EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion

Cell ◽  
2021 ◽  
Author(s):  
Antonio Marzio ◽  
Emma Kurz ◽  
Jennifer M. Sahni ◽  
Giuseppe Di Feo ◽  
Joseph Puccini ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Homologous Recombination ◽  
Immune Evasion ◽  
Interferon Response ◽  
Homologous Recombination Repair ◽  
Recombination Repair

Abstract A091: Targeting homologous recombination repair defects in lung cancer

2019 ◽  
Author(s):  
Asli Muvaffak ◽  
Yinghui Zhou ◽  
Bin Feng ◽  
Sarah Wang ◽  
Jing Ju Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Homologous Recombination ◽  
Homologous Recombination Repair ◽  
Recombination Repair

Comprehensive analysis of somatic reversion mutations in homologous recombination repair genes in a large cohort of Chinese pan-cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15093-e15093
Author(s):  
Wen-Ming Cao ◽  
Hong Zong ◽  
Jian Zhang ◽  
Zhengyang Xu ◽  
HaiTao Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Homologous Recombination Repair ◽  
Platinum Based Chemotherapy ◽  
Recombination Repair ◽  
Somatic Reversion ◽  
Cancer Types ◽  
Pan Cancer

e15093 Background: Mutations leading to homologous recombination deficiency increases the sensitivity towards platinum-based chemotherapy, as well as the PARP inhibitor. The acquired resistance caused by reversion mutations diminishes the prolonged benefit from the treatment. Herein, we aimed to investigate the prevalence and characteristics of reversion mutations in Chinese population. Methods: The next-generation sequencing data from 23,712 pan-cancer patients (including over 17 cancer types) were retrospectively analyzed for pathogenic/likely pathogenic (P/LP) germline mutations in homologous recombination repair (HRR) genes and possible somatic reversion mutations emerged later. Somatic mutations predicted to restore the open reading frame were identified and further classified into definitive or putative reversion mutations depending on whether the somatic mutation could be confirmed to occur on the same allele as the germline mutation by sequencing reads. Results: From the 23,712 patients, 685 (2.9%) were identified with P/LP germline HRR gene mutations, among which we identified 11 cases with 21 definitive and 4 putative somatic reversion mutations upon treatment, including 8 cases of breast cancer, 3 cases of ovarian cancer, 1 case of pancreatic cancers, and another case of lung cancer. The reversion mutations occurred in 3 genes: BRCA1 (7 cases), BRCA2 (5 cases) and PALB2 (1 case), but not in any other HRR genes in our cohort. Therefore, the incidence of reversion mutations in HRR genes was 1.6% (11/685), with the highest incidence observed in BRCA1 (5.26%) followed by BRCA2 (2.7%) and PALB2 (1.96%). Interestingly, multiple somatic reversion mutations could be observed in 3 patients, indicating heterogeneity in the resistance mechanisms. Among 6 patients with detailed treatment history available, 5 of them had reversion mutations detected after systemic platinum-based chemotherapy and/or PARP inhibitor treatment. The other patient of metastatic breast cancer had 6 prior lines of treatment including 2 cycles of thoracic perfusion of endostatin and lobaplatin before BRCA2 reversion mutation was detected. This patient subsequently received olaparib monotherapy with a progression free survival of only 2 months. Conclusions: This retrospective study demonstrated that the reversion mutations were observed in three HRR-associated genes ( BRCA1, BRCA2 and PALB2) with four cancer types (breast cancer, ovarian cancer, lung cancer and pancreatic cancer) from this Chinese patient cohort. The reversion mutations frequently occurred after resistance to platinum-based chemotherapy and/or PARP inhibitor, and may predict poor outcome from ensuing PARP inhibition therapy. Therefore, monitoring HRR mutation status along the course of the disease could be beneficial especially to informing resistance mechanism and guiding subsequent therapies.

scholarly journals Germline Mutations in Other Homologous Recombination Repair-Related Genes Than BRCA1/2: Predictive or Prognostic Factors?

2021 ◽  
Vol 11 (4) ◽  
pp. 245
Author(s):  
Laura Cortesi ◽  
Claudia Piombino ◽  
Angela Toss
Keyword(s):  
Prognostic Factors ◽  
Homologous Recombination ◽  
Pancreatic Adenocarcinoma ◽  
Objective Response ◽  
Metastatic Breast ◽  
Germline Mutations ◽  
Response To Treatment ◽  
Homologous Recombination Repair ◽  
Dna Breaks ◽  
Recombination Repair

The homologous recombination repair (HRR) pathway repairs double-strand DNA breaks, mostly by BRCA1 and BRCA2, although other proteins such as ATM, CHEK2, and PALB2 are also involved. BRCA1/2 germline mutations are targeted by PARP inhibitors. The aim of this commentary is to explore whether germline mutations in HRR-related genes other than BRCA1/2 have to be considered as prognostic factors or predictive to therapies by discussing the results of two articles published in December 2020. The TBCRC 048 trial published by Tung et al. showed an impressive objective response rate to olaparib in metastatic breast cancer patients with germline PALB2 mutation compared to germline ATM and CHEK2 mutation carriers. Additionally, Yadav et al. observed a significantly longer overall survival in pancreatic adenocarcinoma patients with germline HRR mutations compared to non-carriers. In our opinion, assuming that PALB2 is a high-penetrant gene with a key role in the HRR system, PALB2 mutations are predictive factors for response to treatment. Moreover, germline mutations in the ATM gene provide a better outcome in pancreatic adenocarcinoma, being more often associated to wild-type KRAS. In conclusion, sequencing of HRR-related genes other than BRCA1/2 should be routinely offered as part of a biological characterization of pancreatic and breast cancers.

scholarly journals Current gene panels account for nearly all homologous recombination repair-associated multiple-case breast cancer families

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Thibaut S. Matis ◽  
Nadia Zayed ◽  
Bouchra Labraki ◽  
Manon de Ladurantaye ◽  
Théophane A. Matis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Large Fraction ◽  
Homologous Recombination Repair ◽  
Mutational Signatures ◽  
Recombination Repair ◽  
Multiple Case ◽  
Gene Panels ◽  
Tumor Dna

AbstractIt was hypothesized that variants in underexplored homologous recombination repair (HR) genes could explain unsolved multiple-case breast cancer (BC) families. We investigated HR deficiency (HRD)-associated mutational signatures and second hits in tumor DNA from familial BC cases. No candidates genes were associated with HRD in 38 probands previously tested negative with gene panels. We conclude it is unlikely that unknown HRD-associated genes explain a large fraction of unsolved familial BC.

318 Olaparib plus pembrolizumab in patients with previously treated advanced solid tumors with homologous recombination repair mutation and/or homologous recombination repair deficiency: KEYLYNK-007

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A344-A344
Author(s):  
Timothy A Yap ◽  
Mallika Dhawan ◽  
Andrew E Hendifar ◽  
Michele Maio ◽  
Taofeek K Owonikoko ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Homologous Recombination ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Homologous Recombination Repair ◽  
Advanced Solid Tumors ◽  
Repair Deficiency ◽  
Recombination Repair ◽  
Modified Recist ◽  
Previously Treated

BackgroundTreatment with the anti–PD-1 antibody pembrolizumab has improved clinical outcomes in multiple previously treated advanced solid tumors. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity as monotherapy in patients with previously treated advanced ovarian, breast, pancreatic, and prostate cancers with BRCA1/BRCA2 mutations (BRCAm). Activity was also seen in patients with previously treated advanced solid tumors with other homologous recombination repair mutation (HRRm) and in those with ovarian cancer with homologous recombination repair deficiency (HRD) phenotype. PARP inhibitors have been found to increase interferon signaling and tumor infiltrating lymphocytes, enhancing tumor susceptibility to immune checkpoint blockade. Antitumor activity of PD-(L)1 plus PARP inhibition was found to be higher than expected with either agent alone in patients with recurrent ovarian cancer regardless of BRCAm or HRD status and in patients with BRCAm breast cancer. KEYLYNK-007 (NCT04123366) evaluates the antitumor activity and safety of olaparib in combination with pembrolizumab in patients with previously treated advanced solid tumors with HRRm and/or HRD.MethodsThis phase 2, nonrandomized, multicenter, open-label study will enroll approximately 300 patients aged ≥18 years with histologically/cytologically confirmed, previously treated, advanced solid tumors with HRRm and/or HRD per Lynparza HRR-HRD assay (Foundation Medicine, Inc., Cambridge, MA, USA), with an ECOG PS of 0-1. Patients will be grouped by biomarker status: subgroup 1: BRCAm; subgroup 2: HRRm without BRCAm; and subgroup 3: HRD positive without HRRm (loss of heterozygosity score ≥16 per Lynparza HRR-HRD assay). Patients will receive olaparib 300 mg twice daily + pembrolizumab 200 mg intravenously Q3W (35 cycles) until PD, unacceptable AEs, intercurrent illness, investigator decision, withdrawal of consent, or pregnancy. Tumor imaging assessment by blinded independent central review (BICR) per RECIST v1.1 or Prostate Cancer Working Group (PCWG)–modified RECIST v1.1 for prostate cancer will occur Q9W for 12 months, then Q12W until PD, start of new anticancer treatment, withdrawal of consent, pregnancy, or death. AEs will be monitored throughout the study and for 30 days after final dose (90 days for serious AEs). The primary endpoint is ORR (RECIST v1.1 or PCWG–modified RECIST version 1.1 by BICR). Secondary endpoints include duration of response (DOR) and PFS (RECIST v1.1 or PCWG–modified RECIST v1.1 by BICR), OS, and safety. Point estimate and exact Clopper-Pearson CI for ORR, and Kaplan-Meier estimates for DOR, PFS, and OS will be calculated. A total of 89 sites are currently enrolling in 20 countries.ResultsN/AConclusionsN/ATrial RegistrationClinicalTrials. gov identifier, NCT04123366Ethics ApprovalAn independent institutional review board or ethics committee approved the protocol at each study site, and the trial is being conducted in compliance with Good Clinical Practice guidelines and the Declaration of Helsinki.

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