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

TitleCharacterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.
Publication TypeJournal Article
Year of Publication2021
AuthorsDentro SC, Leshchiner I, Haase K, Tarabichi M, Wintersinger J, Deshwar AG, Yu K, Rubanova Y, Macintyre G, Demeulemeester J, Vázquez-García I, Kleinheinz K, Livitz DG, Malikic S, Donmez N, Sengupta S, Anur P, Jolly C, Cmero M, Rosebrock D, Schumacher SE, Fan Y, Fittall M, Drews RM, Yao X, Watkins TBK, Lee J, Schlesner M, Zhu H, Adams DJ, McGranahan N, Swanton C, Getz G, Boutros PC, Imielinski M, Beroukhim R, S Sahinalp C, Ji Y, Peifer M, Martincorena I, Markowetz F, Mustonen V, Yuan K, Gerstung M, Spellman PT, Wang W, Morris QD, Wedge DC, Van Loo P
Corporate AuthorsPCAWG Evolution and Heterogeneity Working Group and the PCAWG Consortium
JournalCell
Volume184
Issue8
Pagination2239-2254.e39
Date Published2021 04 15
ISSN1097-4172
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.

DOI10.1016/j.cell.2021.03.009
Alternate JournalCell
PubMed ID33831375
PubMed Central IDPMC8054914
Grant List / WT_ / Wellcome Trust / United Kingdom
P30 CA008748 / CA / NCI NIH HHS / United States
P50 CA211015 / CA / NCI NIH HHS / United States
FC001202 / CRUK_ / Cancer Research UK / United Kingdom
FC001202 / MRC_ / Medical Research Council / United Kingdom
FC001202 / WT_ / Wellcome Trust / United Kingdom
MR/L016311/1 / MRC_ / Medical Research Council / United Kingdom
WT097678 / WT_ / Wellcome Trust / United Kingdom
C14303/A17197 / / CRUK /
A19274 / / CRUK /
R01 CA132897 / CA / NCI NIH HHS / United States
U24 CA210957 / CA / NCI NIH HHS / United States
211179/Z/18/Z / WT_ / Wellcome Trust / United Kingdom
FC001169 / MRC_ / Medical Research Council / United Kingdom
FC001169 / CRUK_ / Cancer Research UK / United Kingdom
FC001169 / WT_ / Wellcome Trust / United Kingdom
P30 CA016672 / CA / NCI NIH HHS / United States
Related Faculty: 
Marcin Imielinski, M.D., Ph.D.

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