Abstract
The underlying genetic cause of colorectal cancer (CRC) can be identified for 5-10% of all cases, while at least 20% of CRC cases are thought to be due to inherited genetic factors. Screening for highly penetrant mutations in genes associated with Mendelian cancer syndromes using next-generation sequencing (NGS) can be prohibitively expensive for studies requiring large samples sizes. The aim of the study was to identify rare single nucleotide variants and small indels in 40 established or candidate CRC susceptibility genes in 1,046 familial CRC cases (including both MSS and MSI-H tumor subtypes) and 1,006 unrelated controls from the Colon Cancer Family Registry Cohort using a robust and cost-effective DNA pooling NGS strategy. We identified 264 variants in 38 genes that were observed only in cases, comprising either very rare (minor allele frequency <0.001) or not previously reported (n=90, 34%) in reference databases, including six stop-gain, three frameshift, and 255 non-synonymous variants predicted to be damaging. We found novel germline mutations in established CRC genes MLH1, APC, and POLE, and likely pathogenic variants in cancer susceptibility genes BAP1, CDH1, CHEK2, ENG, and MSH3. For the candidate CRC genes, we identified likely pathogenic variants in the helicase domain of POLQ and in the LRIG1, SH2B3, and NOS1 genes and present their clinicopathological characteristics. Using a DNA pooling NGS strategy, we identified novel germline mutations in established CRC susceptibility genes in familial CRC cases. Further studies are required to support the role of POLQ, LRIG1, SH2B3 and NOS1 as CRC susceptibility genes.
Highlights
The underlying genetic cause of colorectal cancer (CRC) can only be identified for 5-10% of cases despite approximately 20% of all CRC cases thought to be due to inherited genetic factors [1], highlighting that the genetic cause for the majority of the heritable CRC is still unknown [2]
The characteristics of the familial CRC cases according to their recruitment category (Tiers 1 to 6) and controls are shown in Table 1 where 89% of the cases were whites
Variants classified as variants of uncertain clinical significance (VUS) by ACMG criteria include candidates suggestive of being pathogenic, www.impactjournals.com/oncotarget such as POLE p.H144R (MSS CRC at 48 years), BLM p.Y1044C (MSS CRC at 48 and 72 years), and MLH1 p.R100P (MSI-H CRC at 28 years)
Summary
The underlying genetic cause of colorectal cancer (CRC) can only be identified for 5-10% of cases despite approximately 20% of all CRC cases thought to be due to inherited genetic factors [1], highlighting that the genetic cause for the majority of the heritable CRC is still unknown [2]. Linkage studies have led to some progress in identifying additional highly penetrant genes including MUTYH [5], STK11 [6], BMPR1A [7], SMAD4, and PTEN [8], when combined might explain a further 1% of CRC. Genome-wide association-based studies (GWAS) have identified common germline alleles, but all have been weakly associated with CRC risk and collectively are likely to explain only a few percent of the missing heritability for CRC [9]. For almost all of these families, no mutation can be identified which has important negative clinical implications for family members. These families have been named “Familial Colorectal Cancer Type X” (FCCTX) [11]. FCCTX is probably not a single disorder, rather, it is more likely to be a heterogeneous group of CRCs including: CRC cases with a chance aggregation of CRC in their relatives (lifetime risk of CRC is 5% in the general population); CRC cases with an undiagnosed syndrome e.g. undetected Lynch syndrome or MUTYH-associated polyposis [12]; but for the majority of CRC cases it will be yet-to-bediscovered genetic mutations
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