1545P DNA damage repair (DDR) gene mutations (mut) are predictors of response to platinum-based chemotherapy in advanced pancreatic cancer (PC) patients (pts)

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.

Download Full-text

Retrospective review of outcomes in patients with DNA-damage repair related pancreatic cancer

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-020-00148-9 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Sarah K. Macklin-Mantia ◽

Stephanie L. Hines ◽

Pashtoon M. Kasi

Keyword(s):

Pancreatic Cancer ◽

Dna Damage ◽

Retrospective Review ◽

Dna Damage Repair ◽

Damage Repair

Download Full-text

Radiosensitization of metformin in pancreatic cancer cells via abrogating the G2 checkpoint and inhibiting DNA damage repair

Cancer Letters ◽

10.1016/j.canlet.2015.08.015 ◽

2015 ◽

Vol 369 (1) ◽

pp. 192-201 ◽

Cited By ~ 24

Author(s):

Zheng Wang ◽

Song-Tao Lai ◽

Ning-Yi Ma ◽

Yun Deng ◽

Yong Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Dna Damage Repair ◽

G2 Checkpoint ◽

Pancreatic Cancer Cells ◽

Damage Repair

Download Full-text

Retrospective analysis of patients using olaparib (O) in pancreatic cancer (PC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.389 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 389-389

Author(s):

Erkut Hasan Borazanci ◽

Carol Guarnieri ◽

Susan Haag ◽

Ronald Lee Korn ◽

Courtney Edwards Snyder ◽

...

Keyword(s):

Pancreatic Cancer ◽

Dna Damage ◽

Dna Repair ◽

Retrospective Analysis ◽

Pearson Correlation ◽

Brca2 Mutation ◽

Dna Damage Repair ◽

Parp Inhibitors ◽

Damage Repair ◽

Repair Deficiency

389 Background: Molecular analysis has revealed four subtypes of PC giving clinicians further insight into treating this deadly disease. One subtype that was elucidated termed “unstable” is significant for the presence of DNA damage repair deficiency and can be targeted therapeutically. One such therapy, O, from the drug class poly ADP ribose polymerase (PARP) inhibitors, has already been FDA approved for individuals with BRCA mutated ovarian cancers. We performed a retrospective analysis on patients with PC treated at a single institution who have DNA damage repair deficiency mutations and have been treated with O. Methods: A chart review identified pancreatic cancer patients with DNA repair pathway mutations who were treated with O. The primary objective examined ORR in patients with PC with DNA repair mutations receiving O. Secondary objectives included tolerability, overall survival (OS), CA 19-9 change, and changes in quantitative textural analysis (QTA) on CT. Results: 11 individuals were identified, 5 carriers of a pathogenic germline (g) BRCA2 mutation, 1 carrier of a pathogenic g ATM mutation, 1 carrier of a pathogenic g BRCA1 mutation. Variants of uncertain significance (VUS) included 1 g ATM mutation, 1 g PALB2 mutation, 1 somatic (s) C11orf30 mutation, and 1 s BRCA2 mutation. Median age at diagnosis was 59, with 4 M and 7 F. No patients met criteria for familial PC and 7 had a family history consistent for breast and ovarian cancer syndrome. All individuals had metastatic PC and had progressed on at least 1 line of systemic therapy. ORR was 18%. Median time of therapy on O was 5 months (mo) (Range 1.4 to 29.567 mo) with 5 of the individuals still undergoing treatment at the time of analysis. Mean OS was 12.35 mo, 9 of the 11 individuals still alive. QTA of baseline CTs from subjects with liver (8/11) and pancreatic tumors (7/11) revealed a strong association between lesion texture and OS (Pearson correlation coefficient (PCC): hepatic mets = 0.952, p = 0.0003) and time on O (PCC: panc lesions = 0.889, p = 0.006). Conclusions: In individuals with metastatic PC with mutations involved in DNA repair, O may provide clinical benefit. QTA of individual tumors may allow for additional information that predicts outcomes to PARP inhibitors in this population.

Download Full-text

Germline and somatic DNA damage repair gene mutations potentially predict the efficacy of relevant treatment in Chinese patients with pancreatic ductal adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16732 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16732-e16732

Author(s):

Lin Shui ◽

Yang Peng ◽

Shuangshuang Li ◽

Jiangfang Tian ◽

Dan Cao

Keyword(s):

Dna Damage ◽

Dna Damage Repair ◽

Chinese Patients ◽

Ductal Adenocarcinoma ◽

Molecular Heterogeneity ◽

Genetic Characteristics ◽

Damage Repair ◽

Potential Biomarker ◽

Platinum Based Chemotherapy

e16732 Background: PDAC is a fatal disease with molecular heterogeneity, inducing differences in biological behaviour and therapeutic strategy. We conducted a study to reveal the mutation landscape of Chinese PDAC patients, and investigate the predictive role of germline and somatic DNA damage repair (DDR) status in precise treatment. Methods: 195 PDAC patients were enrolled from multiple medical centers of China between Jan 2016 to Nov 2019. Baseline clinical or genetic characteristics, and survival status were collected. NGS were performed on paraffin-embedded resected tissues or peripheral blood using a panel of 417 genes, including 50 DDR-related genes. Survival analysis was conducted using Kaplan-Meier, and Cox proportional hazard regression model. Results: The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Patients with KRAS mutation showed worse OS than those without (p = 0.048). DDR deficiency were identified in 15.38% of overall patients, mainly occurred in BRCA2 (4.62%), ATM (4.10%), RAD50 (1.54%) and MLH1 genes (1.03%). No significant improvement of OS existed between patients with or without DDR mutations (p = 0.88). Treatment with olaparib (adjusted HR, 0.2550; P = 0.0720) or platinum-based chemotherapy (adjusted HR, 0.1308; P = 0.0185) respectively decreased hazard of death in patients with DDR mutation. Besides BRCA gene, ATM mutant patients treated with olaparib harbored prolonged median OS than those without olaparib treatment (22.25 vs 15.2 month). Despite a little higher PD-L1 expression rate were seen in DDR mutant patients (29.17% vs 20.51%), no statistical correlation between tumor mutation burden level and DDR mutation was identified. And in patients treated with PD-1 blockade, 2 patients of DDR wild-type group both had SD, whereas of the remaining 5 patients with DDR deficiency, 1 was evaluated as PR, 3 as SD, and 1 as PD (ORR, 0 wt vs 20% mut). Conclusions: In this multi-center retrospective study, we deciphered the intra-tumoral genetic heterogeneity in Chinese PDAC population, which differs from western patients cohort to some extent. We found the potential role of germline and somatic DDR mutation status in predicting the response to olaparib and platinum-based chemotherapy, especially with BRCA or ATM mutation. However, DDR alteration was limited in prediction of hypermutational status and sensitivity to PD-1 blockade. Our study may provide a valuable evidence for clinical application of DDR mutation as a potential biomarker for precise treatment.

Download Full-text

Molecular landscape of gastric cancer (GC) harboring mutations of histone methyltransferases.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.418 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 418-418

Author(s):

Jingyuan Wang ◽

Joanne Xiu ◽

Yasmine Baca ◽

Richard M. Goldberg ◽

Philip Agop Philip ◽

...

Keyword(s):

Dna Damage ◽

Cancer Progression ◽

Dna Damage Repair ◽

Treatment Strategies ◽

Gene Mutations ◽

Mutation Rates ◽

Aberrant Expression ◽

Damage Repair

418 Background: Alteration of histone modifications participating in transcription and genomic instability, has been recognized as an important role in tumorigenesis. Aberrant expression of histone-lysine N-methyltransferase 2 ( KMT2) family, which methylate histone H3 on lysine 4, is significantly correlated with poor survival in GC. Understanding how gene mutations of KMT2 family interact to affect cancer progression could lead to new treatment strategies. Methods: A total of 1,245 GC were analyzed using next-generation sequencing (NGS) and immunohistochemistry (IHC; Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutations, and MSI status was evaluated by a combination of IHC, fragment analysis and NGS. PD-L1 status was analyzed by IHC (SP142). Gene fusions were detected by Archer (N = 59) or whole-transcriptome sequencing (N = 129). Results: The overall mutation rate of genes in KMT2 family was 10.6% ( KMT2A: 1.7 %, KMT2C: 4.7%, KMT2D: 7.1%). Overall, the mutation rates were significantly higher in KMT2-mutated (MT) GC than KMT2-wild type (WT) GC, except for TP53 (43% vs 63%, p < .0001). Interestingly, among the genes with significant higher mutation rates in KMT2-MT GC, 28% (21/76) of them were related to DNA damage repair (including BRCA1/ 2, RAD50) and 33% (25/76) of them were related to chromatin remodeling (including ARID1A/ 2, SMARCA4). Overexpression of HER2, amplifications of KRAS, CDK6 and HER2 were significant lower, while PCM1 and BCL3 amplifications were significant higher in KMT2-MT, compared to KMT2-WT GC ( p < .05). Significantly higher prevalence of TMB-high ( > 17mut/MB) (49% vs 3%), MSI-H (53% vs 2%), and PD-L1 overexpression (20% vs 7%) were present in KMT2-MT GC, compared to KMT2-WT GC ( p < .001). The rates of fusions involving ARHGAP26 (19% vs 3%, p < .01)and RELA (29% vs 0%, p < .0001) were significantly higher in KMT2-MT than those in KMT2-WT GC. Conclusions: This is the largest study to investigate the distinct genomic landscape between KMT2-MT and WT GC. Our data indicates that KMT2-MT GC patients could potentially benefit from agents targeting DNA damage repair and immunotherapy, which warrants further in-vitro and in-vivo investigation.

Download Full-text

Identification of Genetic Determinants of Pancreatic Cancer Immune Phenotypes by Integrative Genome-scale Analysis

10.21203/rs.3.rs-212097/v1 ◽

2021 ◽

Author(s):

Yuhang Ling ◽

Jiaqi Xu ◽

Xuedong Wang ◽

Jie Song ◽

Qiuhui Qian ◽

...

Keyword(s):

Pancreatic Cancer ◽

Immune Response ◽

Dna Damage ◽

Immune System ◽

Immune Cell ◽

Dna Damage Repair ◽

Cell Interactions ◽

Tumor Microenvironments ◽

Damage Repair ◽

Immune Phenotypes

Abstract Background Pancreatic cancer (PC) is a malignant neoplasm of the digestive tract that is highly malignant and difficult to diagnose at an early stage with high postoperative mortality and low cure rates. Cancer immunotherapy is innovating the clinical treatment of several cancers, but has a limited role in PC. The incomplete understanding of immune response hinders the development of gene therapy. To fill this gap, it is very necessary to classify the immunogenic subtypes of PC to understand the relationship between tumor microenvironments and clinical pathological characteristics, DNA damage repair and tumor immune response.Methods We extracted copy number change, somatic mutation and expression data from tumor genome map (TCGA). Using RNA sequencing data, we defined three different immunophenotypes and elucidated how immune cell interactions in immune subtypes vary with the background of the immune system. Further correlation analysis between DNA damage repair (DDR) related genes expression and immune response was conducted to explore the effects of DDR expression on antitumor activity in the tumor microenvironments.Results We defined three different immunophenotypes and elucidated how immune cell interactions in immune subtypes vary with the background of the immune system. When the total number of mutations was standardized, no enrichment of new epitopes was detected in immunocompetent phenotypes. These observations suggest that mutations in Th-1 enriched IS3 tumors are essentially no more immunogenic than those in IS2 cancers. We also found that the expression patterns of key IFN mediators STAT1 and / or STAT3 were increased in tumors with DDR mutations (19 of ATM, ERCC1, Rb1, BRCA2, pole and TP53), which is a reflex activation of IFN pathway.Conclusions Three defined immune subtypes show different characteristics of immune cell infiltration, revealing different manifestations in anti-cancer immune function. That is to say, clinical biological events of differential tumors are associated to immune-phenotypes. The invasive phenotype was driven by somatic mutations across immune subtypes, and DDR defect may also influence the response of tumor immune subtypes. Our results suggested that the occurrence of pancreatic cancer is related to genetic factors of immunophenotype, providing information for clinical prognosis and outcome of pancreatic cancer.

Download Full-text

The germline/somatic DNA damage repair gene mutations modulate the therapeutic response in Chinese patients with advanced pancreatic ductal adenocarcinoma

10.21203/rs.3.rs-72325/v2 ◽

2020 ◽

Author(s):

Lin Shui ◽

Xiaofen Li ◽

Yang Peng ◽

Jiangfang Tian ◽

Shuangshuang Li ◽

...

Keyword(s):

Dna Damage ◽

Retrospective Study ◽

Dna Damage Repair ◽

Chinese Patients ◽

Biological Behavior ◽

Molecular Heterogeneity ◽

Genetic Characteristics ◽

Damage Repair ◽

Platinum Based Chemotherapy

Abstract Background: PDAC is a fatal disease with molecular heterogeneity, inducing differences in biological behavior and therapeutic strategy. NGS profiles of pathogenic alterations in Chinese PDAC population are limited. We conducted a retrospective study to investigate the predictive role of DNA damage repair (DDR) mutations in precise medicine. Methods: NGS were performed on resected tissues or peripheral blood from 195 Chinese PDAC patients. Baseline clinical or genetic characteristics, and survival status were collected. The Kaplan–Meier survival analyses were performed by the R version 3.6.1.Results: The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Advanced patients with KRAS mutation showed worse OS than those without (p=0.048). DDR deficiency was identified in 30 (15.38%) of overall patients, mainly involving BRCA2 (n=9, 4.62%), ATM (n=8, 4.10%) and RAD50 genes (n=3, 1.54%). There was no significant improvement of OS between patients with or without DDR mutations (p=0.88). Treatment with platinum-based chemotherapy (p=0.0096) or olaparib (p=0.018) respectively improved the overall survival of patients with DDR mutation. No statistical correlation between tumor mutation burden (TMB) and DDR mutations was identified. Treatment of PD-1 blockades did not bring significiantly improved OS to DDR-mutated patients than intact DDR group (p=0.14). Conclusions: In this multi-center retrospective study, we showed the role of germline and somatic DDR mutation in predicting the efficacy of olaparib and platinum-based chemotherapy. However, DDR alteration has shown limited value in prediction of hypermutational status and the sensitivity to PD-1 blockade.

Download Full-text