Constitutional chromothripsis of the locus as a cause of genetic predisposition to colon cancer.

Purpose: Approximately 20% of patients with clinical familial adenomatous polyposis (FAP) remain unsolved after molecular genetic analysis of the and other polyposis genes, suggesting additional pathomechanisms.

Methods: 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.

Results: 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 promoter 1B from the coding ORF (open reading frame) thus leading to allele-specific downregulation of mRNA. The rearrangement also involves three additional genes implicated in the -Axin-GSK3B-β-catenin signalling pathway.

Conclusions: Based on comprehensive genomic analysis, we propose that constitutional chromothripsis dampening expression, possibly modified by additional -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.