in one of the genes of the mismatch repair (MMR) pathway: MLH1 , MSH2 , MSH6 , and PMS2 [ 2 , 3 ].…”

It Is a Pleasure to Announce the Issue Titled “Master Class 2021” in Annals of Coloproctology

“…In “ Genotypic and phenotypic characteristics of hereditary colorectal cancer ” [ 1 ], Jin Cheon Kim and Walter F. Bodmer provide an overview of hereditary colorectal cancer. In particular, they emphasize variants and newly identified familial colorectal cancer syndrome as well as comment on the clinical utility of multi-gene panel tests.…”