Abstract
BackgroundEndometrial carcinoma (EC) accounts for 5.8% of all cancers in Saudi females. Although most ECs are sporadic, 2–5% tend to be familial, being associated with Lynch syndrome and Cowden syndrome. In this study, we attempted to uncover the frequency, spectrum and phenotype of germline mutations in the proofreading domain of POLE and POLD1 genes in a large cohort of ECs from Middle Eastern region.MethodsWe performed Capture sequencing and Sanger sequencing to screen for proofreading domains of POLE and POLD1 genes in 432 EC cases, followed by evaluation of protein expression using immunohistochemistry. Variant interpretation was performed using PolyPhen-2, MutationAssessor, SIFT, CADD and Mutation Taster.ResultsIn our cohort, four mutations (0.93%) were identified in 432 EC cases, two each in POLE and POLD1 proofreading domains. Furthermore, low expression of POLE and POLD1 was noted in 41.1% (170/1414) and 59.9% (251/419) of cases, respectively. Both the cases harboring POLE mutation showed high nuclear expression of POLE protein, whereas, of the two POLD1 mutant cases, one case showed high expression and another case showed low expression of POLD1 protein.ConclusionsOur study shows that germline mutations in POLE and POLD1 proofreading region are a rare cause of EC in Middle Eastern population. However, it is still feasible to screen multiple cancer related genes in EC patients from Middle Eastern region using multigene panels including POLE and POLD1.
Highlights
Endometrial carcinoma (EC) accounts for 5.8% of all cancers in Saudi females
Identification of Germline Mutations in Proofreading Domain of polymerase epsilon (POLE) and polymerase delta 1 (POLD1) genes Among 53 EC cases sequenced using Capture sequencing, no mutations were identified in the proofreading domains of POLE and POLD1 genes
Among 379 EC cases analyzed by Sanger sequencing, four variants (1%, 4/379) were detected, two in POLE (0.53%) and two in POLD1 (0.53%) proofreading domain and interpreted as of uncertain significance by ACMG/AMP 2015 guideline
Summary
Endometrial carcinoma (EC) accounts for 5.8% of all cancers in Saudi females. most ECs are sporadic, 2–5% tend to be familial, being associated with Lynch syndrome and Cowden syndrome. POLE and POLD1 are related B family polymerases They form the major catalytic and proofreading subunits of the DNA polymerase Epsilon (Polε) and DNA polymerase Delta (Polδ) enzyme complexes [8]. Both Polε and Polδ are heterotetramers with Polymerase ε involved in replication of leading strand of the replication fork [9], whereas DNA polymerase δ functions in synthesizing the lagging strand [10] Both polymerases δ and ε are responsible for carrying out high fidelity DNA synthesis and mutation affecting the proofreading activity of these genes can lead to genome instability, and subsequent increased risk of developing cancer [11]
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