scholarly journals The deubiquitylating enzyme USP15 regulates homologous recombination repair and cancer cell response to PARP inhibitors

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yihan Peng ◽  
Qingchao Liao ◽  
Wei Tan ◽  
Changmin Peng ◽  
Zhaohua Hu ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Cancer Cell ◽  
Cell Response ◽  
Parp Inhibitors ◽  
Homologous Recombination Repair ◽  
Recombination Repair

Laboratory cross-comparison of homologous recombination repair mutation analysis in tumor in a multicenter epithelial ovarian cancer series: The BORNEO GEICO 60-0 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17550-e17550
Author(s):  
Ignacio Romero ◽  
Ana Oaknin ◽  
Zaida Garcia-Casado ◽  
Raul Marquez ◽  
Alfonso Yubero Esteban ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Epithelial Ovarian Cancer ◽  
Mutational Analysis ◽  
Figo Stage ◽  
Parp Inhibitors ◽  
Homologous Recombination Repair ◽  
Recombination Repair ◽  
Class 1 ◽  
Uncertain Significance

e17550 Background: In epithelial ovarian cancer (EOC), the identification of mutations in homologous recombination repair (HRR) genes on tumor is prognostic, predictive of response to PARP inhibitors, and a tool to identify individuals at genetic cancer risk. The aim of this study is to compare the concordance between two laboratories in identifying and classifying genetic variants in HRR genes. Methods: In a multicentre ambispective series of unselected, non mucinous EOC of all stages formalin-fixed and paraffin embedded tumors were collected. These samples underwent the same mutational analysis of 15 HRR genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L) in two different Laboratories (Lab1, Lab2) that used their own validated multi-gene NGS panels. Variant allele frequency (VAF) threshold was 5% for single nucleotide polymorphism and 10% for indels. Large rearrangements were not analyzed. Variants were classified into three categories based on ACMG criteria: non-mutated (class 1-2), Variants of Uncertain Significance (VUS: class 3) and likely pathogenic/pathogenic (class 4-5). Results: A total of 81 cases were sent for the analysis. One had low DNA quality and therefore 80 cases were finally studied (85% high grade serous and 74% FIGO stage III-IV). Results reported by Lab1 and Lab2 (lab1/Lab2) were the following: 21/19 (26%/24%) cases had BRCA1/2 mutations, 7/8 (8.7%/10%) mutations on other HRR genes including two in ATM and RAD51D, one in CHEK1, CHEK2, and FANCL and one RAD51C reported in Lab2 only while the rest were either VUS 23/27 (29%/34%) or non-mutated 29/26 (36%/33%). Concordance between laboratories in classifying patients was 93.75% (kappa coefficient 0.86). Discrepancies (DC) on variants were classified into arbitrary categories, namely 0= complete concordance, category 1 meaning DC in detection assumed to be due to tumor heterogeneity (VAF nearby the threshold) or technique (1A), or caused by laboratories performance and avoidable (1B) and the category 2 identified DC in interpretation without clinical relevance (2A) or clinically relevant (2B), the results of total number of variants are shown in table. Overall, regarding clinically relevant DC in HRR genes, 9 DC in variants were observed including six 2B, two 1A and one 1B and they affect 5 (6.3%) patients since some were overlapping. Conclusions: In our EOC series the concordance of two Laboratories in the identification of clinically relevant HRR mutations on tumor is high but discrepancies in interpretation remain a challenge that needs further harmonization.[Table: see text]

Decision analysis for secondline maintenance treatment of platinum sensitive recurrent ovarian cancer: a review

2020 ◽  
Vol 30 (5) ◽  
pp. 684-694
Author(s):  
Rebecca Arend ◽  
Shannon Neville Westin ◽  
Robert L Coleman
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Maintenance Treatment ◽  
Recurrent Ovarian Cancer ◽  
Parp Inhibitors ◽  
Homologous Recombination Repair ◽  
Specific Patient ◽  
Link Type ◽  
Platinum Sensitive ◽  
Recombination Repair

Most women with ovarian cancer experience disease relapse, presenting numerous treatment challenges for clinicians. Maintenance therapy in the relapsed setting aims to extend the time taken for a cancer to progress, thus delaying the need for additional treatments. Four therapies are currently approved in the USA for secondline maintenance treatment of platinum sensitive, recurrent ovarian cancer: one antivascular endothelial growth factor agent (bevacizumab) and three poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors (olaparib, niraparib, and rucaparib). In addition to efficacy, maintenance therapies must have a good tolerability profile and no significant detrimental impact on quality of life, as patients who receive maintenance are generally free from cancer related symptoms. Data from key bevacizumab trials (OCEANS, NCT00434642; GOG-0213, NCT00565851; MITO16B, NCT01802749) and PARP inhibitor trials (Study 19, NCT00753545; SOLO2, NCT01874353; NOVA, NCT01847274; ARIEL3, NCT01968213) indicate that bevacizumab and the PARP inhibitors are effective in patients with platinum sensitive, recurrent ovarian cancer but differ in their tolerability profiles. In addition, the efficacy of PARP inhibitors is dependent on the presence of homologous recombination repair deficiency, with patients with the deficiency experiencing greater responses from treatment compared with those who are homologous recombination repair proficient. Allowing for caveats of cross trial comparisons, we advise that clinicians account for the following points when choosing whether and when to administer a secondline maintenance treatment for a specific patient: presence of a homologous recombination repair deficient tumor; the patient’s baseline characteristics, such as platelet count and blood pressure; mode of administration of therapy; and consideration of future treatment options for thirdline and later therapy.

The prognostic significance of homologous recombination repair pathway alterations in metastatic hormone-sensitive prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 150-150
Author(s):  
Justin Shaya ◽  
Aaron Lee ◽  
Angelo Cabal ◽  
Justine Panian ◽  
James Michael Randall ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Cox Regression ◽  
De Novo ◽  
Prognostic Significance ◽  
Parp Inhibitors ◽  
Homologous Recombination Repair ◽  
Significant Difference ◽  
Recombination Repair ◽  
Hormone Sensitive

150 Background: Little is known about the clinical course of patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC) who harbor alterations in the homologous recombination repair (HRR) pathway. Here, we examine the outcomes of men with mHSPC with HRR alterations. Methods: Single center, retrospective analysis of men with mHSPC who underwent next generation sequencing from 2015-2020. The primary endpoint was to assess the time from diagnosis of mHSPC to onset of castrate resistance (mCRPC), as defined by PCWG3 criteria, in pts with HRR alterations vs wild type (WT). Both somatic and germline HRR alterations were permitted. Univariate and multivariate Cox regression were used to assess the effect of HRR alterations on time to mCRPC. Secondary endpoints included time to mCRPC stratified by HRR gene and time to treatment failure (TTF) in HRR altered vs WT pts, stratified by therapy. Results: We identified 151 men with mHSPC for the study. Median age was 66 years and 62% (n = 93) had de novo metastatic disease. 25% (n = 37) had HRR alterations detected and the most common alterations were in BRCA2 (n = 15), ATM (n = 10), CDK12 (n = 7). 78.4% (n = 29) of alterations were somatic and 13.5% (n = 5) of pts had co-alterations in 2 HRR genes. Time to mCRPC was significantly decreased in pts with HRR alterations vs WT (12.7 vs 16.1 mos, HR- 1.95, p- 0.02). In multivariate analysis, the effect of HRR alterations on time to mCRPC remained statistically significant when adjusting for age, mHSPC therapy, presence of visceral metastases, and PSA (adjusted HR- 1.69, p-0.02). Stratified by individual HRR gene, pts with BRCA2, CDK12, or co-occurring alterations had significantly decreased time to mCRPC compared to other HRR alterations (Table). In terms of mHSPC therapy, 45.7% were treated with ADT alone, 27.8% with an androgen receptor signaling inhibitor (ARSI), and 26.5% with docetaxel. TTF was inferior in HRR altered vs WT pts (10.8 vs 13.8 mos, p-0.004, HR- 1.84). Stratified by therapy, TTF was inferior in HRR altered vs WT pts treated with ADT alone (8.9 vs 13.3 mos, p- 0.019, HR-1.94) and there was no significant difference in TTF in HRR altered vs WT pts treated with either the addition of an ARSI or docetaxel. Conclusions: HRR alterations are associated with worsened outcomes in mHSPC patients. Given the established role of PARP inhibitors in mCRPC, these data highlight an opportunity to explore the use of PARP inhibitors in mHSPC to potentially improve outcomes. [Table: see text]

Research progress of PARP inhibitor monotherapy and combination therapy for endometrial cancer.

2021 ◽  
Vol 22 ◽  
Author(s):  
Ke Shen ◽  
Li Yang ◽  
Fei-Yan Li ◽  
Feng Zhang ◽  
Lei-Lei Ding ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Homologous Recombination ◽  
Tumor Cells ◽  
Checkpoint Inhibitors ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Research Progress ◽  
Homologous Recombination Repair ◽  
Recombination Repair

: Endometrial cancer is one of the three most common malignant tumors in the female reproductive system. Advanced and recurrent endometrial cancers have poor prognoses and lack effective treatments. Poly(ADP-ribose) polymerase (PARP) inhibitors have been applied to many different types of tumors, and they can selectively kill tumor cells that are defective in homologous recombination repair. Endometrial cancer is characterized by mutations in homologous recombination repair genes; accordingly, PARP inhibitors have achieved positive results in off-label treatments of endometrial cancer cases. Clinical trials of PARP inhibitors as monotherapies and within combination therapies for endometrial cancer are ongoing. For this review, we searched PubMed with "endometrial cancer" and "PARP inhibitor" as keywords, and we used "olaparib", "rucaparib", "niraparib" and "talazoparib" as search terms in clinicaltrials.gov for ongoing trials. The literature search ended in October 2020, and only English-language publications were selected. Multiple studies confirm that PARP inhibitors play an important role in killing tumor cells with defects in homologous recombination repair. Its combination with immune checkpoint inhibitors, PI3K/AKT/mTOR pathway inhibitors, cell cycle checkpoint inhibitors, and other drugs can improve the treatment of endometrial cancer.

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

2016 ◽  
Vol 23 (10) ◽  
pp. T19-T37 ◽  
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.

scholarly journals Regulation of DNA Damage Response and Homologous Recombination Repair by microRNA in Human Cells Exposed to Ionizing Radiation

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1838
Author(s):  
Magdalena Szatkowska ◽  
Renata Krupa
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Ionizing Radiation ◽  
Dna Damage Response ◽  
Cell Response ◽  
Dna Lesions ◽  
Homologous Recombination Repair ◽  
Recombination Repair ◽  
Damage Response ◽  
Radiation Induced

Ionizing radiation may be of both artificial and natural origin and causes cellular damage in living organisms. Radioactive isotopes have been used significantly in cancer therapy for many years. The formation of DNA double-strand breaks (DSBs) is the most dangerous effect of ionizing radiation on the cellular level. After irradiation, cells activate a DNA damage response, the molecular path that determines the fate of the cell. As an important element of this, homologous recombination repair is a crucial pathway for the error-free repair of DNA lesions. All components of DNA damage response are regulated by specific microRNAs. MicroRNAs are single-stranded short noncoding RNAs of 20–25 nt in length. They are directly involved in the regulation of gene expression by repressing translation or by cleaving target mRNA. In the present review, we analyze the biological mechanisms by which miRNAs regulate cell response to ionizing radiation-induced double-stranded breaks with an emphasis on DNA repair by homologous recombination, and its main component, the RAD51 recombinase. On the other hand, we discuss the ability of DNA damage response proteins to launch particular miRNA expression and modulate the course of this process. A full understanding of cell response processes to radiation-induced DNA damage will allow us to develop new and more effective methods of ionizing radiation therapy for cancers, and may help to develop methods for preventing the harmful effects of ionizing radiation on healthy organisms.

scholarly journals Loss of CtIP disturbs homologous recombination repair and sensitizes breast cancer cells to PARP inhibitors

Oncotarget ◽  
2015 ◽  
Vol 7 (7) ◽  
pp. 7701-7714 ◽  
Author(s):  
Junhui Wang ◽  
Qianshan Ding ◽  
Hiroaki Fujimori ◽  
Akira Motegi ◽  
Yoshio Miki ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Parp Inhibitors ◽  
Homologous Recombination Repair ◽  
Recombination Repair

scholarly journals Homologous Recombination Repair Deficiency and Implications for Tumor Immunogenicity

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2249
Author(s):  
Sandra van Wilpe ◽  
Sofie H. Tolmeijer ◽  
Rutger H. T. Koornstra ◽  
I. Jolanda M. de Vries ◽  
Winald R. Gerritsen ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Parp Inhibitors ◽  
Homologous Recombination Repair ◽  
Multiple Tumor ◽  
Repair Deficiency ◽  
Recombination Repair ◽  
Tumor Immunogenicity

Homologous recombination repair deficiency (HRD) can be observed in virtually all cancer types. Although HRD sensitizes tumors to DNA-damaging chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors, all patients ultimately develop resistance to these therapies. Therefore, it is necessary to identify therapeutic regimens with a more durable efficacy. HRD tumors have been suggested to be more immunogenic and, therefore, more susceptible to treatment with checkpoint inhibitors. In this review, we describe how HRD might mechanistically affect antitumor immunity and summarize the available translational evidence for an association between HRD and antitumor immunity across multiple tumor types. In addition, we give an overview of all available clinical data on the efficacy of checkpoint inhibitors in HRD tumors and describe the evidence for using treatment strategies that combine checkpoint inhibitors with PARP inhibitors.

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