scholarly journals Genomic Profiling of Chinese Cervical Cancer Patients Reveals Prevalence of DNA Damage Repair Gene Alterations and Related Hypoxia Feature

2022 ◽  
Vol 11 ◽  
Author(s):  
Hao Wen ◽  
Qin-Hao Guo ◽  
Xiao-Lan Zhou ◽  
Xiao-Hua Wu ◽  
Jin Li
Keyword(s):  
Cervical Cancer ◽  
Dna Damage ◽  
Mast Cell ◽  
Cancer Patients ◽  
Dna Damage Repair ◽  
Genomic Profiling ◽  
Hub Gene ◽  
Damage Repair ◽  
Depth Analysis ◽  
Gene Alterations

BackgroundCervical cancer is responsible for 10–15% of cancer-related deaths in women worldwide. In China, it is the most common cancer in the female genital tract. However, the genomic profiles of Chinese cervical cancer patients remain unclear.Materials and MethodsA total of 129 cervical cancer patients were enrolled in this study (113 squamous, 12 adenocarcinoma, 2 adenosquamous, and 2 neuroendocrine carcinoma). To classify the clinical features and molecular characteristics of cervical cancer, the genomic alterations of 618 selected genes were analyzed in the samples of these patients, utilizing target next-generation sequencing (NGS) technology. Furthermore, the findings from the Chinese cohort were then compared with the data of Western patients downloaded from The Cancer Genome Atlas (TCGA) database, in terms of gene expression files, mutation data, and clinical information.ResultsAll studied patients had valid somatic gene alterations, and the most frequently altered genes were PIK3C, TP53, FBXW7, ARID1A, ERBB2, and PTEN. Comparison of genomic profiling showed significantly different prevalence of genes, including TP53, KMT2C, and RET, between the Chinese and the TCGA cohorts. Moreover, 57 patients (44.19%) with 83 actionable alterations were identified in our cohort, especially in PI3K and DNA damage repair (DDR) pathways. After an in-depth analysis of cervical cancer data from the TCGA cohort, DDR alteration was found to be associated with extremely higher tumor mutation burden (TMB) (median mutation count: 149.5 vs 66, p <0.0001), and advanced stages (p <0.05). Additionally, DDR alteration, regardless of its function, was positively correlated with hypoxia feature and score. Moreover, patients with a high hypoxia score were positively correlated with a high abundance of mast cell resting, but lower abundance of CD8+ T cells and activated mast cell. Finally, CDHR5 was identified as the hub gene to be involved in the DDR–hypoxia network, which was negatively correlated with both the DDR alteration and hypoxia score.ConclusionsOverall, a unique genomic profiling of Chinese patients with cervical cancer was uncovered. Besides, the prevalent actionable variants, especially in PI3K and DDR pathways, would help promote the clinical management. Moreover, DDR alteration exerted the significant influence on the tumor microenvironment in cervical cancer, which could guide the clinical decisions for the treatment. CDHR5 was the first identified hub gene to be negatively correlated with DDR or hypoxia in cervical cancer, which had potential effects on the treatment of immune checkpoint inhibitors (ICIs).

scholarly journals DNA damage repair and survival outcomes in advanced gastric cancer patients treated with first-line chemotherapy

2017 ◽  
Vol 140 (11) ◽  
pp. 2587-2595 ◽  
Author(s):  
Livia Ronchetti ◽  
Elisa Melucci ◽  
Francesca De Nicola ◽  
Frauke Goeman ◽  
Beatrice Casini ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Damage ◽  
Advanced Gastric Cancer ◽  
Cancer Patients ◽  
Dna Damage Repair ◽  
Survival Outcomes ◽  
First Line ◽  
Damage Repair ◽  
Gastric Cancer Patients ◽  
Line Chemotherapy

scholarly journals Bruceine D and Afatinib Combination Inhibits Ovarian Cancer Cells Proliferation and Migration Through DNA Damage Repair and EGFR Pathway

2021 ◽  
Author(s):  
Feng Lin ◽  
Ju-fan Zhu ◽  
Luo Wang ◽  
Yuan-jun Yang ◽  
Ru-ru Zheng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Cancer Patients ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Dna Damage Repair ◽  
Egfr Signaling ◽  
Damage Repair ◽  
And Migration ◽  
Proliferation And Migration

Abstract Owing to the high rates of relapse and migration, ovarian cancer has been recognized as the most lethal gynecological malignancy worldwide. The activity of the EGFR signaling pathway is frequently associated with ovarian cancer cell proliferation and migration. Despite this knowledge, inhibition of EGFR signaling in ovarian cancer patients failed to achieve satisfactory therapeutic effects. In this study, we identified that Bruceine D and EGFR inhibitor, afatinib, combination resulted in synergistic anti- ovarian cancer effects. The results indicated that compared with one of both drugs alone, the combination of Bruceine D and afatinib slowed the DNA replication rate, inhibition of cell viability, and proliferation and clone formation. This resulted in cell cycle arrest and cell apoptosis. In addition, the combination of Bruceine D and afatinib possessed a stronger ability to inhibit the ovarian cancer cell adhesion and migration than treatment with Bruceine D or afatinib alone. Mechanistically, the combined treatment triggered intense DNA damage, suppressed DNA damage repair, and enhanced the inhibition of the EGFR pathway. These results demonstrated that compared with each pathway inhibition, combined blocking of both DNA damage repair and the EGFR pathway appears to more effective against ovarian cancer treatment. The results support the potential of Bruceine D and afatinib combination as a therapeutic strategy for ovarian cancer patients.

scholarly journals Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making

2017 ◽  
pp. 1-16 ◽  
Author(s):  
Wassim Abida ◽  
Joshua Armenia ◽  
Anuradha Gopalan ◽  
Ryan Brennan ◽  
Michael Walsh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Clinical Decision Making ◽  
Dna Damage Repair ◽  
Genomic Profiling ◽  
Castration Resistant Prostate Cancer ◽  
Disease States ◽  
Castration Resistant ◽  
Damage Repair ◽  
Increased Risk

Purpose A long natural history and a predominant osseous pattern of metastatic spread are impediments to the adoption of precision medicine in patients with prostate cancer. To establish the feasibility of clinical genomic profiling in this disease, we performed targeted deep sequencing of tumor and normal DNA from patients with locoregional, metastatic noncastrate, and metastatic castration-resistant prostate cancer. Patients and Methods Patients consented to genomic analysis of their tumor and germline DNA. A hybridization capture-based clinical assay was used to identify single-nucleotide variations, small insertions and deletions, copy number alterations, and structural rearrangements in more than 300 cancer-related genes in tumors and matched normal blood. Results We successfully sequenced 504 tumors from 451 patients with prostate cancer. Potentially actionable alterations were identified in DNA damage repair, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase pathways. Twenty-seven percent of patients harbored a germline or a somatic alteration in a DNA damage repair gene that may predict for response to poly (ADP-ribose) polymerase inhibition. Profiling of matched tumors from individual patients revealed that somatic TP53 and BRCA2 alterations arose early in tumors from patients who eventually developed metastatic disease. In contrast, comparative analysis across disease states revealed that APC alterations were enriched in metastatic tumors, whereas ATM alterations were specifically enriched in castration-resistant prostate cancer. Conclusion Through genomic profiling of prostate tumors that represent the disease clinical spectrum, we identified a high frequency of potentially actionable alterations and possible drivers of disease initiation, metastasis, and castration resistance. Our findings support the routine use of tumor and germline DNA profiling for patients with advanced prostate cancer for the purpose of guiding enrollment in targeted clinical trials and counseling families at increased risk of malignancy.

Inhibition of EGFR nuclear translocation attenuate radioresistance through decreased p-DNA-PK expression in cervical cancer cells.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17011-e17011
Author(s):  
Yunxiang Qi ◽  
Jinyi Lang ◽  
Lu Li ◽  
Mei Feng ◽  
Yecai Huang
Keyword(s):  
Cervical Cancer ◽  
Dna Damage ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Nuclear Translocation ◽  
Dna Damage Repair ◽  
Cervical Cancer Cell Line ◽  
Phosphorylation Level ◽  
Damage Repair ◽  
Cervical Cancer Cells

e17011 Background: The commonly used treatment for cervical cancer is radiotherapy. However, the resistance to irradiation and metastasis at the advanced stage is a common reason for the poor prognosis and high mortality. This study was designed to elucidate the role of epidermal growth factor receptor (EGFR) nuclear translocation in radioresistance, and its correlation with DNA damage repair pathway in the cervical cancer cells. Methods: The dynamic expression of EGFR, DNA-dependent protein kinase (DNA-PK), PDK-1, PKN1 and their phosphorylation level in irradiated cervical cancer cell line CaSki at 0 10 20 40 minutes was determined by western blotting. Besides, nuclear localization signal (NLS) peptide inhibitor and control peptides was synthesized and treated cells before irradiation to elucidate the correlation between EGFR nuclear translocation and DNA damage repair after irradiation. Results: Expression of EGFR, protein kinase N1 (PKN1), and DNA-PK in nucleus was increased after irradiation in CaSki cells. Irradiation also enhanced the phosphorylation level of EGFR at Thr654, PKN1 at T774 and DNA-PK at T2609. Inhibition of EGFR nuclear translocation by NLS peptide decreased the expression level of EGFR and DNA-PK in the nucleus, and attenuated their phosphorylation process. Conclusions: EGFR nuclear translocation riggered by irradiation promoted DNA damage repair in irradiated cervical cancer cells. This work facilitated us to understand the possible molecular mechanism of the resistance to irradiation in the treatment of cervical cancer, providing a potentially potent clinical method to cancer therapy.

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.

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