Dataset Information

Genomic Amplification and Functional Dependency of the Gamma Actin Gene ACTG1 in Uterine Cancer.

ABSTRACT: Sarcomere and cytoskeleton genes, or actomyosin genes, regulate cell biology including mechanical stress, cell motility, and cell division. While actomyosin genes are recurrently dysregulated in cancers, their oncogenic roles have not been examined in a lineage-specific fashion. In this report, we investigated dysregulation of nine sarcomeric and cytoskeletal genes across 20 cancer lineages. We found that uterine cancers harbored the highest frequencies of amplification and overexpression of the gamma actin gene, ACTG1. Each of the four subtypes of uterine cancers, mixed endometrial carcinomas, serous carcinomas, endometroid carcinomas, and carcinosarcomas harbored between 5~20% of ACTG1 gene amplification or overexpression. Clinically, patients with ACTG1 gains had a poor prognosis. ACTG1 gains showed transcriptional patterns that reflect activation of oncogenic signals, repressed response to innate immunity, or immunotherapy. Functionally, the CRISPR-CAS9 gene deletion of ACTG1 had the most robust and consistent effects in uterine cancer cells relative to 20 other lineages. Overall, we propose that ACTG1 regulates the fitness of uterine cancer cells by modulating cell-intrinsic properties and the tumor microenvironment. In summary, the ACTG1 functions relative to other actomyosin genes support the notion that it is a potential biomarker and a target gene in uterine cancer precision therapies.

SUBMITTER: Richter C

PROVIDER: S-EPMC7698702 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Genomic Amplification and Functional Dependency of the Gamma Actin Gene <i>ACTG1</i> in Uterine Cancer.

Richter Camden C Mayhew David D Rennhack Jonathan P JP So Jonathan J Stover Elizabeth H EH Hwang Justin H JH Szczesna-Cordary Danuta D

International journal of molecular sciences 20201118 22

Sarcomere and cytoskeleton genes, or actomyosin genes, regulate cell biology including mechanical stress, cell motility, and cell division. While actomyosin genes are recurrently dysregulated in cancers, their oncogenic roles have not been examined in a lineage-specific fashion. In this report, we investigated dysregulation of nine sarcomeric and cytoskeletal genes across 20 cancer lineages. We found that uterine cancers harbored the highest frequencies of amplification and overexpression of the ...[more]

PMID: 33217970

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Project description:ImportanceUnderstanding RAS dependency and mechanisms of RAS activation in non-V600 BRAF variant cancers has important clinical implications. This is the first study to date to systematically assess RAS dependency of BRAF alterations with real-world cancer genomic databases.ObjectiveTo evaluate RAS dependency of individual BRAF alterations through alteration coexistence analysis using cancer genomic databases.Design and settingA cross-sectional data analysis of 119 538 nonredundant cancer samples using cancer genomics databases including GENIE (Genomics Evidence Neoplasia Information Exchange) and databases in cBioPortal including TCGA (The Cancer Genome Atlas) (accessed March 24, 2020), in addition to 2745 cancer samples from Mayo Clinic Genomics Laboratory (January 1, 2015, to July 1, 2020). Frequencies and odds ratios of coexisting alterations of RAS (KRAS, NRAS and HRAS) and RAS regulatory genes (NF1, PTPN11 and CBL) were calculated for individual BRAF alterations, and compared according to the current BRAF alteration classification; cancer type specificity of coexisting alterations of RAS or RAS regulatory genes was also evaluated.Main outcomes and measuresPrimary outcome measurement is enrichment of RAS (KRAS, NRAS and HRAS) alterations in BRAF variant cancers. Secondary outcome measurement is enrichment of RAS regulatory gene (NF1, PTPN11, and CBL) in BRAF variant cancers.ResultsA total of 2745 cancer samples from 2708 patients (female/male ratio: 1.0) tested by Mayo Clinic Genomics Laboratory and 119 538 patients (female/male ratio: 1.1) from GENIE and cBioPortal database were included in the study. In 119 538 nonredundant cancer samples, class 1 BRAF alterations and BRAF fusions were found to be mutually exclusive to alterations of RAS or RAS regulatory genes (odds ratio range 0.03-0.13 and 0.03-0.73 respectively), confirming their RAS independency. Both class 2 and class 3 BRAF alterations show variable and overlapping levels of enriched RAS alterations (odds ratio range: 0.03-5.9 and 0.63-2.52 respectively), suggesting heterogeneity in RAS dependency and a need to revisit BRAF alteration classification. For RAS-dependent BRAF alterations, the coexisting alterations also involve RAS regulatory genes by enrichment analysis (for example, S467L shows an odds ratio of 8.26 for NF1, 9.87 for PTPN11, and 15.23 for CBL) and occur in a variety of cancer types with some coalterations showing cancer type specificity (for example, HRAS variations account for 46.7% of all coexisting RAS alterations in BRAF variant bladder cancers, but 0% in non-small cell lung cancers). Variant-level assessment shows that BRAF alterations involving the same codon may differ in RAS dependency. In addition, RAS dependency of previously unclassified BRAF alterations could be assessed.Conclusions and relevanceCurrent BRAF alteration classification based on in vitro assays does not accurately predict RAS dependency in vivo for non-V600 BRAF alterations. RAS-dependent BRAF variant cancers with different mechanisms of RAS activation suggest the need for different treatment strategies.

Dataset Information

Genomic Amplification and Functional Dependency of the Gamma Actin Gene ACTG1 in Uterine Cancer.

Publications

Genomic Amplification and Functional Dependency of the Gamma Actin Gene <i>ACTG1</i> in Uterine Cancer.

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