Germline and Somatic Whole-Exome Sequencing Identifies New Candidate Genes Involved in Familial Predisposition to Serrated Polyposis Syndrome

Abstract

The serrated polyposis syndrome (SPS) is the most common and yet underdiagnosed colorectal polyposis syndrome. It is characterized by multiple and/or large colonic serrated polyps and a higher associated risk for colorectal cancer (CRC). The main objective of this study was to identify new candidate genes involved in the germline predisposition to SPS/CRC. Thirty-nine SPS patients from 16 families (≥2 patients per family) were recruited without alterations in well-known hereditary CRC genes, and germline and somatic whole-exome sequencing were performed. Germline rare variants with plausible pathogenicity, located in genes involved in cancer development, senescence and epigenetic regulation were selected. Somatic mutational profiling and signature analysis was pursued in one sample per family, when possible. After data filtering, ANXA10, ASXL1, CFTR, DOT1L, HIC1, INO80, KLF3, MCM3AP, MCM8, PDLIM2, POLD1, TP53BP1, WNK2 and WRN were highlighted as the more promising candidate genes for SPS germline predisposition with potentially pathogenic variants shared within families. Somatic analysis characterized mutational profiles in advanced serrated polyps/tumors, revealing a high proportion of hypermutated samples, with a prevalence of clock-like mutational signatures in most samples and the presence of DNA mismatch repair-defective signatures in some cases. In conclusion, we identified new candidate genes to be involved in familial SPS. Further functional studies and replication in additional cohorts are required to confirm the selected candidates.

Germline mutations inWNK2could be associated with serrated polyposis syndrome

“…The single-base substitution (SBS) signatures SBS.1 and SBS.5, considered clock-like mutational signatures, were the most represented in both samples, and no other distinctive signature was apparent. 24 In a validation SPS cohort of 211 unrelated patients, gene panel sequencing revealed four additional rare, missense variants in WNK2 including c.2105C>T (p.Pro702Leu) in PanSPS_044, c.2792C>T (p.Thr931Met) in PanSPS_095, c.3341C>T (p.Thr1114Met) in PanSPS_078 and c.5588T>C (p.Leu1863Pro) in PanSPS_055. The c.2792C>T variant was detected in a male SPS patient (onset at 67 years) in a family where an additional sample for variant segregation was available.…”

Personalized Immunotherapy in Colorectal Cancers: Where Do We Stand?

“…Despite the efforts to study CRC heterogeneity, our current knowledge in this field is just the tip of the iceberg. Expanding next-generation sequencing (NGS), single-cell sequencing, and whole-exome sequencing techniques along with the application of omics data at various levels, including genomics, epigenomics, transcriptomics, peptidomics, proteinomics, and metabolomics, could give us valuable information on the heterogeneity of CRCs (116)(117)(118)(119)(120)(121)(122)(123).…”

CFTR and Gastrointestinal Cancers: An Update

“…Another recent study identified 14 polymorphic variants involved in familial predisposition to serrated polyposis syndrome, a condition in which colorectal polyps are highly susceptible to progression to adenocarcinomas. Of the 14 polymorphic variants identified, 2 of the 14 were found in CFTR [ 42 ].…”

“…Germline heterozygous carriers of specific CFTR polymorphic variants are also at a higher risk for CRC, including in young adults [ 41 ] and in patients with familial serrated polyposis syndrome [ 42 ].…”

“…CFTR also acts as a tumor suppressor and is downregulated in non-CF, non-germline, sporadic human CRC, with CFTR expression linked to DFS and better prognosis [ 37 , 42 , 45 ]. Expression of CFTR inhibited the proliferation, invasion and migration of CRC cells [ 43 ].…”