학술논문

Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.
Document Type
article
Source
Cell. 184(8)
Subject
PCAWG Evolution and Heterogeneity Working Group and the PCAWG Consortium
branching evolution
cancer driver genes
cancer evolution
intra-tumor heterogeneity
pan-cancer genomics
subclonal reconstruction
tumor phylogeny
whole-genome sequencing
Genetics
Cancer
Human Genome
2.1 Biological and endogenous factors
Developmental Biology
Biological Sciences
Medical and Health Sciences
Language
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.