Dataset Information

Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response.

ABSTRACT: Genomic instability, which is a hallmark of cancer, is generally thought to occur in the middle to late stages of tumourigenesis, following the acquisition of permissive molecular aberrations such as TP53 mutation or whole genome doubling. Tumours with somatic POLE exonuclease domain mutations are notable for their extreme genomic instability (their mutation burden is among the highest in human cancer), distinct mutational signature, lymphocytic infiltrate, and excellent prognosis. To what extent these characteristics are determined by the timing of POLE mutations in oncogenesis is unknown. Here, we have shown that pathogenic POLE mutations are detectable in non-malignant precursors of endometrial and colorectal cancer. Using genome and exome sequencing, we found that multiple driver mutations in POLE-mutant cancers show the characteristic POLE mutational signature, including those in genes conventionally regarded as initiators of tumourigenesis. In POLE-mutant cancers, the proportion of monoclonal predicted neoantigens was similar to that in other cancers, but the absolute number was much greater. We also found that the prominent CD8⁺ T-cell infiltrate present in POLE-mutant cancers was evident in their precursor lesions. Collectively, these data indicate that somatic POLE mutations are early, quite possibly initiating, events in the endometrial and colorectal cancers in which they occur. The resulting early onset of genomic instability may account for the striking immune response and excellent prognosis of these tumours, as well as their early presentation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

SUBMITTER: Temko D

PROVIDER: S-EPMC6032922 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response.

Temko Daniel D Van Gool Inge C IC Rayner Emily E Glaire Mark M Makino Seiko S Brown Matthew M Brown Matthew M Chegwidden Laura L Palles Claire C Depreeuw Jeroen J Beggs Andrew A Stathopoulou Chaido C Mason John J Baker Ann-Marie AM Williams Marc M Cerundolo Vincenzo V Rei Margarida M Taylor Jenny C JC Schuh Anna A Ahmed Ahmed A Amant Frédéric F Lambrechts Diether D Smit Vincent Thbm VT Bosse Tjalling T Graham Trevor A TA Church David N DN Tomlinson Ian I

The Journal of pathology 20180430 3

Genomic instability, which is a hallmark of cancer, is generally thought to occur in the middle to late stages of tumourigenesis, following the acquisition of permissive molecular aberrations such as TP53 mutation or whole genome doubling. Tumours with somatic POLE exonuclease domain mutations are notable for their extreme genomic instability (their mutation burden is among the highest in human cancer), distinct mutational signature, lymphocytic infiltrate, and excellent prognosis. To what exten ...[more]

PMID: 29604063

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Project description:Retrospective data support overall survival (OS) advantage to high clonal tumor mutation burden (cTMB), high clonal neoantigen load (cNEO) and low intratumor heterogeneity (ITH) in cancer patients who receive immunotherapy. In order to explore this relationship prospectively with Vigil, a triple function targeted immunotherapy involving ovarian cancer patients in long term follow up of the Phase 2b VITAL trial, we developed an exome sequencing procedure and associated bioinformatics pipeline to determine clonal signal patterns. DNA libraries containing exome sequences tagged with unique molecular identifiers (UMI) were prepared from paired samples and sequenced on Illumina sequencers to high coverage depths of ~ 930X (tumor) and ~ 130X (normal). Raw sequence reads were processed into optimized binary alignment map (BAM) files, using the UMI information. The BAM files were inputted into modules for calling MHC-I alleles, annotating single nucleotide variants (SNVs) and small insertions/deletions (InDels), and for determination of allelic copy number. The outputs were used to predict the sequence of peptide neoantigens and to perform clonality analysis in order to assign each SNV and InDel in a patient tumor sample to a primary clone or subclone. The Clonal Neoantigen pipeline was further assessed using whole exome Illumina sequencing data from three previously published studies. Evaluation of the pipeline using synthetic sequencing data from a sub-clonal deconvolution tool benchmarking study, showed positive predictive value (PPV) and positive percent agreement (PPA) of > 97.5% and > 96.5%, respectively, for SNV and InDel detection with minimum requirements for variant density and allele fraction. Haplotype calls from the Clonal Neoantigen pipeline MHC-I/ MHC-II typing module matched a published benchmark for 91.5% of the calls in a sample of 99 patients. Analysis of exome sequencing data from 14 patients with advanced melanoma revealed a strong correlation between cTMB values determined by the Clonal Neoantigen pipeline as compared to those calculated from the published data (R2 = 0.99). Following validation, the wet lab process and Clonal Neoantigen pipeline was applied to a set of matched normal, tumor, and Vigil product samples from 9 (n = 27 samples) ovarian cancer subjects entered into the VITAL (CL-PTL-119) trial. Results demonstrated marked correlation (R2 = 0.98) of cTMB between tumor used to construct Vigil and Vigil product. Correlation between tumor and Vigil for the cNEO and ITH metrics, showed R2 values of 0.95 and 0.87, respectively. The consistency of the Clonal Neoantigen pipeline results with previously published data as well as the agreement between results for tumor and Vigil for the entire system provide a strong basis of support for utilization of this pipeline for prospective determination of cTMB, cNEO, and ITH values in clinical tumor tissue in order to explore possible correlative relationships with clinical response parameters.

Dataset Information

Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response.

Publications

Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response.

Similar Datasets

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