Abstract 2055: Evaluation of DNA damage repair gene alterations, microsatellite instability status, and tumor mutational burden as predictive biomarkers of olaparib sensitivity in gastric cancer

2021 ◽  
Author(s):  
Jihyun Hwang ◽  
Woo sun Kwon ◽  
Juin Park ◽  
Hyun Joo Bae ◽  
Inhye Jeong ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Damage ◽  
Microsatellite Instability ◽  
Dna Damage Repair ◽  
Predictive Biomarkers ◽  
Repair Gene ◽  
Mutational Burden ◽  
Damage Repair ◽  
Tumor Mutational Burden ◽  
Gene Alterations

Association between germline DNA damage repair-related genes mutation and tumor mutational burden in lung cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21163-e21163
Author(s):  
Wei Nie ◽  
Hua Zhong ◽  
Ding Zhang ◽  
Shiqing Chen ◽  
Baohui Han
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Gene Mutations ◽  
Related Gene ◽  
Mutational Burden ◽  
Damage Repair ◽  
Tumor Mutational Burden ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

e21163 Background: Deleterious somatic DNA damage repair (DDR) gene mutations are frequent in non-small cell lung cancer (NSCLC) and are associated with improved clinical outcomes of immunotherapy. DDR gene mutations are associated with higher tumor mutational burden (TMB) in cancer. However, the effect of germline DDR-related genes mutation with different functional annotations on TMB in NSCLC patients is still unclear. Methods: 1671 Chinese patients with NSCLC were enrolled in this study. Genomic profiling was performed on formalin-fixed paraffin-embedded tumor samples or peripheral blood by next generation sequencing (NGS) with 733 cancer-related genes panel. The germline mutation data were obtained. All annotations in clinical significance were according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines. Results: 1076 patients (64.39%) had germline DDR-related gene mutations and 595 (35.61%) had no germline DDR-related gene mutations. Among patients with DDR-related gene mutations, 78 (7.25%) patients had the pathogenic (P) mutations or likely pathogenic (LP) mutations and 1056 (98.14%) had variants of unknown significance (VOUS) mutations. In total, the median TMB was 3.91 mutations/MB (range, 0-68.16) and 4.47 mutations/MB (range, 0-51.40) in patients with P, LP or VOUS mutations and no germline DDR-related gene mutations, respectively. To the further analysis, we divided patients with germline DDR-related gene mutations into three groups: only P or LP mutations (Group 1), only VOUS mutations (Group 2) and concurrence with P/LP/VOUS mutations (Group 3). Compare to the DDR-negative group, TMB was significantly lower in Group 2 (P < 0.001). No significant differences in Group 1 and Group 3 were observed. In addition, we found that mutations in different DDR pathway could not affect TMB value significantly. Conclusions: Germline DNA damage repair-related genes mutation may be not associated with TMB.

Association of alterations in DNA damage repair and Notch pathways with high tumor mutational burden in patients with cervical cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17511-e17511
Author(s):  
Dongling Zou ◽  
Zirong Li ◽  
Jing Liu ◽  
Yunong Gao ◽  
Hong Zheng ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Enrichment Analysis ◽  
Pathway Enrichment Analysis ◽  
Pathway Enrichment ◽  
Mutational Burden ◽  
Damage Repair ◽  
Tumor Mutational Burden ◽  
Notch Pathways

e17511 Background: The outstanding efficacy of pembrolizumab reported in study KEYNOTE-158 led to FDA approval of pembrolizumab in the treatment of patients (pts) with positive PD-L1 expression (CPS ≥1) cervical cancer (CC) and tumor mutational burden-high [TMB-H, ≥10 mutations/megabase (mut/Mb)] solid tumors including CC. This study aims to investigate the immunotherapy-related molecular characteristics in pts with CC. Methods: The study recruited pts with CC whose tissues were send to perform parallel hybridization-based next-generation sequencing and/or immunohistochemistry of PD-L1 with 22C3 assay. KEGG pathway enrichment analysis was conducted to explore whether the differentiated mutated genes (DMGs) that were more frequently mutated in the TMB-H cohort were enriched in certain pathways. In addition, pair-wise comparison of TMB and PD-L1 was analyzed to identify the proportion of pts who might benefit from immunotherapy. Results: Among 249 pts with TMB evaluated, median TMB was 5 muts/Mb (range: 0 - 58.56 muts/Mb). The prevalence of microsatellite instability was 1.2% (3/255). The threshold of TMB was defined as 10 muts/Mb according to KEYNOTE-158. Consequently, 47 pts were considered as TMB-H and 202 pts were TMB-L. Regardless that TERC amplification was only found in the TMB-L group (9.5%, 19/202), Fisher’s exact test identified 98 genes with significantly higher alteration frequency in the TMB-H group compared with TMB-L group, including MLL2/3, TERT, PIK3CA, LRP1B, EP300 and ARID1A. Pathway enrichment analysis suggested that these DMGs were mainly enriched in mismatch repair, Notch, homologous recombination and Fanconi anemia pathways. There was no evident correlation between TMB and MSI (spearman r=0.2401, p=0.0101). The positivity rate of TMB or PD-L1 was 71.9%. Conclusions: Mutations in DNA damage repair and Notch pathways may explain TMB-H in pts with CC who might may serve as surrogate markers for TMB in CC.

scholarly journals DNA Damage Repair Gene Set as a Potential Biomarker for Stratifying Patients with High Tumor Mutational Burden

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 528
Author(s):  
To-Yuan Chiu ◽  
Ryan Weihsiang Lin ◽  
Chien-Jung Huang ◽  
Da-Wei Yeh ◽  
Yu-Chao Wang
Keyword(s):  
Dna Damage ◽  
Clinical Practice ◽  
Dna Damage Repair ◽  
Mutation Status ◽  
Gene Set ◽  
Mutational Burden ◽  
Damage Repair ◽  
Potential Biomarker ◽  
Tumor Mutational Burden ◽  
Cancer Types

Tumor mutational burden (TMB) is a promising predictive biomarker for cancer immunotherapy. Patients with a high TMB have better responses to immune checkpoint inhibitors. Currently, the gold standard for determining TMB is whole-exome sequencing (WES). However, high cost, long turnaround time, infrastructure requirements, and bioinformatics demands have prevented WES from being implemented in routine clinical practice. Panel-sequencing-based estimates of TMB have gradually replaced WES TMB; however, panel design biases could lead to overestimation of TMB. To stratify TMB-high patients better without sequencing all genes and avoid overestimating TMB, we focused on DNA damage repair (DDR) genes, in which dysfunction may increase somatic mutation rates. We extensively explored the association between the mutation status of DDR genes and TMB in different cancer types. By analyzing the mutation data from The Cancer Genome Atlas, which includes information for 33 different cancer types, we observed no single DDR gene/pathway in which mutation status was significantly associated with high TMB across all 33 cancer types. Therefore, a computational algorithm was proposed to identify a cancer-specific gene set as a surrogate for stratifying patients with high TMB in each cancer. We applied our algorithm to skin cutaneous melanoma and lung adenocarcinoma, demonstrating that the mutation status of the identified cancer-specific DDR gene sets, which included only 9 and 14 genes, respectively, was significantly associated with TMB. The cancer-specific DDR gene set can be used as a cost-effective approach to stratify patients with high TMB in clinical practice.

scholarly journals A DNA damage repair gene‐associated signature predicts responses of patients with advanced soft‐tissue sarcoma to treatment with trabectedin

2021 ◽  
Author(s):  
David S. Moura ◽  
Maria Peña‐Chilet ◽  
Juan Antonio Cordero Varela ◽  
Ramiro Alvarez‐Alegret ◽  
Carolina Agra‐Pujol ◽  
...  
Keyword(s):  
Dna Damage ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Dna Damage Repair ◽  
Advanced Soft Tissue Sarcoma ◽  
Repair Gene ◽  
Damage Repair

scholarly journals Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1289 ◽  
Author(s):  
Xing Bian ◽  
Wenchu Lin
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Repair ◽  
Predictive Biomarkers ◽  
Replication Stress ◽  
Genotoxic Stress ◽  
Repair System ◽  
Damage Repair ◽  
Repair Pathways

Small cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate of SCLC to standard treatment, almost all patients are invariably relapsed within one year. Effective therapeutic strategies are urgently needed to improve clinical outcomes. Replication stress is a hallmark of SCLC due to several intrinsic factors. As a consequence, constitutive activation of the replication stress response (RSR) pathway and DNA damage repair system is involved in counteracting this genotoxic stress. Therefore, therapeutic targeting of such RSR and DNA damage repair pathways will be likely to kill SCLC cells preferentially and may be exploited in improving chemotherapeutic efficiency through interfering with DNA replication to exert their functions. Here, we summarize potentially valuable targets involved in the RSR and DNA damage repair pathways, rationales for targeting them in SCLC treatment and ongoing clinical trials, as well as possible predictive biomarkers for patient selection in the management of SCLC.

scholarly journals DISTRIBUTION OF DNA DAMAGE REPAIR GENE POLYMORPHISM hOGG1, XRCC1 and p53 AMONG SICKLE CELL DISEASE PATIENTS IN INDIA

2015 ◽  
Vol 7 ◽  
pp. e2015046 ◽  
Author(s):  
Sudhansu Sekhar Nishank
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Sickle Cell Disease ◽  
Gene Polymorphisms ◽  
Clinical Effect ◽  
Dna Damage Repair ◽  
Cell Disease ◽  
Repair Gene ◽  
Damage Repair ◽  
Repair Genes

Background– Defect in DNA damage repair genes due to oxidative stress predispose the humans to malignancies. There are many cases of association of malignancies with sickle cell disease patients (SCD) throughout the world, the molecular cause of which has never been investigated. DNA damage repair genes such as  hOGG1, XRCC1 and p53 play significant role in repair of DNA damage during oxidative stress but the distribution and clinical effect of these genes are not known till date in SCD patients who are associated with oxidative stress related clinical complications.        Objective – The aim of the study was to characterize the distribution and clinical effect of DNA damage gene polymorphisms p53 (codon 72 Arg> Pro), hOGG1 (codon 326 Ser>Cyst) and XRCC1 (codons 194 Arg>Trp, codon 280 Arg> His, codon 399 Arg> Gln) among SCD patients of  central India. Methods- A case control study of  250 SCD patients and 250 normal individuals were investigated by PCR-RFLP techniques.     Result- The prevalence of mutant alleles of hOGG1 gene, XRCC1 codon 280 Arg>His  were found to be significantly high among SCD patients as compared to controls. However, SCD patients did not show clinical association with any of these DNA repair gene polymorphisms.  Conclusion- This indicates that hOGG1, p53  and XRCC1 gene polymorphisms  may not have any clinical impact among SCD patients in India.

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