Constitutional chromothripsis of the <i>APC</i> locus as a cause of genetic predisposition to colon cancer.

Abstract

Approximately 20% of patients with clinical familial adenomatous polyposis (FAP) remain unsolved after molecular genetic analysis of the <i>APC</i> and other polyposis genes, suggesting additional pathomechanisms. We applied multidimensional genomic analysis employing chromosomal microarray profiling, optical mapping, long-read genome and RNA sequencing combined with FISH and standard PCR of genomic and complementary DNA to decode a patient with an attenuated FAP that had remained unsolved by Sanger sequencing and multigene panel next-generation sequencing for years. We identified a complex 3.9 Mb rearrangement involving 14 fragments from chromosome 5q22.1q22.3 of which three were lost, 1 reinserted into chromosome 5 and 10 inserted into chromosome 10q21.3 in a seemingly random order and orientation thus fulfilling the major criteria of chromothripsis. The rearrangement separates <i>APC</i> promoter 1B from the coding ORF (open reading frame) thus leading to allele-specific downregulation of <i>APC</i> mRNA. The rearrangement also involves three additional genes implicated in the <i>APC</i>-Axin-GSK3B-β-catenin signalling pathway. Based on comprehensive genomic analysis, we propose that constitutional chromothripsis dampening <i>APC</i> expression, possibly modified by additional <i>APC</i>-Axin-GSK3B-β-catenin pathway disruptions, underlies the patient's clinical phenotype. The combinatorial approach we deployed provides a powerful tool set for deciphering unsolved familial polyposis and potentially other tumour syndromes and monogenic diseases.