Association between polymorphisms of DNA repair genes and survival of advanced NSCLC patients treated with platinum-based chemotherapy

Lung Cancer ◽  
2012 ◽  
Vol 75 (1) ◽  
pp. 102-109 ◽  
Author(s):  
Shengxiang Ren ◽  
Songwen Zhou ◽  
Fengyin Wu ◽  
Ling Zhang ◽  
Xuefei Li ◽  
...  
Keyword(s):  
Dna Repair ◽  
Advanced Nsclc ◽  
Dna Repair Genes ◽  
Platinum Based Chemotherapy ◽  
Nsclc Patients ◽  
Repair Genes

Comparative assessment of abiraterone or enzalutamide activity in the PROREPAIR-B study.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 164-164 ◽  
Author(s):  
Rebeca Lozano ◽  
Nuria Romero-Laorden ◽  
Angela del Pozo ◽  
Ana Medina ◽  
Maria Jose Mendez ◽  
...  
Keyword(s):  
Dna Repair ◽  
Progression Free Survival ◽  
Germline Mutations ◽  
Parp Inhibitors ◽  
Dna Repair Genes ◽  
Mutational Status ◽  
Platinum Based Chemotherapy ◽  
Brca1 Brca2 ◽  
The Impact ◽  
Repair Genes

164 Background: Germline mutations in DNA repair genes have been associated with poor prostate cancer outcomes in retrospectives studies. Such defects have been identified in 12% of mCRPC patients. Several studies are ongoing to assess the benefit of these patients from platinum-based chemotherapy and PARP inhibitors, but no conclusive data are available with regards to currently approved therapies for mCRPC, as Abiraterone or Enzalutamide. Methods: PROREPAIR-B (NCT03075735) is a prospective multicentre observational cohort study. Patients diagnosed with mCRPC, with unknown mutational status at study entry and who were going to start a first-line treatment for mCRPC were eligible. For this sub-analysis patients who received Abiraterone or Enzalutamide as first androgen receptor targeted therapy (ART) were selected. The endpoints of this sub-analysis included to assess the impact of BRCA1, BRCA2, ATM, PALB2 and other germline mutations in DNA repair genes on cause-specific survival (CSS), progression-free survival (PFS), time to PSA progression (bPFS) and response to the first ART received as 1st or 2nd line therapy. Results: 337 patients were eligible for this analysis. CSS from mCRPC was not significantly different between gDDR carriers and non-carriers. However, CSS from mCRPC in BRCA2 carriers was significantly shorter than in non-carriers (23.3 Vs 34.6 months, p = 0.02). CSS from first ART, PFS and response-rates were not significantly different between both groups. However, the bPFS was significantly shorter in patients harbouring gDDR mutations (7.3 Vs 3.8 months, p = 0.04), especially in BRCA2 carriers (7.3 Vs 3.0 months, p = 0.03). Conclusions: This is the first study to prospectively follow-up DNA repair germline mutations to determine the outcome on standard treatment for mCRPC. The results suggest that different gDDR defects may have different impact on mCRPC outcomes. Clinical trial information: NCT03075735.

Pilot investigation of variants in DNA repair pathways and association with response to platinum-based chemotherapy in bladder cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 343-343
Author(s):  
Ryan P. Kopp ◽  
Kelly Lynn Stratton ◽  
Ilana Rebecca Garcia-Grossman ◽  
Emily C. Zabor ◽  
Irina Ostrovnaya ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Dna Repair ◽  
Validation Cohort ◽  
Dna Repair Genes ◽  
Repair Pathway ◽  
First Line ◽  
Discovery Cohort ◽  
Platinum Based Chemotherapy ◽  
Phenotype Model ◽  
Repair Genes

343 Background: Germline single-nucleotide variations (SNVs) in DNA repair genes may have a role in response to platinum-based chemotherapy in bladder cancer (BC). As a pilot project we created a discovery cohort using an extreme phenotype model of BC response to neoadjuvant chemotherapy; we identified candidate SNVs in DNA repair genes via whole exome sequencing, and sought to replicate these findings in a validation cohort. Methods: We sequenced exomes of a discovery cohort with ≥ cT2 BC and neoadjuvant chemotherapy [6 complete responders (CR, pT0N0 and 1 year disease free interval) vs. 9 non-responders]. We identified SNVs within 377 DNA repair pathway genes. We filtered for SNVs with high impact effects, and moderate impact missense variants. The discovery phase resulted in 16 candidate SNVs which we genotyped (matrix-assisted laser desorption/ionization-time of flight) within a validation cohort of 303 BC patients treated with platinum-based neoadjuvant or first-line chemotherapy. Primary outcome was pathologic (neoadjuvant) or radiographic (first-line) CR, with secondary outcome CR+partial response (PR; RECIST criteria or pathologic downstaging). We used additive genetic model and logistic regression to analyze association between individual SNVs and both CR and CR+PR. Multivariate models included MSK risk score for CR or chemotherapy (cis- vs carboplatin) for CR+PR. Results: We included 303 patients (186 neoadjuvant, 117 first-line; 272 cisplatin, 31 carboplatin), median age 64, including 67 (22%) CR and 153 (50%) CR+PR. Genotyping was adequate for analysis in 14 of 16 SNVs—none were associated with CR. SNVs associated with CR+PR were rs2072454 (EGFR, p=0.031 unadjusted, p=0.035 adjusted for chemotherapy) and rs1805321 (PMS2, p=0.014 unadjusted, p=0.019 adjusted for chemotherapy). Findings were not significant after adjusting for multiple comparisons. Conclusions: Using an extreme phenotype model we identified SNVs in genes of the DNA repair pathway that may have an association with platinum-based chemotherapy response in BC. A larger validation study is required to increase power and reduce the impact of multiple testing prior to confirming significance.

scholarly journals Common Variations of DNA Repair Genes are Associated with Response to Platinum-based Chemotherapy in NSCLCs

2013 ◽  
Vol 14 (1) ◽  
pp. 145-148 ◽  
Author(s):  
Xian-Dong Li ◽  
Ji-Chang Han ◽  
Yi-Jie Zhang ◽  
Hong-Bing Li ◽  
Xue-Yan Wu
Keyword(s):  
Dna Repair ◽  
Dna Repair Genes ◽  
Platinum Based Chemotherapy ◽  
Repair Genes

Truncating variants in DNA-repair genes and their effect on AAO of hereditary breast cancer

2018 ◽  
Author(s):  
I Sepahi ◽  
U Faust ◽  
M Sturm ◽  
K Bosse ◽  
M Kehrer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Hereditary Breast Cancer ◽  
Dna Repair Genes ◽  
Repair Genes

scholarly journals Coexistence of SOS-Dependent and SOS-Independent Regulation of DNA Repair Genes in Radiation-Resistant Deinococcus Bacteria

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 924
Author(s):  
Laurence Blanchard ◽  
Arjan de Groot
Keyword(s):  
Dna Repair ◽  
Deinococcus Radiodurans ◽  
Dna Repair Genes ◽  
Lesion Bypass ◽  
Radiation Resistant ◽  
Radiation Induced ◽  
Induced Mutagenesis ◽  
High Doses ◽  
Translesion Polymerases ◽  
Repair Genes

Deinococcus bacteria are extremely resistant to radiation and able to repair a shattered genome in an essentially error-free manner after exposure to high doses of radiation or prolonged desiccation. An efficient, SOS-independent response mechanism to induce various DNA repair genes such as recA is essential for radiation resistance. This pathway, called radiation/desiccation response, is controlled by metallopeptidase IrrE and repressor DdrO that are highly conserved in Deinococcus. Among various Deinococcus species, Deinococcus radiodurans has been studied most extensively. Its genome encodes classical DNA repair proteins for error-free repair but no error-prone translesion DNA polymerases, which may suggest that absence of mutagenic lesion bypass is crucial for error-free repair of massive DNA damage. However, many other radiation-resistant Deinococcus species do possess translesion polymerases, and radiation-induced mutagenesis has been demonstrated. At least dozens of Deinococcus species contain a mutagenesis cassette, and some even two cassettes, encoding error-prone translesion polymerase DnaE2 and two other proteins, ImuY and ImuB-C, that are probable accessory factors required for DnaE2 activity. Expression of this mutagenesis cassette is under control of the SOS regulators RecA and LexA. In this paper, we review both the RecA/LexA-controlled mutagenesis and the IrrE/DdrO-controlled radiation/desiccation response in Deinococcus.

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