From APC to the genetics of hereditary and familial colon cancer syndromes

Abstract

Hereditary colorectal cancer syndromes attributable to high penetrance mutations represent 9–26% of young-onset colorectal cancer cases. The clinical significance of many of these mutations is understood well enough to be used in diagnostics and as an aid in patient care. However, despite the advances made in the field, a significant proportion of familial and early-onset cases remains molecularly uncharacterized and extensive work is still needed to fully understand the genetic nature of colorectal cancer susceptibility. With the emergence of next generation sequencing and associated methods, several predisposition loci have been unravelled but validation is incomplete. Individuals with cancer predisposing mutations are currently enrolled in life-long surveillance, but with the development of new treatments, such as cancer vaccinations, this might change in the not so distant future for at least some individuals. For individuals without a known cause for their disease susceptibility, prevention and therapy options are less precise. Herein, we review the progress achieved in the last three decades with a focus on how colorectal cancer predisposition genes were discovered. Furthermore, we discuss the clinical implications of these discoveries and anticipate what to expect in the next decade.

Merged testing for colorectal cancer syndromes and re‐evaluation of genetic variants improve diagnostic yield: Results from a nationwide prospective cohort

“…LS was by far the most frequent Mendelian CRC syndrome detected in our study, followed by FAP and MAP both at approximately 1% levels, that is, mutual ratios for LS, FAP, and MAP repeatedly shown in other studies of selected and unselected patients with CRC and in line with reported prevalences in general populations. 2,3,[5][6][7] Given their rarity, the absence of identified patients with PPAP, PJS, PTHS, and PJS is not surprising as the size of our cohort is limited. Also, as symptoms may present early in life, some patients with these conditions might have been diagnosed before adulthood by pediatricians and thus have escaped our study.…”

“…2,3 There are several less common Mendelian conditions that predispose to CRC, such as juvenile polyposis syndrome (JPS), PTEN hamartoma tumor syndrome (PHTS), Peutz-Jeghers syndrome (PJS), polymerase proofreading-associated polyposis (PPAP), and a handful additional more recently defined conditions. 3,4 Because DV may have prognostic, therapeutic, and prophylactic implications, screening for DV in selected patients with CRC and/or colorectal polyposis is routine in many health-care systems. In addition, identification of DV permits carrier testing and personalized health care for relatives.…”

“…Approximately 5% of patients with colorectal cancer (CRC) have a constitutional disease‐causing genetic variant (DV) that causes autosomal dominant (AD) or autosomal recessive (AR) predisposition to the disease 1 . Lynch syndrome (LS) is by far the most common known Mendelian CRC condition with a prevalence approximately 1:300, followed by familial adenomatous polyposis (FAP) and MUTYH ‐associated polyposis (MAP; AR inheritance) with estimated prevalences approximately 1:10 000 to 1:40 000, respectively 2,3 . There are several less common Mendelian conditions that predispose to CRC, such as juvenile polyposis syndrome (JPS), PTEN hamartoma tumor syndrome (PHTS), Peutz–Jeghers syndrome (PJS), polymerase proofreading‐associated polyposis (PPAP), and a handful additional more recently defined conditions 3,4 .…”

Immunohistochemical Profile of Parathyroid Tumours: A Comprehensive Review

“…Adenomatous polyposis coli (APC) gene is a tumour suppressor that inhibits the Wnt molecular pathway. It is known for its role in colorectal carcinogenesis and association with familial adenomatous polyposis (FAP) [107,108]. Its protein product can be detected by immunohistochemistry and has been recommended by WHO (2022) as an adjunct in the diagnostics of parathyroid carcinoma [12].…”

Molecular Network of Colorectal Cancer and Current Therapeutic Options

“…Approximately 65% of CRC cases developed sporadically, without a family history or inherited genetic mutations predisposition, through multiple acquired somatic genomic and epigenetic alterations ( 3 , 4 ). Other cases are associated with heritable components such as family history (25%), hereditary cancer syndrome (5%), some known CRCs low-penetrance genetic variations (<1%), and other unknown inherited genomic alterations ( 4 , 5 ).…”