Dataset Information

Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure.

ABSTRACT: Somatic mutations in driver genes may ultimately lead to the development of cancer. Understanding how somatic mutations accumulate in cancer genomes and the underlying factors that generate somatic mutations is therefore crucial for developing novel therapeutic strategies. To understand the interplay between spatial genome organization and specific mutational processes, we studied 3,000 tumor-normal-pair whole-genome datasets from 42 different human cancer types. Our analyses reveal that the change in somatic mutational load in cancer genomes is co-localized with topologically-associating-domain boundaries. Domain boundaries constitute a better proxy to track mutational load change than replication timing measurements. We show that different mutational processes lead to distinct somatic mutation distributions where certain processes generate mutations in active domains, and others generate mutations in inactive domains. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation-rate variations observed in human cancers.

SUBMITTER: Akdemir KC

PROVIDER: S-EPMC8350746 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure.

Akdemir Kadir C KC Le Victoria T VT Kim Justin M JM Killcoyne Sarah S King Devin A DA Lin Ya-Ping YP Tian Yanyan Y Inoue Akira A Amin Samirkumar B SB Robinson Frederick S FS Nimmakayalu Manjunath M Herrera Rafael E RE Lynn Erica J EJ Chan Kin K Seth Sahil S Klimczak Leszek J LJ Gerstung Moritz M Gordenin Dmitry A DA O'Brien John J Li Lei L Deribe Yonathan Lissanu YL Verhaak Roel G RG Campbell Peter J PJ Fitzgerald Rebecca R Morrison Ashby J AJ Dixon Jesse R JR Andrew Futreal P P

Nature genetics 20201005 11

Somatic mutations in driver genes may ultimately lead to the development of cancer. Understanding how somatic mutations accumulate in cancer genomes and the underlying factors that generate somatic mutations is therefore crucial for developing novel therapeutic strategies. To understand the interplay between spatial genome organization and specific mutational processes, we studied 3,000 tumor-normal-pair whole-genome datasets from 42 different human cancer types. Our analyses reveal that the cha ...[more]

PMID: 33020667

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Project description:Development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human hematological malignancies, recurrent chromosomal translocation of nucleoporin (NUP98 or NUP214) generates an aberrant chimera that invariably retains nucleoporin’s IDR, tandemly dispersed phenylalanine-andglycine (FG) repeats1-3. However, it remains largely elusive how unstructured IDRs contribute to oncogenesis. We here show that IDR or FG repeats harbored within NUP98-HOXA9, a homeodomain-containing transcription factor (TF) chimera recurrently detected in acute leukemia patients1,4,5, is essential for establishing nuclear liquid-liquid phase separation (LLPS) puncta and for inducing leukemic transformation of primary hematopoietic cells in vitro and in vivo. Strikingly, LLPS of NUP98-HOXA9 not only promotes chromatin occupancy of chimera TF oncoproteins but is also required for formation of a broad, ‘super-enhancer’-like binding pattern, typically seen at a battery of leukemia-related loci exemplified by HOX, MEIS and PBX genes, potentiating their transcriptional activation. An artificial HOX chimera, created by replacing NUP98’s FG repeats with an unrelated LLPSforming IDR of FUS6,7, had similar enhancement effects on chimera’s chromatin binding and target gene activation. Via Hi-C mapping, we further demonstrated that the phase-separated NUP98-HOXA9 protein assembly is able to induce formation of CTCF-independent chromatin looping enriched at leukemic oncogenes. Together, this report describes a proof-of-principle example wherein cancer acquires mutation to establish condensates of oncogenic TFs via a phase separation mechanism, which simultaneously enhances their chromatin targeting and induces organization of aberrant three-dimensional chromatin structure during tumorous transformation. As a range of LLPS-competent molecules are implicated in various human cancers, this mechanism can potentially be generalized to many malignant and diseased settings.

Dataset Information

Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure.

Publications

Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure.

Similar Datasets

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