Abstract
Simple SummaryMethods used for the identification of hereditary cancer genes have evolved in parallel to technological progress; however, much of the genetic predisposition to cancer remains unexplained. A new in silico method based on Knudson’s two-hit hypothesis recently identified ~50 putative cancer predisposing genes, but their actual association with cancer has not yet been validated. In our study, we aimed to assess the involvement of these genes in familial/early-onset colorectal cancer (CRC) using different lines of evidence. Our results indicated that most of those genes were not associated with a genetic predisposition to CRC, but suggested a possible association for NSD1, KRT24 and ACACA.The ALFRED (Allelic Loss Featuring Rare Damaging) in silico method was developed to identify cancer predisposition genes through the identification of somatic second hits. By applying ALFRED to ~10,000 tumor exomes, 49 candidate genes were identified. We aimed to assess the causal association of the identified genes with colorectal cancer (CRC) predisposition. Of the 49 genes, NSD1, HDAC10, KRT24, ACACA and TP63 were selected based on specific criteria relevant for hereditary CRC genes. Gene sequencing was performed in 736 patients with familial/early onset CRC or polyposis without germline pathogenic variants in known genes. Twelve (predicted) damaging variants in 18 patients were identified. A gene-based burden test in 1596 familial/early-onset CRC patients, 271 polyposis patients, 543 TCGA CRC patients and >134,000 controls (gnomAD, non-cancer), revealed no clear association with CRC for any of the studied genes. Nevertheless, (non-significant) over-representation of disruptive variants in NSD1, KRT24 and ACACA in CRC patients compared to controls was observed. A somatic second hit was identified in one of 20 tumors tested, corresponding to an NSD1 carrier. In conclusion, most genes identified through the ALFRED in silico method were not relevant for CRC predisposition, although a possible association was detected for NSD1, KRT24 and ACACA.
Highlights
Estimates indicate that ~4% to 15% of all tumors, depending on tumor type, are considered hereditary [1], with genetic alterations being the key determinants of cancer development
We evaluated the characteristics of the 49 most frequently enriched genes in the original publication based on the following parameters: (i) relevance of the encoded protein in colorectal carcinogenesis; (ii) gene function, focused on relevant hereditary colorectal cancer (CRC) pathways such as DNA repair, Wnt, BMP/TGF-β or mTOR
When comparing the results to non-Finnish European, non-cancer gnomAD individuals as controls, the tendency for NSD1, KRT24 and ACACA disruptive alleles remained, and significant association was detected for KRT24 damaging and predicted damaging variants when comparing The Cancer Genome Atlas (TCGA) CRC patients to controls (OR = 2.57; 95% CI: 1.35–4.45; p = 0.002)
Summary
Estimates indicate that ~4% to 15% of all tumors, depending on tumor type, are considered hereditary [1], with genetic alterations being the key determinants of cancer development. Methods used for the identification of hereditary cancer genes have evolved in parallel to technological progress. Classical linkage analysis of large pedigrees followed by positional cloning, and the more recent use of high-throughput sequence capture methods and generation sequencing technologies, have allowed for the discovery of hereditary cancer genes. The genetic predisposition to colorectal cancer (CRC) is partially explained by germline pathogenic variants in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2, APC, MUTYH, NTHL1, MSH3, MLH3, POLE, POLD1, MBD4, AXIN2, PTEN, BMPR1A, SMAD4, RNF43 and RPS20. Despite the efforts made in recent years to identify additional hereditary CRC genes, much of the genetic predisposition remains unexplained [4]
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