Prevalence of homologous recombination deficiency among all tumor types.

1502 Background: Triple negative breast and ovarian cancer are known to have a high frequency of homologous recombination deficiencies (HRDef). The prevalence of HRDef among all tumors is unknown. Methods: Molecular profiles of 48,733 tumors obtained from pts with bladder, breast, ovarian, pancreas, prostate, thyroid, cervical, hepatobiliary, colorectal (CRC), endometrial, gastric/esophageal (GE), head/neck, renal, non-small cell lung (NSCLC), small cell lung (SCLC), GIST, glioma, melanoma, sarcoma and unknown 1° cancers were reviewed to identify somatic pathogenic mutations (mut) in HR genes ATM, ATRX, BARD1, BLM, BRCA1/2, BRIP1, FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51, RAD51B, or WRN. Molecular profiles were generated from tumors submitted to Caris Life Sciences using multiple technologies including next generation sequencing (average read depth 500X). Results: Overall frequency of HR mut among all tumors is 11.61% (5658/48733). Cancer lineages with highest frequency of HR mut are endometrial (38.08%, 1956/5137), glioma (15.90%, 265/1667), ovarian (12.99%, 1151/8862), prostate (11.21%, 77/687), cervix (10.06%, 79/785) & breast (9.66%, 562/5818). Least commonly mutated lineages include GIST (1.50%, 3/200), sarcoma (3.12%, 55/1763), head/neck (3.70%, 24/648), hepatobiliary (4.72%, 39/827) & pancreas (5.05%, 102/2022). Frequencies of HR gene mutations are depicted in Table 1. Conclusions: HR mutations were seen in 11.61% of tumors. While the percentage of HRDef in pancreatic cancer pts is lower than what has been seen in other datasets, the percentage in breast and ovarian cancer, as well as the percentage of other tumors with HRDef, provide a path to employ HRDef-directed therapies such as platinums, but especially PARP inhibitors and newer agents such as ATRX inhibitors. [Table: see text]

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Comparison of molecular signatures in small cell lung cancer with or without homologous recombination associated gene mutations.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20580 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e20580-e20580

Author(s):

Lili Fu ◽

Feifei Li ◽

Dandan Ren ◽

Beibei Mao ◽

Huan Chen ◽

...

Keyword(s):

Lung Cancer ◽

Homologous Recombination ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Gene Mutations ◽

Small Cell ◽

Small Cell Lung ◽

Homologous Recombination Deficiency

e20580 Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. Recently, Immune checkpoint inhibitors (ICIs) have been shown to have the potential to improve the prognosis of SCLC, but little is known about immunotherapeutic biomarkers. Homologous recombination deficiency (HRD) is demonstrated to be a response predictor to immunotherapies in gynecologic cancers, while limited studies were reported in small cell lung cancer. Herein, we analyze the mutational pattern of HRR related genes in a Chinese SCLC cohort and further analyze the relationship between HRR-gene mutations and tumor mutational burden. Methods: Target gene sequencing (543 genes) was performed in 133 Genecast cohort with small cell lung cancer. PD-L1 expression were evaluated for 90 among 133 patients using the SP142 PD-L1 immunohistochemistry assay. Results: Among 133 patients, 47 (35.3%) had HRR-gene mutations. ATM (8.3%), NBN (4.5%) and BRCA2 (4.5%) were the top 3 mutated HRR-gene in the cohort，followed by ATR (3.8%), BARD1 (3.8%), BRCA1 (3.8%), PALB2 (3.8%), RAD50 (3.8%), CHEK2 (3.0%), BLM (3.0%), BRIP1(2.3%), CHEK1(1.5%), RAD52(1.5%), and MRE11A (0.8%). Pathogenic somatic and germline mutations of HRR genes were identified in 11 (11/47, 23.4%) and 3 (3/47, 6.4%) patients, respectively. 1 (1/47, 2.1%) patient carried both germline and somatic variants. Genomic landscape revealed that TP53 and RB1 were commonly mutated genes in SCLC cohort. Mutations in KMT2D, AR and RTK-RAS pathway occurred more frequently in the HRR-Mut group, compared with the wildtype ones. Furthermore, we found that mutations in HRR-gene were associated with high TMB (Wilcoxon, p = 0.048), and patients with high TMB (≥median) showed a higher proportion of positive PD-L1 expression in 90 SCLC patients. Conclusions: Our data indicated that genomic alterations associated with HRR-genes have a positive correlation with high TMB, and detection of HRR-gene mutation status probably could help identify patients who might benefit from immune checkpoint blockade therapy. Keywords: Small cell lung cancer, Homologous recombination deficiency, Immunotherapy.

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Prevalence of Homologous Recombination–Related Gene Mutations Across Multiple Cancer Types

JCO Precision Oncology ◽

10.1200/po.17.00286 ◽

2018 ◽

pp. 1-13 ◽

Cited By ~ 34

Author(s):

Arielle L. Heeke ◽

Michael J. Pishvaian ◽

Filipa Lynce ◽

Joanne Xiu ◽

Jonathan R. Brody ◽

...

Keyword(s):

Homologous Recombination ◽

Gene Mutations ◽

Cost Effective ◽

Illumina Miseq ◽

Read Depth ◽

Multiple Cancer ◽

Damage Repair ◽

Cost Effective Method ◽

Molecular Profiles ◽

Comprehensive Evaluations

Purpose The prevalence of homologous recombination DNA damage repair (HR-DDR) deficiencies among all tumor lineages is not well characterized. Therapy directed toward homologous recombination DDR deficiency (HRD) is now approved in ovarian and breast cancer, and there may be additional opportunities for benefit for patients with other cancers. Comprehensive evaluations for HRD are limited in part by the lack of a uniform, cost-effective method for testing and defining HRD. Methods Molecular profiles of 52,426 tumors were reviewed to identify pathogenic mutations in the HR-DDR genes ARID1A, ATM, ATRX, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, or WRN. From solid tumors submitted to Caris Life Sciences, molecular profiles were generated using next-generation sequencing (NGS; average read depth, 500×). A total of 17,566 tumors were sequenced with NGS600 (n = 592 genes), and 34,860 tumors underwent hotspot Illumina MiSeq platform testing (n = 47 genes). Results Of the tumors that underwent NGS600 testing, the overall frequency of HR-DDR mutations detected was 17.4%, and the most commonly mutated lineages were endometrial (34.4%; n = 1,475), biliary tract (28.9%; n = 343), bladder (23.9%; n = 201), hepatocellular (20.9%; n = 115), gastroesophageal (20.8%; n = 619), and ovarian (20.0%; n = 2,489). Least commonly mutated lineages included GI stromal (3.7%; n = 108), head and neck (6.8%; n = 206), and sarcoma (9.3%; n = 592). ARID1A was the most commonly mutated gene (7.2%), followed by BRCA2 (3.0%), BRCA1 (2.8%), ATM (1.3%), ATRX (1.3%), and CHEK2 (1.3%). Conclusions HR-DDR mutations were seen in 17.4% of tumors across 21 cancer lineages, providing a path to explore the role of HRD-directed therapies, including poly-ADP ribose polymerase inhibitors, DNA-damaging chemotherapies, and newer agents such as ATR inhibitors.

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Germline and somatic mutations of homologous recombination-associated genes in Japanese ovarian cancer patients

Scientific Reports ◽

10.1038/s41598-019-54116-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 7

Author(s):

Kentaro Sugino ◽

Ryo Tamura ◽

Hirofumi Nakaoka ◽

Nozomi Yachida ◽

Manako Yamaguchi ◽

...

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Cancer Patients ◽

Somatic Mutations ◽

Clear Cell ◽

Gene Mutations ◽

Parp Inhibitors ◽

Low Grade ◽

Mmr Genes ◽

Selection Of

AbstractWe explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p = 0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.

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Defects in homologous recombination repair behind the human diseases: FA and HBOC

Endocrine Related Cancer ◽

10.1530/erc-16-0221 ◽

2016 ◽

Vol 23 (10) ◽

pp. T19-T37 ◽

Cited By ~ 15

Author(s):

Yoko Katsuki ◽

Minoru Takata

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Molecular Mechanisms ◽

Genome Instability ◽

Cancer Therapeutics ◽

Parp Inhibitors ◽

Homologous Recombination Repair ◽

Breast And Ovarian Cancer ◽

Recombination Repair ◽

Exciting Development

Hereditary breast and ovarian cancer (HBOC) syndrome and a rare childhood disorder Fanconi anemia (FA) are caused by homologous recombination (HR) defects, and some of the causative genes overlap. Recent studies in this field have led to the exciting development of PARP inhibitors as novel cancer therapeutics and have clarified important mechanisms underlying genome instability and tumor suppression in HR-defective disorders. In this review, we provide an overview of the basic molecular mechanisms governing HR and DNA crosslink repair, highlightingBRCA2, and the intriguing relationship between HBOC and FA.

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Non-small cell lung cancer cells with deficiencies in homologous recombination genes are sensitive to PARP inhibitors

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2019.11.050 ◽

2020 ◽

Vol 522 (1) ◽

pp. 121-126

Author(s):

Wenchao Ji ◽

Xiang Weng ◽

Danhua Xu ◽

Shufan Cai ◽

Honggang Lou ◽

...

Keyword(s):

Lung Cancer ◽

Homologous Recombination ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Cell Lung Cancer ◽

Parp Inhibitors ◽

Small Cell ◽

Lung Cancer Cells ◽

Small Cell Lung

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Abstract 4189: Homologous recombination pathway-based biomarkers for treatment of non-small cell lung cancer with PARP inhibitors

10.1158/1538-7445.am2017-4189 ◽

2017 ◽

Cited By ~ 1

Author(s):

Peter V. Deraska ◽

Hunter D. Reavis ◽

Shelby Labe ◽

Alan D. D'Andrea ◽

David Kozono

Keyword(s):

Lung Cancer ◽

Homologous Recombination ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Parp Inhibitors ◽

Small Cell ◽

Small Cell Lung ◽

Homologous Recombination Pathway ◽

Recombination Pathway

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Translational Highlights in Breast and Ovarian Cancer 2019 – Immunotherapy, DNA Repair, PI3K Inhibition and CDK4/6 Therapy

Geburtshilfe und Frauenheilkunde ◽

10.1055/a-1039-4458 ◽

2019 ◽

Vol 79 (12) ◽

pp. 1309-1319 ◽

Cited By ~ 2

Author(s):

Andreas D. Hartkopf ◽

Volkmar Müller ◽

Achim Wöckel ◽

Michael P. Lux ◽

Wolfgang Janni ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Homologous Recombination ◽

Parp Inhibitor ◽

Complete Response ◽

Parp Inhibitors ◽

Breast And Ovarian Cancer ◽

First Line Therapy ◽

Recent Developments ◽

Patient Groups

AbstractIn the near future, important translational questions of clinical relevance will be adressed by studies currently in progress. On the one hand, the role of PD-L1 expression must be further understood, after it was found to be relevant in the use of atezolizumab in first-line therapy of patients with metastatic triple-negative breast cancer (TNBC). No association between efficacy and PD-L1 expression was found in a neoadjuvant study that included pembrolizumab in TNBC. The pathological complete response rate (pCR) was higher in both patient groups with and without PD-L1 expression when pembrolizumab was added to chemotherapy. Another future question is the identification of further patient groups in which efficacy of PARP inhibitors is seen, which are licensed for the pBRCA1/2 germline mutation. These include, for example, patients with mutations in other genes, which are involved in homologous recombination, or patients with tumours that show an abnormality in global tests of homologous recombination deficiencies (HRD tests). The question of whether a PARP inhibitor can be given and with which chemotherapy combination partners is currently being investigated in both breast and ovarian cancer. While the data on improved overall survival are being consolidated for the CDK4/6 inhibitors, knowledge of molecular changes during the therapy and during progression on the therapy is growing. Both the accumulation of PI3K mutations and also PTEN changes might play a part in planning subsequent therapies. This review article summarises these recent developments in breast cancer and in part also in ovarian cancer.

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Aberrant transcript usage induces homologous recombination deficiency and predicts therapeutic responses

10.1101/2021.08.31.21262939 ◽

2021 ◽

Author(s):

Jung Kyoon Choi

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Clinical Utility ◽

Parp Inhibitors ◽

Platinum Resistance ◽

Molecular Evidence ◽

Breast And Ovarian Cancer ◽

Aberrant Transcript ◽

Dna Damaging Agents ◽

Repair Genes

BRCA1/2 mutations account for only a small fraction of homologous recombination (HR) deficiency (HRD) cases. Recently developed genomic HRD (gHRD) tests suffer confounding factors causing low precision in predicting samples that will respond to poly (ADP-ribose) polymerase (PARP) inhibitors and DNA damaging agents. Here, we present molecular evidence and clinical utility of transcriptional HRD (tHRD) that is based on aberrant transcript usage (TU) of minor isoforms. Specifically, increased TU of non-functional isoforms of DNA repair genes was prevalent in breast and ovarian cancer with gHRD. Our functional assays validated its association with impaired HR activity. Remarkably, tHRD detection based on the TU pattern of key genes was superior to gHRD or BRCA1/2 screening in accuracy for predicting the responses of cell lines and cancer patients to PARP inhibitors and genotoxic drugs. In particular, this approach demonstrated the capability to reflect functional HR status, particularly when applied to our cohort of olaparib users with acquired platinum resistance in ovarian cancer. Hence, the tHRD-based diagnostic tests are expected to broaden the clinical utility of PARP inhibitors.

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