scholarly journals Landscape of homologous recombination deficiencies in solid tumours: analyses of two independent genomic datasets

BMC Cancer ◽  
2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Zhongwu Lai ◽  
Matthew Brosnan ◽  
Ethan S. Sokol ◽  
Mingchao Xie ◽  
Jonathan R. Dry ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Checkpoint Inhibitors ◽  
Parp Inhibitors ◽  
The Cancer Genome Atlas ◽  
Future Research ◽  
Allelic Loss ◽  
Similar Degree ◽  
Precision Oncology ◽  
Sequencing Data ◽  
Brca Mutations

Abstract Background DNA repair deficiencies are characteristic of cancer and homologous recombination deficiency (HRD) is the most common. HRD sensitizes tumour cells to PARP inhibitors so it is important to understand the landscape of HRD across different solid tumour types. Methods Germline and somatic BRCA mutations in breast and ovarian cancers were evaluated using sequencing data from The Cancer Genome Atlas (TCGA) database. Secondly, a larger independent genomic dataset was analysed to validate the TCGA results and determine the frequency of germline and somatic mutations across 15 different candidate homologous recombination repair (HRR) genes, and their relationship with the genetic events of bi-allelic loss, loss of heterozygosity (LOH) and tumour mutation burden (TMB). Results Approximately one-third of breast and ovarian cancer BRCA mutations were somatic. These showed a similar degree of bi-allelic loss and clinical outcomes to germline mutations, identifying potentially 50% more patients that may benefit from precision treatments. HRR mutations were present in sizable proportions in all tumour types analysed and were associated with high TMB and LOH scores. We also identified numerous BRCA reversion mutations across all tumour types. Conclusions Our results will facilitate future research into the efficacy of precision oncology treatments, including PARP and immune checkpoint inhibitors.

scholarly journals PARP Inhibitors in Melanoma—An Expanding Therapeutic Option?

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4520
Author(s):  
Wei Yen Chan ◽  
Lauren J. Brown ◽  
Lee Reid ◽  
Anthony M. Joshua
Keyword(s):  
Homologous Recombination ◽  
Synthetic Lethality ◽  
Checkpoint Inhibitors ◽  
Therapeutic Option ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Brca Mutations ◽  
Immune Priming ◽  
Combination Strategies ◽  
Damage Repair

Immunotherapy has transformed the treatment landscape of melanoma; however, despite improvements in patient outcomes, monotherapy can often lead to resistance and tumour escape. Therefore, there is a need for new therapies, combination strategies and biomarker-guided decision making to increase the subset of patients most likely to benefit from treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors act by synthetic lethality to target tumour cells with homologous recombination deficiencies such as BRCA mutations. However, the application of PARP inhibitors could be extended to a broad range of BRCA-negative cancers with high rates of DNA damage repair pathway mutations, such as melanoma. Additionally, PARP inhibition has the potential to augment the therapeutic effect of immunotherapy through multi-faceted immune-priming capabilities. In this review, we detail the immunological role of PARP and rationale for combining PARP and immune checkpoint inhibitors, with a particular focus on a subset of melanoma with homologous recombination defects that may benefit most from this targeted approach. We summarise the biology supporting this combined regimen and discuss preclinical results as well as ongoing clinical trials in melanoma which may impact future treatment.

scholarly journals Effect of Different Expression of Immune-Related lncRNA on Colon Adenocarcinoma and Its Relation to Prognosis

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Meiwei Mu ◽  
Yi Tang ◽  
Zheng Yang ◽  
Yuling Qiu ◽  
Xiaohong Li ◽  
...  
Keyword(s):  
Cox Regression ◽  
Colon Adenocarcinoma ◽  
The Cancer Genome Atlas ◽  
Risk Scores ◽  
Future Research ◽  
Sequencing Data ◽  
Tissue Samples ◽  
Gene Sets ◽  
Cancer Genome Atlas ◽  
Immune Related Genes

Objective. To explore the expression of immune-related lncRNAs in colon adenocarcinoma and find out the effect on how these lncRNAs influence the development and prognosis of colon adenocarcinoma. Method. Transcriptome data of colon adenocarcinoma from The Cancer Genome Atlas (TCGA) were downloaded, and gene sets “IMMUNE RESPONSE” and “IMMUNE SYSTEM PROCESS” were sought from the Molecular Signatures Database (MSigDB). The expression of immune-related genes was extracted that were immune-related mRNAs. Then, the immune-related lncRNAs were sought out by utilizing of the above data. Clinical traits were combined with immune-related lncRNAs, so that prognostic-related lncRNAs were identified by Cox regression. Multivariate Cox regression was built to calculate risk scores. Relationships between clinical traits and immune-related lncRNAs were also calculated. Result. A total of 480 colorectal adenocarcinoma patients and 41 normal control patients’ transcriptome sequencing data of tissue samples were obtained from TCGA database. 918 immune-related lncRNAs were screened. Cox regression showed that 34 immune-related lncRNAs were associated with colon adenocarcinoma prognosis. Seven lncRNAs were independent risk factors. Conclusion. This study revealed that some lncRNAs can affect the development and prognosis of colon adenocarcinoma. It may provide new theory evidence of molecular mechanism for the future research and molecular targeted therapy of colon adenocarcinoma.

scholarly journals Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Daniel R. Principe ◽  
Matthew Narbutis ◽  
Regina Koch ◽  
Ajay Rana
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Synthetic Lethality ◽  
Parp Inhibitors ◽  
The Cancer Genome Atlas ◽  
Parp Inhibition ◽  
Repair Pathway ◽  
Wide Range ◽  
Recombination Pathway ◽  
Pan Cancer

AbstractPARP inhibitors have shown remarkable efficacy in the clinical management of several BRCA-mutated tumors. This approach is based on the long-standing hypothesis that PARP inhibition will impair the repair of single stranded breaks, causing synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination. While this is now well accepted and has been the basis of several successful clinical trials, emerging evidence strongly suggests that mutation to several additional genes involved in homologous recombination may also have predictive value for PARP inhibitors. While this notion is supported by early clinical evidence, the mutation frequencies of these and other functionally related genes are largely unknown, particularly in cancers not classically associated with homologous recombination deficiency. We therefore evaluated the mutation status of 22 genes associated with the homologous recombination DNA repair pathway or PARP inhibitor sensitivity, first in a pan-cancer cohort of 55,586 patients, followed by a more focused analysis in The Cancer Genome Atlas cohort of 12,153 patients. In both groups we observed high rates of mutations in a variety of HR-associated genes largely unexplored in the setting of PARP inhibition, many of which were associated also with poor clinical outcomes. We then extended our study to determine which mutations have a known oncogenic role, as well as similar to known oncogenic mutations that may have a similar phenotype. Finally, we explored the individual cancer histologies in which these genomic alterations are most frequent. We concluded that the rates of deleterious mutations affecting genes associated with the homologous recombination pathway may be underrepresented in a wide range of human cancers, and several of these genes warrant further and more focused investigation, particularly in the setting of PARP inhibition and HR deficiency.

scholarly journals Pharmacologic induction of innate immune signaling directly drives homologous recombination deficiency

2020 ◽  
Vol 117 (30) ◽  
pp. 17785-17795
Author(s):  
Lena J. McLaughlin ◽  
Lora Stojanovic ◽  
Aksinija A. Kogan ◽  
Julia L. Rutherford ◽  
Eun Yong Choi ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Dna Methyltransferase ◽  
Innate Immune ◽  
The Cancer Genome Atlas ◽  
Epigenetic Therapy ◽  
Brca Mutations ◽  
Cancer Subtypes ◽  
Dna Methyltransferase Inhibitors ◽  
Repair Mechanisms

Poly(ADP ribose) polymerase inhibitors (PARPi) have efficacy in triple negative breast (TNBC) and ovarian cancers (OCs) harboring BRCA mutations, generating homologous recombination deficiencies (HRDs). DNA methyltransferase inhibitors (DNMTi) increase PARP trapping and reprogram the DNA damage response to generate HRD, sensitizing BRCA-proficient cancers to PARPi. We now define the mechanisms through which HRD is induced in BRCA-proficient TNBC and OC. DNMTi in combination with PARPi up-regulate broad innate immune and inflammasome-like signaling events, driven in part by stimulator of interferon genes (STING), to unexpectedly directly generate HRD. This inverse relationship between inflammation and DNA repair is critical, not only for the induced phenotype, but also appears as a widespread occurrence in The Cancer Genome Atlas datasets and cancer subtypes. These discerned interactions between inflammation signaling and DNA repair mechanisms now elucidate how epigenetic therapy enhances PARPi efficacy in the setting of BRCA-proficient cancer. This paradigm will be tested in a phase I/II TNBC clinical trial.

Correlation between JAK1/2 expression and immune-related genes and JAK2 gene variants: A pan-cancer analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15057-e15057
Author(s):  
Lichao Xu ◽  
Ding Zhang ◽  
Guoqiang Wang ◽  
Chao Chen ◽  
Ying Wang ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Copy Number ◽  
Checkpoint Inhibitors ◽  
The Cancer Genome Atlas ◽  
Gene Variants ◽  
Missense Mutations ◽  
Sequencing Data ◽  
Primary Resistance ◽  
Immune Related Genes ◽  
Pan Cancer

e15057 Background: Loss of function mutations for Janus kinases 1/2 (JAK1/2) have shown to be the underling mechanism of primary resistance to immune checkpoint inhibitors (ICIs). However, the correlation between JAK1/2 expression and immune-related genes have not been studied. Methods: Survival, mRNA expression and whole-exome sequencing data from 32 pan-cancer atlas studies were obtained from The Cancer Genome Atlas (TCGA). Correlations between JAK1/2 expression and immune-related genes were depicted in heatmaps. We also analyzed the association between JAK2 gene variants and JAK2 expression. Results: In total, 10071 samples with mRNA expression data were included for analysis. Expression of 46 immune-related genes were positively correlated with JAK2 expression in 25 tumors instead of JAK1 expression. Patients with higher expression of JAK2 had better prognosis than patients with lower expression of JAK2 in 13 tumors. Among 10071 patients, 363 (3.60%) patients harbored JAK2 variants, including 8 with frame shift mutations, 44 with nonsense mutations, 142 with missense mutations, 11 with splices, 8 with fusions, 90 with copy-number reduction and 116 with copy-number amplification. There was no difference in JAK2 expression between patients with JAK2 variants and those without JAK2 variants. However, JAK2 fusion (2.20%, 8/363) and amplification (31.96%, 116/363) were associated with higher JAK2 expression. Conclusions: Our pan-cancer analysis found that JAK2 expression was correlated with immune-related genes and the prognosis of cancer patients. JAK2 fusion and amplification increased the expression of JAK2. Altogether, patients with high JAK2 expression may benefit from ICIs.

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 Identification of RB1 Gene as a Immune-Related Prognostic Signature Based on Tumor Mutation Burdens in Bladder Cancer

2021 ◽  
Author(s):  
Ming Chen ◽  
Hong Cheng ◽  
Tiange Wu ◽  
Zeping Gui ◽  
Ying Gao ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Immune Cells ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Cancer Genome ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Sequencing Data ◽  
Poor Overall Survival ◽  
Mutant Type

Abstract Background: Bladder cancer (BC) is known as the eleventh most common malignant tumor all over the world, for either males or females. Developing effective regimens targeting more promising biomarkers aiming for better prognosis are required. Immune checkpoint inhibitors (ICI) have been demonstrated as a prospective and practical means to resist cancers. Theoretically, adequate infiltration of immune cells indicates more immunotherapy targets and may promise better prognosis.Methods: Full transcriptome data (n=433), clinical information (n=581) and mutation sequencing (n=412) were obtained freely from The Cancer Genome Atlas and independent mutation sequencing data of 101 samples were acquired from International Cancer Genome Consortium. Statistical processing was conducted using R packages with R x64 4.0.2. Gene biologically functional research was performed with gene set enrichment analysis (GSEA) based on Kyoto Encyclopedia of Genes and Genomes (KEGG) database. 22 types of immune cell infiltration were assessed and calculated in 398 samples of BC tumors.Results: Tumor mutation burdens (TMB) of mutant type groups were higher than wild type groups for 19 genes, except for FGFR3 and CREBBP verifying that genomic mutation associates positively with TMB in BC tumor. Kaplan-Meier analysis showed high mutation frequency on RB1 had a negative effect on prognosis of BC patients and RB1 was an independent prognostic factor (p=0.004, HR=1.776) in BC. It was also demonstrated that RB1 mainly participate in singling pathways of cell proliferation and cell cycle. Proportions and correlation of 22 types of immune cells in 433 samples were determined. Immune cells with similar function are inclined to co-exist in tumor microenvironment of BC. Among them, regulatory T cells (Tregs) were detected as a negatively correlated type immune cell to mutation of RB1 that probably increases the incidence of tumor immune escaping in BC.Conclusion: RB1 can be identified as an independent prognostic predictor, and there is a chance for contribution to poor overall survival as the mutation occurs. What's more, mutation of RB1 also functions as a biomarker that represses the infiltration of Tregs, increasing the incidence of tumor immune escaping in BC.

Homologous recombination deficiency in ovarian cancer and beyond

2016 ◽  
Vol 4 (2) ◽  
pp. 17-22
Author(s):  
Ilary Ruscito ◽  
Susana Banerjee
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Cell Transformation ◽  
Parp Inhibitors ◽  
Molecular Signature ◽  
Current Evidence ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Homologous Recombination Deficiency ◽  
Response To Chemotherapy

It has been well established that failure in the homologous recombination repair (HRR) mechanism for DNA double strand repair causes genomic instability and increases the risk for cell transformation. Mutations in BRCA1 and BRCA2 are currently known to be the most frequent responsible for homologous recombination deficiency (HRD) but HRD can occur through other processes including mutations and epigenetic aberration of HRD-related genes and the indirect interaction of BRCA proteins with other proteins involved in the DNA repair. Current efforts in this field are concentrating in identifying an HRD molecular signature able to predict response to chemotherapy and PARP inhibitors, thus allowing to extend novel targeted treatments beyond germline BRCA mutated ovarian cancer patients. The aim of this brief review is to summarize the current evidence regarding HRD beyond germline BRCA mutations and therapeutic approaches.

Mutation in homologous recombination to predict a better prognosis in endometrial cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6082-6082
Author(s):  
Luyang Zhao ◽  
Dai Yibo ◽  
Yuanjin Hu ◽  
Zhiqi Wang ◽  
Chengcheng Li ◽  
...  
Keyword(s):  
T Cells ◽  
Endometrial Cancer ◽  
Homologous Recombination ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
The Cancer Genome Atlas ◽  
Research Network ◽  
Sequencing Data ◽  
Activated T Cells ◽  
Endometrial Cancers

6082 Background: Endometrial cancers have been categorized into four genomic classes by The Cancer Genome Atlas Research Network (TCGA) with comprehensive genomic analysis. However, TCGA molecular subtypes are hard to utilize in clinic as the expensive cost and a simply version of POLE, TP53 genes cannot fully differentiate the four subtypes. Therefore, more convenient and reliable biomarkers need to be identified for clinical practice. Methods: Whole-exome sequencing and RNA sequencing data for 515 patients with endometrial carcinomas were downloaded from TCGA. Mutations in 48 genes of homologous recombination repair (HR) signaling were defined as HR mutation. Associations between HR mutation and survival and RNA expression were analyzed.Gene set enrichment analysis (GSEA) were used to invesgate the gene signaling. Results: HR mutation was associated with a prolonged disease specific survival (DSS) (HR, 0.39; 95% CI, 0.22-0.71; P = 0.002), progression-free survival (PFS) (HR, 0.46; 95% CI, 0.31-0.68; P < 0.001) and overall survival (OS) (HR, 0.45; 95% CI, 0.28-0.72; P = 0.001) in endometrial cancers. HR mutation was related with clinical characteristics including histological types (P < 0.05). In the multivariable cox proportional hazards regression model including FIGO 2008, histology types, tumor grade and TCGA subtypes, TP53 mutation, POLE mutation, the association between HR mutation and PFS was still significant (HR, 0.48; 95% CI, 0.27-0.86; P < 0.05), which indicating the HR mutation is an independent prognostic factor for PFS. HR mutations were associated with a higher tumor mutation burden. GSEA suggested that HR mutation was involved with the increase of genes related to activated T cells, immune cytolytic activity, and IFN-γ release. In MSS endometrial cancers, HR mutation still showed a longer PFS (HR, 0.57; 95% CI, 0.34-0.98; P = 0.04), suggested HR mutation may help predict the effect of immunotherapy in MSS endometrial carcinoma. Conclusions: HR mutation was related with a favorable prognosis through increasing T cells signature. Identification of HR mutation by genomic profiling provides a potentially novel and convenient approach for endometrial cancer patients to predict the prognosis independent of TCGA four subtype classifications and provides an inspiration for screening patients who may benefit from ICBs in endometrial cancer in the future.

Plasma ctDNA sequencing supplementary to tissue-based molecular profiling as a source of additional actionable information in advanced cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15554-e15554
Author(s):  
Bradley Allen Hancock ◽  
Swee Seong Wong ◽  
Saloni Sinha ◽  
Tom Barber ◽  
Benjamin A. Salisbury ◽  
...  
Keyword(s):  
Liquid Biopsy ◽  
Tumor Tissue ◽  
Brca1 Mutation ◽  
Molecular Data ◽  
Parp Inhibitors ◽  
Molecular Profiling ◽  
Tumor Board ◽  
Precision Oncology ◽  
Sequencing Data ◽  
Targeted Interventions

e15554 Background: The standard for tumor molecular profiling in precision oncology is the tissue-based biopsy. However, tissue biopsies are limited in the ability to capture the bulk of heterogeneity in advanced cancers. The integration of liquid biopsy diagnostics complementary to tissue-based sequencing may provide a broader perspective of heterogeneity and actionability. Methods: Patients with metastatic solid tumors were evaluated in the Indiana University Health Precision Genomics (PG) Program. We retrospectively analyzed existing genomic data from matched plasma and tissue that were collected within a 90-day window. Plasma sequencing was generated with a CLIA-certified test: FoundationACT/FoundationLiquid. Tumor tissue sequencing was performed either with CLIA-grade whole exome or a gene-panel. All sequencing data was reviewed by a molecular tumor board for the determination of a personalized treatment strategy. Molecular data for this analysis was concatenated and analyzed for mutations present in ctDNA but absent in tissue. Clinical actionability was defined based on clinical evidence of a biomarker to guide therapy or match a patient to a clinical trial. Results: 288 subjects with tissue- and plasma-derived mutation data were analyzed. Discordance, defined by the presence of a somatic mutation in the plasma that was not present in the tumor tissue, was detected in 156/288 (54%) of pairs. Interestingly, the discordance was clinically actionable in 26/288 (9%) subjects. In the 32 gene-level instances of actionable discordance, the 3 top mutated genes were PIK3CA (7), PTEN (4), and EGFR (4). Discordant mutations in ATM and CHEK2, which are actionable with PARP inhibitors, but also frequently mutated in clonal hematopoiesis of indeterminant potential (CHIP) represented 4/26 (15%) instances. A complete and formal CHIP analysis is ongoing. As a result of plasma discordance, targeted interventions were employed in 3/26 (12%) subjects targeting high TMB with immunotherapy, an ERBB2 mutation with ado-trastuzumab emtansine, and a BRCA1 mutation with olaparib. All 3 patients were non-responders. Conclusions: Discordant mutations that appear in ctDNA but not in matched tumor tissue is a common occurrence. The majority of these mutations are either not druggable or variants of unknown significance, but a significant subset would be deemed clinically actionable. Clinical efficacy of targeted intervention based on actionable liquid biopsy discordance warrants further investigation.

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