Dataset Information

The genomic landscape of 2,023 colorectal cancers.

ABSTRACT: Colorectal carcinoma (CRC) is a common cause of mortality¹, but a comprehensive description of its genomic landscape is lacking^2-9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia coli^pks+ colibactin in rectal cancers¹⁰ and the importance of the SBS93 signature^11-13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations¹⁴ are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.

SUBMITTER: Cornish AJ

PROVIDER: S-EPMC11374690 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature

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The genomic landscape of 2,023 colorectal cancers.

Cornish Alex J AJ Gruber Andreas J AJ Kinnersley Ben B Chubb Daniel D Frangou Anna A Caravagna Giulio G Noyvert Boris B Lakatos Eszter E Wood Henry M HM Thorn Steve S Culliford Richard R Arnedo-Pac Claudia C Househam Jacob J Cross William W Sud Amit A Law Philip P Leathlobhair Maire Ni MN Hawari Aliah A Woolley Connor C Sherwood Kitty K Feeley Nathalie N Gül Güler G Fernandez-Tajes Juan J Zapata Luis L Alexandrov Ludmil B LB Murugaesu Nirupa N Sosinsky Alona A Mitchell Jonathan J Lopez-Bigas Nuria N Quirke Philip P Church David N DN Tomlinson Ian P M IPM Sottoriva Andrea A Graham Trevor A TA Wedge David C DC Houlston Richard S RS

Nature 20240807 8028

Colorectal carcinoma (CRC) is a common cause of mortality<sup>1</sup>, but a comprehensive description of its genomic landscape is lacking<sup>2-9</sup>. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurre ...[more]

PMID: 39112709

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Project description:PurposeMale breast cancer is rare, and its genomic landscape has yet to be fully characterized. Lacking studies in men, treatment of males with breast cancer is extrapolated from results in females with breast cancer. We sought to define whether male breast cancers harbor somatic genetic alterations in genes frequently altered in female breast cancers.Experimental designAll male breast cancers were estrogen receptor-positive, and all but two were HER2-negative. Fifty-nine male breast cancers were subtyped by immunohistochemistry, and tumor-normal pairs were microdissected and subjected to massively parallel sequencing targeting all exons of 241 genes frequently mutated in female breast cancers or DNA-repair related. The repertoires of somatic mutations and copy number alterations of male breast cancers were compared with that of subtype-matched female breast cancers.ResultsTwenty-nine percent and 71% of male breast cancers were immunohistochemically classified as luminal A-like or luminal B-like, respectively. Male breast cancers displayed a heterogeneous repertoire of somatic genetic alterations that to some extent recapitulated that of estrogen receptor (ER)-positive/HER2-negative female breast cancers, including recurrent mutations affecting PIK3CA (20%) and GATA3 (15%). ER-positive/HER2-negative male breast cancers, however, less frequently harbored 16q losses, and PIK3CA and TP53 mutations than ER-positive/HER2-negative female breast cancers. In addition, male breast cancers were found to be significantly enriched for mutations affecting DNA repair-related genes.ConclusionsMale breast cancers less frequently harbor somatic genetic alterations typical of ER-positive/HER2-negative female breast cancers, such as PIK3CA and TP53 mutations and losses of 16q, suggesting that at least a subset of male breast cancers are driven by a distinct repertoire of somatic changes. Given the genomic differences, caution may be needed in the application of biologic and therapeutic findings from studies of female breast cancers to male breast cancers. Clin Cancer Res; 22(16); 4045-56. ©2016 AACR.

Dataset Information

The genomic landscape of 2,023 colorectal cancers.

Publications

The genomic landscape of 2,023 colorectal cancers.

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