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.

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.

Germline and somatic mutations in 25 hereditary breast and ovarian cancer related genes and platinum-based chemotherapy response among Chinese patients with epithelial ovarian cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18088-e18088
Author(s):  
Lei Li ◽  
Ming Wu ◽  
Changbin Zhu ◽  
Di Shao ◽  
Meng Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Somatic Mutation ◽  
Deleterious Mutation ◽  
Homologous Recombination Repair ◽  
Chemotherapy Response ◽  
Deleterious Mutations ◽  
Breast And Ovarian Cancer ◽  
Platinum Based Chemotherapy ◽  
Recombination Repair

e18088 Background: Insight on the germline and somatic mutation in BRCA1/2 was predictable on the sensitivity on platinum-based therapy. The therapeutic impact of mutations in other hereditary breast and ovarian cancer related genes is uncertain. Methods: We sought to investigate the germline and somatic deleterious mutations through all exons in 25 hereditary breast and ovarian cancer related genes in paired blood and frozen tumor samples from 235 Chinese women diagnosed with epithelial ovarian carcinomas. Results: Forty-seven subjects (24.6%) had a germline deleterious mutation, and 126 subjects (66%) had a somatic deleterious mutation. Thirty-four (17.8%) had both a germline and somatic mutation. Of the 203 germline and somatic deleterious mutations, 114 (56.2%) occurred in TP53, 41 (20.2%) in BRCA1, 11 (5.4%) in BRCA2 and 37 (23.6%) in 13 other genes: ATM, BARD1, BRIP1, CDH1, CHEK2, MLH1, MRE11A, MSH2, NF1, PALB2, PTEN, RAD51C and, STK11. In 235 patients, 215 (91.5%) and 20 (8.5%) cases were sensitive and resistant to the platinum-based chemotherapy. In the whole population, homologous recombination repair (HRR) mutations, non- homologous recombination repair(non-HRR) mutations, mismatch repair (MMR) mutations had no impact on the platinum-based chemotherapy response. No significant difference in platinum response were found in HRR, non-HRR and MRR mutation(P = 0.788). In 235 patients, ones with ATM (10), CHEK2(9), NF1(5), PALB2(8), PTEN (8) mutations were available for platinum response information; Among them, there were three patients with either ATM, CHEK2 or PALB2 mutation presented platinum resistance. Conclusions: Multi-gene panel testing of germline and somatic HBOC related gene mutations was feasible to characterize a comprehensive molecular profile of ovarian cancer and showed non-BRCA gene stratification potential value in predicting patient’s response for platinum-based chemotherapy.

Frequency of homologous recombination repair alterations in ovarian cancer in Chinese population.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17531-e17531
Author(s):  
Tongtong Yang ◽  
Huanhuan Liu ◽  
Mingwei Li ◽  
Yanrui Zhang ◽  
Yun Zhang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Chinese Population ◽  
Parp Inhibitors ◽  
Homologous Recombination Repair ◽  
Non Invasive ◽  
Recombination Repair ◽  
The Difference ◽  
Brca1 Brca2 ◽  
Tumor Dna

e17531 Background: Ovarian Cancer (OC) is the most lethal cancer of all gynecological malignancies.Circulating tumor DNA (ctDNA) has received substantial attention in recent years resulting from the non-invasive, safe and effective method with considerable potential for clinical diagnosis and treatment management in patients with OC. Here, we assessed the mutational feature in homologous recombination repair (HRR) using ctDNA in OC. Methods: Plasma ctDNA was isolated from blood of patients and then was analyzed by AcornMed Biotechnology NGS-based assay for 808 genes panel for genomic alterations. The somatic and germline pathogenic mutations were identified in 12 HRR genes (ATM, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, PALB2, RAD51B, RAD51C, RAD51D, RAD54L). Results: At our institution, 85 patients underwent NGS analysis of ovarian cancer specimens. The median age was 57 (range from 26 to 83). Twenty-six patients(42.34%) harbored a mutation in at least 1 of the HRR genes in their tumor. The most commonly altered HRR gene was BRCA1 (18.25%), followed by BRCA2 (8.76%), ATM (5.84%), RAD51D(3.65%), CHEK2 (2.92%), FANCA(2.19%) and RAD51C (0.73%). To determine the difference of mutation landscape in HRR between Chinese and western populations, we compared prevalence and spectrum in cases between our cohort and the cohort of Heeke et al 1(Table). Prevalence of HRR were different from the Western cases(42.34% vs 20%, P＜0.05). Of note, BRCA1, BRCA2, ATM and CHEK2 alterations rate was higher in our cohort, and BRIP1 and PALB2 were only detected in the western cohort. Conclusions: CtDNA can characterize the mutational feature of HRR in OC. Around 42.3% of patients with OC harbour germline or somatic HRR mutations. The expanded use of PARP inhibitors in HRR deficient tumours using a signature of HRR by ctDNA in clinical practice requires validation.[Table: see text]

scholarly journals Panobinostat enhances olaparib efficacy by modifying expression of homologous recombination repair and immune transcripts in ovarian cancer

Neoplasia ◽  
2022 ◽  
Vol 24 (2) ◽  
pp. 63-75
Author(s):  
Andrew J. Wilson ◽  
Vijayalaxmi G Gupta ◽  
Qi Liu ◽  
Fiona Yull ◽  
Marta A. Crispens ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Homologous Recombination Repair ◽  
Recombination Repair
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