Increased frequency of CHD1 deletions in prostate cancers of African American men is associated with distinct homologous recombination deficiency associated DNA aberration profiles

AbstractBackgroundAfrican American (AA) men have significantly higher mortality rates from prostate cancer (PC) than individuals of European ancestry (EA). Therapeutically targetable molecular differences may hold the potential to reduce this disparity.ObjectiveTo investigate chromodomain helicase DNA-binding protein 1 (CHD1) deletion both as a cause of aggressive disease and therapeutic vulnerability in the prostate cancer of AA men.Design, setting, and participants91 AA and 109 EA prostate cancer cases were analyzed by fluorescence in situ hybridization (FISH) for the deletion of CHD1. Whole exome and whole genome sequencing data from prostate adenocarcinoma cases were analyzed for mutational signatures from AA and EA individuals.Outcome measurements and statistical analysisAssociations with biochemical recurrence were evaluated using Cox proportional hazard regression models. Association between mutational signatures and CHD1 deletion were assessed by Wilcoxon ranked sum tests.Results and limitationsSubclonal deletion of CHD1 is nearly three times as frequent in prostate tumors of men than in EA men. CHD1 deletion is associated with some of the homologous recombination deficiency associated mutational signatures in prostate cancer. In a cell line model CHD1 deletion induced 1-10 kb deletions resembling those induced by BRCA2 deficiency. CHD1 deficient cells showed markedly increased sensitivity to both talazoparib and the radiomimetic bleomycin.ConclusionsCHD1 is more frequently deleted in the prostate cancer of AA men. This deletion is both associated with and induces mutational signatures characteristic of BRCA2 deficiency. CHD1 deficient prostate cancer is more sensitive to talazoparib or bleomycin treatment.Patient summarySubclonal deletion of CHD1 is more frequent in the prostate cancer of AA men and this could be one of the reasons behind more aggressive disease. CHD1 deletion, however, also constitutes a therapeutic vulnerability to the PARP inhibitor talazoparib. This treatment may significantly improve the outcome of disease in AA men.

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Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer

10.1101/681114 ◽

2019 ◽

Cited By ~ 1

Author(s):

Zsofia Sztupinszki ◽

Miklos Diossy ◽

Marcin Krzystanek ◽

Judit Borcsok ◽

Mark Pomerantz ◽

...

Keyword(s):

Prostate Cancer ◽

Homologous Recombination ◽

Parp Inhibitor ◽

Next Generation Sequencing Data ◽

Parp Inhibition ◽

Sequencing Data ◽

Mutational Signatures ◽

Homologous Recombination Deficiency ◽

Platinum Based Chemotherapy ◽

Inhibitor Treatment

AbstractBackgroundProstate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. It is not clear, however, whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, rendering them sensitive to HR-directed therapies.To identify a more comprehensive set of prostate cancer cases with homologous recombination deficiency (HRD) including those cases that do not harbor mutations in known HR genes.HRD levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Whole genome (n=311) and whole exome sequencing data (n=498) of both primary and metastatic prostate adenocarcinomas (PRAD) were analyzed.ResultsKnown BRCA-deficient samples showed robust signs of HR-deficiency associated mutational signatures. HRD-patterns were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR related genes. Patients with HRD signatures had a significantly worse prognosis than patients without signs of HRD.ConclusionsThese findings may expand the number of cases likely to respond to PARP-inhibitor treatment. Based on the HRD associated mutational signatures, 5-8 % of prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).

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The TRITON clinical trial programme: Evaluation of the PARP inhibitor rucaparib in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination deficiency (HRD)

Annals of Oncology ◽

10.1093/annonc/mdx370.053 ◽

2017 ◽

Vol 28 ◽

pp. v291

Author(s):

S. Chowdhury ◽

W. Abida ◽

J. Arranz Arija ◽

G. Daugaard ◽

K. Fizazi ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

Homologous Recombination ◽

Parp Inhibitor ◽

Programme Evaluation ◽

Castration Resistant Prostate Cancer ◽

Homologous Recombination Deficiency ◽

Castration Resistant ◽

Clinical Trial Programme

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Novel Nomogram That Predicts Aggressive Disease and Treatment Failure Among African-American Men with Prostate Cancer

10.21236/ada613820 ◽

2014 ◽

Author(s):

Simeon J. Yamoah

Keyword(s):

Prostate Cancer ◽

African American ◽

Treatment Failure ◽

African American Men ◽

Aggressive Disease

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A subset of lung cancer cases shows robust signs of homologous recombination deficiency associated genomic mutational signatures

npj Precision Oncology ◽

10.1038/s41698-021-00199-8 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Miklos Diossy ◽

Zsofia Sztupinszki ◽

Judit Borcsok ◽

Marcin Krzystanek ◽

Viktoria Tisza ◽

...

Keyword(s):

Lung Cancer ◽

Homologous Recombination ◽

Cell Lines ◽

Cancer Cell ◽

Parp Inhibitor ◽

Cancer Cell Lines ◽

Lung Cancer Cell ◽

Mutational Signatures ◽

Homologous Recombination Deficiency ◽

Tumor Types

AbstractPARP inhibitors are approved for the treatment of solid tumor types that frequently harbor alterations in the key homologous recombination (HR) genes, BRCA1/2. Other tumor types, such as lung cancer, may also be HR deficient, but the frequency of such cases is less well characterized. Specific DNA aberration profiles (mutational signatures) are induced by homologous recombination deficiency (HRD) and their presence can be used to assess the presence or absence of HR deficiency in a given tumor biopsy even in the absence of an observed alteration of an HR gene. We derived various HRD-associated mutational signatures from whole-genome and whole-exome sequencing data in the lung adenocarcinoma and lung squamous carcinoma cases from TCGA, and in a patient of ours with stage IVA lung cancer with exceptionally good response to platinum-based therapy, and in lung cancer cell lines. We found that a subset of the investigated cases, both with and without biallelic loss of BRCA1 or BRCA2, showed robust signs of HR deficiency. The extreme platinum responder case also showed a robust HRD-associated genomic mutational profile. HRD-associated mutational signatures were also associated with PARP inhibitor sensitivity in lung cancer cell lines. Consequently, lung cancer cases with HRD, as identified by diagnostic mutational signatures, may benefit from PARP inhibitor therapy.

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