Dataset Information

Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.

ABSTRACT: Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

SUBMITTER: Dentro SC

PROVIDER: S-EPMC8054914 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.

Dentro Stefan C SC Leshchiner Ignaty I Haase Kerstin K Tarabichi Maxime M Wintersinger Jeff J Deshwar Amit G AG Yu Kaixian K Rubanova Yulia Y Macintyre Geoff G Demeulemeester Jonas J Vázquez-García Ignacio I Kleinheinz Kortine K Livitz Dimitri G DG Malikic Salem S Donmez Nilgun N Sengupta Subhajit S Anur Pavana P Jolly Clemency C Cmero Marek M Rosebrock Daniel D Schumacher Steven E SE Fan Yu Y Fittall Matthew M Drews Ruben M RM Yao Xiaotong X Watkins Thomas B K TBK Lee Juhee J Schlesner Matthias M Zhu Hongtu H Adams David J DJ McGranahan Nicholas N Swanton Charles C Getz Gad G Boutros Paul C PC Imielinski Marcin M Beroukhim Rameen R Sahinalp S Cenk SC Ji Yuan Y Peifer Martin M Martincorena Inigo I Markowetz Florian F Mustonen Ville V Yuan Ke K Gerstung Moritz M Spellman Paul T PT Wang Wenyi W Morris Quaid D QD Wedge David C DC Van Loo Peter P

Cell 20210407 8

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe pos ...[more]

PMID: 33831375

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Project description:Colorectal cancer arises in part from the cumulative effects of multiple gene lesions. Recent studies in selected cancer types have revealed significant intra-tumor genetic heterogeneity and highlighted its potential role in disease progression and resistance to therapy. We hypothesized the existence of significant intra-tumor genetic heterogeneity in rectal cancers involving variations in localized somatic mutations and copy number abnormalities. Two or three spatially disparate regions from each of six rectal tumors were dissected and subjected to the next-generation whole-exome DNA sequencing, Oncoscan SNP arrays, and targeted confirmatory sequencing and analysis. The resulting data were integrated to define subclones using SciClone. Mutant-allele tumor heterogeneity (MATH) scores, mutant allele frequency correlation, and mutation percent concordance were calculated, and copy number analysis including measurement of correlation between samples was performed. Somatic mutations profiles in individual cancers were similar to prior studies, with some variants found in previously reported significantly mutated genes and many patient-specific mutations in each tumor. Significant intra-tumor heterogeneity was identified in the spatially disparate regions of individual cancers. All tumors had some heterogeneity but the degree of heterogeneity was quite variable in the samples studied. We found that 67-97% of exonic somatic mutations were shared among all regions of an individual's tumor. The SciClone computational method identified 2-8 shared and unshared subclones in the spatially disparate areas in each tumor. MATH scores ranged from 7 to 41. Allele frequency correlation scores ranged from R(2)=0.69-0.96. Measurements of correlation between samples for copy number changes varied from R(2)=0.74-0.93. All tumors had some heterogeneity, but the degree was highly variable in the samples studied. The occurrence of significant intra-tumor heterogeneity may allow selected tumors to have a genetic reservoir to draw from in their evolutionary response to therapy and other challenges.

Dataset Information

Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.

Publications

Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.

Similar Datasets

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