Dataset Information

The mutational pattern of homologous recombination-related (HRR) genes in Chinese colon cancer and its relevance to immunotherapy responses.

ABSTRACT:

Background

Microsatellite-stable (MSS) colon adenocarcinoma (COAD) patients are not sensitive to immune checkpoint inhibitors. Here, we focused on analyzing the relationship between homologous recombination repair (HRR)-related gene mutations and clinical immunotherapy responses in MSS COAD.

Methods

The mutational landscape was profiled in a cohort of 406 Chinese COAD patients via next-generation sequencing (NGS). Correlations between HRR gene mutations and tumor immunity or clinical outcomes in two COAD genomic datasets were analyzed via bioinformatics.

Results

In the Chinese cohort, seventy (17%) patients exhibited genomic alterations in HRR genes; ATM (9%), BRCA2 (4%), ATR (3%), RAD50 (3%) and BRIP1 (3%) were the most frequently mutated. In the MSK-IMPACT COAD cohort (immune checkpoint inhibitor-treated), HRR-mut patients (n=34) survived longer than HRR-wt patients (n=50) (log-rank P < 0.01). Based on the TCGA MSS COAD cohort, HRR gene mutations increased immune activities, such as infiltration of cytotoxic cells (P < 0.05) and exhausted CD8+ T cells (P < 0.01), and increased the IFN-? scores (P < 0.05). The results differed in MSI-H COAD patients (all P > 0.05).

Conclusion

HRR gene mutations significantly increased immune activities in MSS COAD patients, implying the feasibility of the HRR-mut status as an immunotherapy response predictor in MSS COAD.

SUBMITTER: Zhou P

PROVIDER: S-EPMC7880324 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

The mutational pattern of homologous recombination-related (HRR) genes in Chinese colon cancer and its relevance to immunotherapy responses.

Zhou Pei P Wu Xueying X Chen Huan H Hu Ying Y Zhang Henghui H Wu Lijia L Yang Ying Y Mao Beibei B Wang Huaqing H

Aging 20201209 2

<h4>Background</h4>Microsatellite-stable (MSS) colon adenocarcinoma (COAD) patients are not sensitive to immune checkpoint inhibitors. Here, we focused on analyzing the relationship between homologous recombination repair (HRR)-related gene mutations and clinical immunotherapy responses in MSS COAD.<h4>Methods</h4>The mutational landscape was profiled in a cohort of 406 Chinese COAD patients via next-generation sequencing (NGS). Correlations between HRR gene mutations and tumor immunity or clini ...[more]

PMID: 33318301

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Project description:BackgroundHomologous recombination deficiency (HRD) is a well-known biomarker which could predict poly-ADP ribose polymerase 1 (PARP) inhibitor and platinum drug response. As an aggressive cancer, small-cell lung cancer (SCLC) is sensitive to platinum drugs, but relapse occurs rapidly. Herein, we aim to illustrate the genomic alteration patterns of homologous recombination repair (HRR)-related genes in a Chinese SCLC cohort and further analyze the relationship among HRR gene mutations and known biomarkers of immune checkpoint inhibitor (ICI) response, including tumor mutation burden (TMB) and programmed cell death-ligand 1 (PD-L1) expression.MethodsNext-generation sequencing (NGS)-based target capture sequencing of 543 cancer-related genes was performed to analyze the genomic profiles of 133 Chinese SCLC patients, and TMB was calculated. PD-L1 expression was evaluated in 90 out of 133 patients using the SP142 PD-L1 immunohistochemistry assay.ResultsAmong the 133 patients with SCLC, 47 (35.3%) had HRR gene mutations. ATM (8.3%) was the most frequently mutated HRR gene in the cohort, followed by NBN (4.5%). Pathogenic somatic and germline mutations of HRR genes were identified in 11 (23.4%) and 4 (8.5%) patients, respectively. HRR gene mutations cooccurred with KMT2D gene mutations. There were several differences in genomic alterations between patients with HRR gene mutations (HRR-Mut) and without HRR mutations (HRR-WT). The results revealed that TP53 and RB1 were commonly mutated genes in both groups. Mutations in the KMT2D gene and genes in the RTK-RAS pathway occurred more frequently in the HRR-Mut group. Furthermore, we found that mutations in HRR genes were associated with high TMB (Wilcoxon, p = 0.048), but there was no correlation of HRR gene mutation status with PD-L1 expression.ConclusionsWe exhaustively describe the genomic alteration profile of Chinese SCLC patients and provide further evidence that HRR gene mutations are prevalent in SCLC patients.

Project description:PTEN mutation occurs in a variety of aggressive cancers and is associated with poor patient outcomes. Recent studies have linked mutational loss of PTEN to reduced RAD51 expression and function, a key factor involved in the homologous recombination (HR) pathway. However, these studies remain controversial, as they fail to establish a definitive causal link to RAD51 expression that is PTEN-dependent, while other studies have not been able to recapitulate the relationship between the PTEN expression and the RAD51/HR function. Resolution of this apparent conundrum is essential due to the clinically-significant implication that PTEN-deficient tumors may be sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) commonly used in the clinical management of BRCA-mutated and other HR-deficient (HRD) tumors.MethodsPrimary Pten-deficient (and corresponding wild-type) mouse embryonic fibroblasts (MEFs) and astrocytes and PTEN-null human tumor cell lines and primary cells were assessed for RAD51 expression (via the Western blot analysis) and DNA damage repair analyses (via alkali comet and γH2AX foci assays). RAD51 foci analysis was used to measure HR-dependent DNA repair. Xrcc2-deficient MEFs served as an HR-deficient control, while the stable knockdown of RAD51 (shRAD51) served to control for the relative RAD51/HR-mediated repair and the phospho-53BP1 foci analysis served to confirm and measure non-homologous end joining (NHEJ) activity in PTEN-deficient and shRAD51-expressing (HRD) lines. Cell proliferation studies were used to measure any potential added sensitivity of PTEN-null cells to the clinically-relevant PARPi, olaparib. RAD51 levels and DNA damage response signaling were assessed in PTEN-mutant brain tumor initiating cells (BTICs) derived from primary and recurrent glioblastoma multiforme (GBM) patients, while expression of RAD51 and its paralogs were examined as a function of the PTEN status in the RNA expression datasets isolated from primary GBM tumor specimens and BTICs.ResultsPten knockout primary murine cells display unaltered RAD51 expression, endogenous and DNA strand break-induced RAD51 foci and robust DNA repair activity. Defective HR was only observed in the cells lacking Xrcc2. Likewise, human glioblastoma multiforme (GBM) cell lines with known PTEN deficiency (U87, PTEN-mutated; U251 and U373, PTEN-null) show apparent expression of RAD51 and display efficient DNA repair activity. Only GBM cells stably expressing shRNAs against RAD51 (shRAD51) display dysfunctional DNA repair activity and reduced proliferative capacity, which is exacerbated by PARPi treatment. Furthermore, GBM patient-derived BTICs displayed robust RAD51 expression and intact DNA damage response signaling in spite of PTEN-inactivating mutations. RNA expression analysis of primary GBM tissue specimens and BTICs demonstrate stable levels of RAD51 and its paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and DMC1), regardless of the PTEN mutational status.ConclusionsOur findings demonstrate definitively that PTEN loss does not alter the RAD51 expression, its paralogs, or the HR activity. Furthermore, deficiency in PTEN alone is not sufficient to impart enhanced sensitivity to PARPi associated with HRD. This study is the first to unequivocally demonstrate that PTEN deficiency is not linked to the RAD51 expression or the HR activity amongst primary neural and non-neural Pten-null cells, PTEN-deficient tumor cell lines, and primary PTEN-mutant GBM patient-derived tissue specimens and BTICs.

Project description:Objective: This study used homologous recombination (HR) related signatures to develop a clinical prediction model for screening immune checkpoint inhibitors (ICIs) advantaged populations and identify hub genes in advanced metastatic urothelial carcinoma. Methods: The single-sample gene enrichment analysis and weighted gene co-expression network analysis were applied to identify modules associated with immune response and HR in IMvigor210 cohort samples. The principal component analysis was utilized to determine the differences in HR-related module gene signature scores across different tissue subtypes and clinical variables. Risk prediction models and nomograms were developed using differential gene expression analysis associated with HR scores, least absolute shrinkage and selection operator, and multivariate proportional hazards model regression. Additionally, hub genes were identified by analyzing the contribution of HR-related genes to principal components and overall survival analysis. Finally, clinical features from GSE133624, GSE13507, the TCGA, and other data sets were analyzed to validate the relationship between hub genes and tumor growth and mutation. Results: The HR score was significantly higher in the complete/partial response group than in the stable/progressive disease group. The majority of genes associated with HR were discovered to be involved in the cell cycle and others. Genomically unstable, high tumor level, and high immune level samples all exhibited significantly higher HR score than other sample categories, and higher HR scores were related to improved survival following ICIs treatment. The risk scores for AUNIP, SEPT, FAM72D, CAMKV, CXCL9, and FOXN4 were identified, and the training and verification groups had markedly different survival times. The risk score, tumor neoantigen burden, mismatch repair, and cell cycle regulation were discovered to be independent predictors of survival time following immunotherapy. Patients with a high level of expression of hub genes such as EME1, RAD51AP1, and RAD54L had a greater chance of surviving following immunotherapy. These genes are expressed at significantly higher levels in tumors, high-grade cancer, and invasive cancer than other categories, and are associated with TP53 and RB1 mutations. Conclusion: HR-related genes are upregulated in genomically unstable samples, the survival time of mUC patients after treatment with ICIs can be predicted using a normogram model based on HR signature.

Dataset Information

The mutational pattern of homologous recombination-related (HRR) genes in Chinese colon cancer and its relevance to immunotherapy responses.

Background

Methods

Results

Conclusion

Publications

The mutational pattern of homologous recombination-related (HRR) genes in Chinese colon cancer and its relevance to immunotherapy responses.

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