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Pan-Cancer Analysis of the Genomic Alterations and Mutations of the Matrisome.

ABSTRACT: The extracellular matrix (ECM) is a master regulator of all cellular functions and a major component of the tumor microenvironment. We previously defined the "matrisome" as the ensemble of genes encoding ECM proteins and proteins modulating ECM structure or function. While compositional and biomechanical changes in the ECM regulate cancer progression, no study has investigated the genomic alterations of matrisome genes in cancers and their consequences. Here, mining The Cancer Genome Atlas (TCGA) data, we found that copy number alterations and mutations are frequent in matrisome genes, even more so than in the rest of the genome. We also found that these alterations are predicted to significantly impact gene expression and protein function. Moreover, we identified matrisome genes whose mutational burden is an independent predictor of survival. We propose that studying genomic alterations of matrisome genes will further our understanding of the roles of this compartment in cancer progression and will lead to the development of innovative therapeutic strategies targeting the ECM.

SUBMITTER: Izzi V

PROVIDER: S-EPMC7463652 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Pan-Cancer Analysis of the Genomic Alterations and Mutations of the Matrisome.

Izzi Valerio V Davis Martin N MN Naba Alexandra A

Cancers 20200724 8

The extracellular matrix (ECM) is a master regulator of all cellular functions and a major component of the tumor microenvironment. We previously defined the "matrisome" as the ensemble of genes encoding ECM proteins and proteins modulating ECM structure or function. While compositional and biomechanical changes in the ECM regulate cancer progression, no study has investigated the genomic alterations of matrisome genes in cancers and their consequences. Here, mining The Cancer Genome Atlas (TCGA ...[more]

PMID: 32722287

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Project description:BackgroundCDK12 genomic alterations occur in several tumor types, but little is known about their oncogenic role and clinical significance.ObjectiveTo describe the landscape of CDK12 alterations across solid cancers and the clinical features of CDK12-altered prostate cancer.Design, setting, and participantsA single-center retrospective study of 26743 patients across 25 solid tumor types who underwent tumor sequencing was performed. Clinicopathologic features and outcomes were assessed in prostate cancer.Outcome measurements and statistical analysisCDK12 alterations and their association with genomic characteristics are described. For prostate cancer patients, overall survival and time to castration resistance were assessed using univariable and multivariable Cox regression analysis.Results and limitationsCDK12 alterations were identified in 404/26743 patients (1.5%) overall, but were most frequent in prostate (100/1875, 5.3%) and ovarian cancer (43/1034, 4.2%), in which they were associated with a high prevalence of truncating variants and biallelic inactivation. CDK12 alterations defined a genomic subtype of prostate cancer with a unique copy-number alteration profile and involvement of distinct oncogenic pathway alterations, including cell-cycle pathway genes. CDK12-altered prostate cancer was associated with somewhat more aggressive clinical features and shorter overall survival (median 64.4 vs 74.9 mo; p=0.032) independent of standard clinical factors and tumor copy-number alteration burden (adjusted hazard ratio 1.80, 95% confidence interval 1.12-2.89; p=0.024). The study is limited by its retrospective nature.ConclusionsCDK12 alteration is a rare event across solid cancers but defines a clinically distinct molecular subtype of prostate cancer associated with unique genomic alterations and slightly more aggressive clinical features.Patient summaryCDK12 gene alterations occur rarely across tumor types, but more frequently in prostate cancer, where they are associated with genomic instability, cell-cycle pathway gene alterations, and somewhat worse clinical outcomes, warranting further investigation of therapeutic targeting of this disease subset.

Dataset Information

Pan-Cancer Analysis of the Genomic Alterations and Mutations of the Matrisome.

Publications

Pan-Cancer Analysis of the Genomic Alterations and Mutations of the Matrisome.

Similar Datasets

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