Pan-cancer landscape of homologous recombination deficiency

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Nov. 4, 2020

Abstract Homologous recombination deficiency (HRD) results in impaired double strand break repair and is a frequent driver of tumorigenesis. Here, we develop genome-wide mutational scar-based pan-cancer Classifier HOmologous Recombination Deficiency (CHORD) that can discriminate BRCA1 - BRCA2 -subtypes. Analysis metastatic ( n = 3,504) primary 1,854) cohort reveals HRD most ovarian breast cancer, followed by pancreatic prostate cancer. We identify biallelic inactivation , RAD51C or PALB2 as the common genetic cause HRD, with resulting -type HRD. find while specific cancer type specific, predominantly associated loss-of-heterozygosity (LOH), increased contribution deep deletions Our demonstrate value genomics-based testing its potential diagnostic for patient stratification towards treatment e.g. poly ADP-ribose polymerase inhibitors (PARPi).

Language: Английский

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PARP inhibition enhances tumor cell–intrinsic immunity in ERCC1-deficient non–small cell lung cancer

Journal of Clinical Investigation, Journal Year: 2018, Volume and Issue: 129(3), P. 1211 - 1228

Published: Dec. 27, 2018

The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non–small lung (NSCLC) exhibit an enhanced type I transcriptomic signature low expression correlates increased lymphocytic infiltration. We demonstrated clinical PARPi, including olaparib rucaparib, have cell-autonomous immunomodulatory properties in NSCLC BRCA1-defective triple-negative breast (TNBC) cells. Mechanistically, PARPi generated cytoplasmic chromatin fragments characteristics micronuclei; these were found cGAS/STING, downstream signaling, CCL5 secretion. Importantly, effects suppressed PARP1-null TNBC cells, suggesting this phenotype resulted from on-target effect on PARP1. also potentiated IFN-γ–induced PD-L1 fresh patient tumor cells; was ERCC1-deficient contexts. Our data provide a preclinical rationale for using agents appropriately molecularly selected populations.

Language: Английский

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Targeting the DNA damage response in immuno-oncology: developments and opportunities

Nature reviews. Cancer, Journal Year: 2021, Volume and Issue: 21(11), P. 701 - 717

Published: Aug. 10, 2021

Language: Английский

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Mutational signatures: emerging concepts, caveats and clinical applications

Nature reviews. Cancer, Journal Year: 2021, Volume and Issue: 21(10), P. 619 - 637

Published: July 27, 2021

Language: Английский

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Olaparib monotherapy as primary treatment in unselected triple negative breast cancer

Annals of Oncology, Journal Year: 2020, Volume and Issue: 32(2), P. 240 - 249

Published: Nov. 24, 2020

•We observed an objective response to olaparib in 18 out of 32 (56%) unselected, primary triple negative breast cancers.•Homologous recombination deficiency (HRD) was determined by targeted DNA sequencing and BRCA1 methylation.•HRD predictive present 16 responders.•HRD also beyond germline BRCA1/2 gPALB2 mutations; 12 14 responders.•Olaparib associated with minor side-effects did not influence subsequent tolerance chemotherapy. BackgroundThe antitumor efficacy PARP inhibitors (PARPi) for cancer patients harboring (gBRCA1/2) mutations is well established. While PARPi monotherapy ineffective metastatic (TNBC) wild type BRCA1/2, we hypothesized that may be effective TNBCs without previous chemotherapy exposure.Patients methodsIn the phase II PETREMAC trial, TNBC >2 cm received up 10 weeks before Tumor biopsies collected after underwent (360 genes) methylation analyses. In addition, BRCAness (multiplex ligation-dependent probe amplification), PAM50 gene expression, RAD51 foci, tumor-infiltrating lymphocytes (TILs) PD-L1 analyses were performed on pretreatment samples.ResultsThe median tumor diameter 60 mm (range 25-112 mm). Eighteen obtained (OR) (56.3%). Somatic or affecting homologous (HR) 10/18 responders [OR 55.6%, 95% confidence interval (CI) 33.7-75.4] contrasting 1/14 non-responders (OR 7.1%; CI 1.3-31.5, P = 0.008). Among tumors HR mutations, 6/8 versus 3/13 revealed hypermethylation (P 0.03). Thus, 16/18 (88.9%, 67.2-96.9), contrast 4/14 (28.6%, 11.7-54.7, 0.0008), carried and/or methylation. Excluding one four gBRCA1/2 mutation carriers, 12/14 (85.7%, 60.1-96.0) (23.1%, 8.2-50.3, 0.002) somatic signature basal-like subtype, low scores, high TIL expression all correlated response.ConclusionOlaparib yielded a clinical rate treatment-naïve revealing deficiency, mutations.Trial registrationClinicalTrials.gov identifier: NCT02624973. The exposure. samples. response. Olaparib mutations.

Language: Английский

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Mechanism, cellular functions and cancer roles of polymerase-theta-mediated DNA end joining

Nature Reviews Molecular Cell Biology, Journal Year: 2021, Volume and Issue: 23(2), P. 125 - 140

Published: Sept. 14, 2021

Language: Английский

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PARP inhibition in breast cancer: progress made and future hopes

npj Breast Cancer, Journal Year: 2022, Volume and Issue: 8(1)

Published: April 8, 2022

PARP inhibitors have been approved for the treatment of metastatic breast cancer in germline BRCA mutation (gBRCAm) carriers. The recent OlympiA trial demonstrated improved progression-free and distant disease-free survival with adjuvant olaparib gBRCAm carriers HER2-negative high-risk early-stage cancer. current article addresses some questions raised by regarding how to incorporate into as well future directions prevention.

Language: Английский

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Heterogeneity of triple negative breast cancer: Current advances in subtyping and treatment implications

Journal of Experimental & Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 41(1)

Published: Sept. 1, 2022

As the field of translational 'omics has progressed, refined classifiers at both genomic and proteomic levels have emerged to decipher heterogeneity breast cancer in a clinically-applicable way. The integration knowledge DNA, RNA protein is further expanding biologic understanding opportunities for customized treatment, particularly pressing need clinically triple negative tumors. For this group aggressive cancers, work from multiple groups now validated least four major biologically distinct omics-based subtypes. While date most clinical trial designs considered cancers as single group, with an arsenal targeted therapies applicable biological pathways, survival benefits may be best realized by designing analyzing trials context molecular RNA-based are developed, proposed based on new technologies potential more directly identify clinically-relevant biomarkers therapeutic targets. Phospho-proteomic data targetable signalling pathways unique subtype-specific manner. Single cell profiling tumor microenvironment represents promising way allow better characterization which could integrated spatially resolved build ecosystem-based patient classification. Multi-omic allows silico analysis genetic pharmacologic screens map vulnerabilities context. This review describes current about subtyping cancer, recent advances genomics proteomics diagnostics addressing diversity disease, key made through approaches, developments treatments including therapeutics being tested trials.

Language: Английский

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Synonymous mutations promote tumorigenesis by disrupting m6A-dependent mRNA metabolism

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer

Cancer Research, Journal Year: 2021, Volume and Issue: 81(11), P. 2888 - 2902

Published: April 22, 2021

Abstract Inactivation of Polybromo 1 (PBRM1), a specific subunit the PBAF chromatin remodeling complex, occurs frequently in cancer, including 40% clear cell renal carcinomas (ccRCC). To identify novel therapeutic approaches to targeting PBRM1-defective cancers, we used series orthogonal functional genomic screens that identified PARP and ATR inhibitors as being synthetic lethal with PBRM1 deficiency. The PBRM1/PARP inhibitor lethality was recapitulated using several clinical vitro model systems vivo xenograft ccRCC. In absence exogenous DNA damage, cells exhibited elevated levels replication stress, micronuclei, R-loops. exposure exacerbated these phenotypes. Quantitative mass spectrometry revealed multiple R-loop processing factors were downregulated tumor cells. Exogenous expression resolution enzyme RNase H1 reversed sensitivity PBRM1-deficient inhibitors, suggesting excessive R-loops could be cause this lethality. also induced cyclic GMP-AMP synthase/stimulator interferon genes (cGAS/STING) innate immune signaling Overall, findings provide preclinical basis for cancers. Significance: This study demonstrates are loss PBRM1, PBAF-specific subunit, thus providing rationale assessing patients cancer.

Language: Английский

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