Dataset Information

Hypermutation of the inactive X chromosome is a frequent event in cancer

ABSTRACT: Mutation is a fundamental process in tumorigenesis. However the degree to which the rate of somatic mutation varies across the human genome and the mechanistic basis underlying this variation remain to be fully elucidated. As part of the ICGC PedBrain and Malignant Lymphoma (MMML-Seq) consortium we performed a cross-cancer comparison of whole genomes comprising a diverse set of childhood and adult tumors including both solid and hematopoietic malignancies. In addition we performed whole genome sequencing of clonally expanded hematopoietic stem/progenitor cells (HSPCs) from healthy individuals to compare somatic mutation rates.

PROVIDER: EGAS00001000565 | EGA |

REPOSITORIES: EGA

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Hypermutation of the inactive X chromosome is a frequent event in cancer.

Jäger Natalie N Schlesner Matthias M Jones David T W DT Raffel Simon S Mallm Jan-Philipp JP Junge Kristin M KM Weichenhan Dieter D Bauer Tobias T Ishaque Naveed N Kool Marcel M Northcott Paul A PA Korshunov Andrey A Drews Ruben M RM Koster Jan J Versteeg Rogier R Richter Julia J Hummel Michael M Mack Stephen C SC Taylor Michael D MD Witt Hendrik H Swartman Benedict B Schulte-Bockholt Dietrich D Sultan Marc M Yaspo Marie-Laure ML Lehrach Hans H Hutter Barbara B Brors Benedikt B Wolf Stephan S Plass Christoph C Siebert Reiner R Trumpp Andreas A Rippe Karsten K Lehmann Irina I Lichter Peter P Pfister Stefan M SM Eils Roland R

Cell 20131017 3

Mutation is a fundamental process in tumorigenesis. However, the degree to which the rate of somatic mutation varies across the human genome and the mechanistic basis underlying this variation remain to be fully elucidated. Here, we performed a cross-cancer comparison of 402 whole genomes comprising a diverse set of childhood and adult tumors, including both solid and hematopoietic malignancies. Surprisingly, we found that the inactive X chromosome of many female cancer genomes accumulates on av ...[more]

PMID: 24139898

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Project description: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.

Dataset Information

Hypermutation of the inactive X chromosome is a frequent event in cancer

Publications

Hypermutation of the inactive X chromosome is a frequent event in cancer.

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