POLE and POLD1 germline exonuclease domain pathogenic variants, a rare event in colorectal cancer from the Middle East

Abstract

Background Colorectal cancer (CRC) is a major contributor to morbidity and mortality related to cancer. Only ~5% of all CRCs occur as a result of pathogenic variants in well‐defined CRC predisposing genes. The frequency and effect of exonuclease domain pathogenic variants of POLE and POLD1 genes in Middle Eastern CRCs is still unknown. Methods Targeted capture sequencing and Sanger sequencing technologies were employed to investigate the germline exonuclease domain pathogenic variants of POLE and POLD1 in Middle Eastern CRCs. Immunohistochemical analysis of POLE and POLD1 was performed to look for associations between protein expression and clinico‐pathological characteristics. Results Five damaging or possibly damaging variants (0.44%) were detected in 1,135 CRC cases, four in POLE gene (0.35%, 4/1,135) and one (0.1%, 1/1,135) in POLD1 gene. Furthermore, low POLE protein expression was identified in 38.9% (417/1071) cases and a significant association with lymph node involvement ( p = .0184) and grade 3 tumors ( p = .0139) was observed. Whereas, low POLD1 expression was observed in 51.9% (555/1069) of cases and was significantly associated with adenocarcinoma histology ( p = .0164), larger tumor size (T3 and T4 tumors; p = .0012), and stage III tumors ( p = .0341). Conclusion POLE and POLD1 exonuclease domain pathogenic variants frequency in CRC cases was very low and these exonuclease domain pathogenic variants might be rare causative events of CRC in the Middle East. POLE and POLD1 can be included in multi‐gene panels to screen CRC patients.

POLE and POLD1 pathogenic variants in the proofreading domain in papillary thyroid cancer

“…The early onset of PTC suggests that POLE p.Thr457Met might have strong cause-effect on pathogenesis of PTC. Interestingly, this variant was also identified in one CRC patient previously by us ( 45 ). Our data indicate that this variant might predispose to not only PTC but also CRC.…”

“…Low expression of POLD1 was associated with poorer prognostic markers such as distant metastasis and stage IV tumours. We also found low expression of POLE and POLD1 to be associated with poor prognostic factors such as lymph node involvement, grade 3 tumours and stage III tumours in CRC ( 45 ). However, no significant association with disease-free survival was noted with both biomarkers.…”

Unraveling the impact of a germline heterozygous POLD1 frameshift variant in serrated polyposis syndrome

“…Several studies have focused on the effect of POLE/POLD1 germline variants located in the exonuclease domain ( Elsayed et al, 2015 ; Bellido et al, 2016 ; Buchanan et al, 2018 ; Mur et al, 2020a ; Siraj et al, 2020 ), but limited efforts have been made to determine the functional impact of those variants identified in the polymerase domain. Their potential pathogenicity is usually based on rarity of these variants in the general population and loss-of-function intolerance scores.…”

Complete Response to Pembrolizumab in Advanced Colon Cancer Harboring Somatic POLE F367S Mutation with Microsatellite Stability Status: A Case Study

“…POLE mutations in patients with colorectal cancer present distinct clinical characteristics, including younger age, a greater proportion of males than females, diagnosis at an earlier stage, as well as significant increasing tumor mutation burden (TMB). 8 , 13 However, owing to its low frequency, there were limited prospective, controlled, clinical trials designed to evaluate the efficacy of ICIs in colorectal cancer patients harboring POLE mutations. Instead of that, several retrospective researches and case studies have reported the efficacy of ICIs in colorectal patients with POLE mutations.…”