Beyond adenomatous polyposis coli: Redefining the genetic architecture of familial adenomatous polyposis through recurrent variants of uncertain significance

Abstract

This editorial provides a critical commentary on the forthcoming prospective study published in the World Journal of Gastroenterology by Tóth et al. Familial adenomatous polyposis (FAP), as the prototypical hereditary colorectal cancer syndrome, has long been regarded as a monogenic disorder solely driven by germline adenomatous polyposis coli (APC) mutations. Tóth et al confirmed this classic paradigm in their Hungarian cohort, identifying pathogenic APC variants in > 90% of clinically suspected cases. However, their extended whole-exome sequencing approach unveiled a more complex genetic landscape. Nearly all patients exhibited a striking enrichment of recurrent variants of uncertain significance, particularly in the DNA polymerase epsilon catalytic subunit and mechanosensitive ion channel genes. This finding challenges the binary APC or not APC dichotomy and suggests that FAP is a polygenic or oligogenic disorder, wherein the core APC defect is modulated by a constellation of co-occurring genetic variants. The authors urge the field to move beyond the traditional single-gene diagnostic lens and embrace a systems genetics framework to more deeply understand the variable expressivity, penetrance, and extracolonic manifestations of FAP. Critical questions remain unresolved. Do these recurrent variants of uncertain significance s act as disease modifiers influencing polyp burden, age of cancer onset, or extraintestinal tumor risk? Can they account for the phenotypic heterogeneity observed among individuals harboring identical APC mutations? Most crucially, what is the functional interplay between APC, the DNA polymerase epsilon catalytic subunit, and the mechanosensitive ion channel in driving colonic tumorigenesis? Despite these unknowns, the work by Tóth et al represents more than a population-specific genetic report - it is a conceptual recalibration that redefines FAP as a genomic ecosystem. Only by fully deciphering its intrinsic complexity can we achieve truly individualized risk prediction and precision management.

Keywords: Familial adenomatous polyposis; Adenomatous polyposis coli; The DNA polymerase epsilon catalytic subunit; The mechanosensitive ion channel; Genomic ecosystem

Core Tip: This commentary reinterprets a recent Hungarian cohort study on familial adenomatous polyposis (FAP) to propose a paradigm shift in our understanding of the disease. We argue that FAP is not a simple monogenic disorder but a genomic ecosystem, where the core adenomatous polyposis coli mutation is modified by a constellation of co-occurring variants, most notably in POLE and PIEZO1. We integrate recent findings on the role of POLE in generating an ultramutated, immunotherapy-responsive phenotype and the function of PIEZO1 as a key mechanosensor in the gut to explain the clinical heterogeneity of FAP and chart a course for precision management.