Frequent POLE-driven hypermutation in ovarian endometrioid cancer revealed by mutational signatures in RNA sequencing

Jaime I Davila,Zachary C Fogarty,Vivekananda Sarangi,Chen Wang,S John Weroha,Pritha Chanana,Ruifeng Guo,Yajue Huang,Ellen L Goode

doi:10.1186/s12920-021-01017-7

Jaime I Davila, Zachary C Fogarty + Show 7 more

Open Access

https://doi.org/10.1186/s12920-021-01017-7

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Abstract

BackgroundDNA polymerase epsilon (POLE) is encoded by the POLE gene, and POLE-driven tumors are characterized by high mutational rates. POLE-driven tumors are relatively common in endometrial and colorectal cancer, and their presence is increasingly recognized in ovarian cancer (OC) of endometrioid type. POLE-driven cases possess an abundance of TCT > TAT and TCG > TTG somatic mutations characterized by mutational signature 10 from the Catalog of Somatic Mutations in Cancer (COSMIC). By quantifying the contribution of COSMIC mutational signature 10 in RNA sequencing (RNA-seq) we set out to identify POLE-driven tumors in a set of unselected Mayo Clinic OC.MethodsMutational profiles were calculated using expressed single-nucleotide variants (eSNV) in the Mayo Clinic OC tumors (n = 195), The Cancer Genome Atlas (TCGA) OC tumors (n = 419), and the Genotype-Tissue Expression (GTEx) normal ovarian tissues (n = 84). Non-negative Matrix Factorization (NMF) of the mutational profiles inferred the contribution per sample of four distinct mutational signatures, one of which corresponds to COSMIC mutational signature 10.ResultsIn the Mayo Clinic OC cohort we identified six tumors with a predicted contribution from COSMIC mutational signature 10 of over five mutations per megabase. These six cases harbored known POLE hotspot mutations (P286R, S297F, V411L, and A456P) and were of endometrioid histotype (P = 5e−04). These six tumors had an early onset (average age of patients at onset, 48.33 years) when compared to non-POLE endometrioid OC cohort (average age at onset, 60.13 years; P = .008). Samples from TCGA and GTEx had a low COSMIC signature 10 contribution (median 0.16 mutations per megabase; maximum 1.78 mutations per megabase) and carried no POLE hotspot mutations.ConclusionsFrom the largest cohort of RNA-seq from endometrioid OC to date (n = 53), we identified six hypermutated samples likely driven by POLE (frequency, 11%). Our result suggests the clinical need to screen for POLE driver mutations in endometrioid OC, which can guide enrollment in immunotherapy clinical trials.

Highlights

DNA polymerase epsilon (POLE) is encoded by the POLE gene, and POLE-driven tumors are characterized by high mutational rates
Somatic POLE mutations are uncommon in serous ovarian cancer (OC) [9, 10] but the presence of POLE mutations is increasingly recognized in ovarian endometrioid cancer (OEC) [10,11,12,13,14]
The Mayo Clinic OC cohort with existing RNA sequencing (RNA-seq) consisted of 195 patients whose clinical characteristics are described in Table 1 [20, 21]

Summary

Introduction

DNA polymerase epsilon (POLE) is encoded by the POLE gene, and POLE-driven tumors are characterized by high mutational rates. POLE-driven tumors are relatively common in endometrial and colorectal cancer, and their presence is increasingly recognized in ovarian cancer (OC) of endometrioid type. In a Japanese cohort of concurrent ovarian and endometrial cancer, the frequency of POLE mutations was high (five of 8 cases; 62%) detected by Sanger sequencing [13]; the reported POLE mutations (Q292E, E396V, D287N, and N293D) do not correspond to known hotspot mutations. This result highlights the need to ascertain the effects of particular POLE mutations and whether they are accompanied by hypermutation

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