Exome sequencing of early-onset patients supports genetic heterogeneity in colorectal cancer

Abstract

Colorectal cancer (CRC) is a complex disease that can be caused by a spectrum of genetic variants ranging from low to high penetrance changes, that interact with the environment to determine which individuals will develop the disease. In this study, we sequenced 20 early-onset CRC patients to discover novel genetic variants that could be linked to the prompt disease development. Eight genes, CHAD, CHD1L, ERCC6, IGTB7, PTPN13, SPATA20, TDG and TGS1, were selected and re-sequenced in a further 304 early onset CRC patients to search for rare, high-impact variants. Although we found a recurring truncating variant in the TDG gene shared by two independent patients, the results obtained did not help consolidate any of the candidates as promising CRC predisposing genes. However, we found that potential risk alleles in our extended list of candidate variants have a tendency to appear at higher numbers in younger cases. This supports the idea that CRC onset may be oligogenic in nature and may show molecular heterogeneity. Further, larger and robust studies are thus needed to unravel the genetics behind early-onset CRC development, coupled with novel functional analyses and omic approaches that may offer complementary insight.

Gut microbiota display alternative profiles in patients with early-onset colorectal cancer

“…The structure of the colorectal cancer population is gradually changing, and the rapidly increasing incidence of early-onset colorectal cancer requires vigilance ( Collaborative et al., 2021 ; Sinicrope, 2022 ). The heterogeneity of clinical and molecular features of early-onset colorectal cancer is quite distinct, which means that it may be independent of traditional colorectal cancer ( Silla et al., 2014 ; Fernandez-Rozadilla et al., 2021 ). As research progresses, the characteristics of the intestinal flora can be a major consideration in the etiology of many cancers ( Murphy et al., 2019 ).…”

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines

“…A full summary of relevant evidence for G.1, 110-122 G.2, [110][111][112][113][114][115][116][117][118][119][120][121][122]125,126 and G.3 [127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142] -H) tumors are associated with LS, a decreased response to 5fluorouracil-based chemotherapy, an enhanced response to immunotherapy, and in general have an improved prognosis compared with MMR-proficient tumors (MMR-p). 143,144 Pretreatment MMR-d testing is particularly critical in 2 scenarios.…”

“…In 1 recent study of patients with eoCRC, 126 whole genome sequencing of 20 patients with eoCRC identified 8 candidate genes (CHAD, CHD1L, ERCC6, IGTB7, PTPN13, SPATA20, TDG, and TGS1). These genes were then resequenced in 304 patients with eoCRC, but the results could not claim any of these as CRC predisposing genes.…”

Potential Involvement of NSD1, KRT24 and ACACA in the Genetic Predisposition to Colorectal Cancer

“…Amplification of the genes' coding exons (+/-20bp flanking regions) was performed in each pool, using Phusion High-Fidelity DNA Polymerase (New England Biolabs, Ipswich, MA, USA) (Primers used are listed in Table S4). Each PCR product was processed as previously described [11,12]. DNA libraries were generated and sequencing at high coverage was performed on a HiSeq-4000 (Illumina, San Diego, CA, USA) at the Centro Nacional de Análisis Genómico (CNAG, Barcelona, Spain).…”