scholarly journals Association of somatic mutations in BRCA2 BRC domain with chemotherapy sensitivity and survival in high grade serous ovarian cancer

2021 ◽  
pp. 112742
Author(s):  
Guonan Zhang ◽  
Jie Zhang ◽  
Yi Zhu ◽  
Hong Liu ◽  
Yu Shi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Somatic Mutations ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Chemotherapy Sensitivity

scholarly journals Somatic Mutations in BRCA2 BRC Repeat Associated with Outcome in Patients with High Grade Serous Ovarian Cancer

2020 ◽  
Author(s):  
Guonan Zhang ◽  
Jie Zhang ◽  
Yi Zhu ◽  
Hong Liu ◽  
Yu Shi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Somatic Mutations ◽  
Progression Free Survival ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Blood Leukocytes ◽  
Free Survival ◽  
Chemotherapy Sensitivity ◽  
Factors Affecting ◽  
Platinum Based Chemotherapy

Abstract BackgroundThe interaction between BRCA2 BRC repeats and RAD51 is one of the great important factors affecting the homologous recombination in DNA damage repair of tumor cells. We investigated the effect of BRCA2 BRC repeat mutations on outcome in patients with high grade serous ovarian cancer (HGSOC) who received platinum-based chemotherapy.MethodsWe identified the type and location of BRCA2 BRC repeat mutations by PCR and DNA sequencing in tumor and peripheral blood leukocytes (PBL) samples of 113 patients with stage IIIC/IV high grade serous ovarian cancer (HGSOC), and assessed chemotherapy-free interval (CFI), progression-free survival (PFS) and overall survival (OS).Results24 (21.23%) cases with somatic mutation were identified in 113 HGSOC patients. Among them, 8 (7.1%) cases with nonsense mutation resulting in BRCA2 truncation significantly prolonged median CFI (37 vs 8 months,P=0.000), PFS (43 vs 14 months, p=0.000) and OS (56 vs 31 months, P=0.002); Interestingly, 16 (14.13%) cases with missense mutation also prolonged median CFI (15 vs 8 months, P=0.044), PFS (21 vs 14 months, P=0.049) and OS ( 38 vs 31 months, P=0.037). ConclusionsSomatic mutations in BRCA2 BRC5-8 repeat motifs are associated with platinum-based chemotherapy sensitivity and a better outcome in patients with HGSOC.

Genomic characterization of brain metastases (BM) in high-grade serous ovarian cancer (HGSOC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13580-e13580
Author(s):  
Renata Duchnowska ◽  
Anna Maria Supernat ◽  
Rafał Pęksa ◽  
Marta Łukasiewicz ◽  
Tomasz Stokowy ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Somatic Mutations ◽  
Dna Damage Repair ◽  
Genetic Alterations ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Primary Tumors ◽  
Tp53 Mutations ◽  
Damage Repair

e13580 Background: BM are a rare occurrence in ovarian cancer (OC) and their molecular characteristics is virtually unknown. DNA damage repair (DDR) deficiency is prevalent in OC, and co-mutated TP53 and any DDR denotes high tumor mutation burden (TMB). We genetically characterized a unique series of high-grade serous ovarian cancer (HGSOC) patients who developed BM to identify alterations of potential clinical relevance. Methods: Whole-exome sequencing (2x150bp, SureSelectXT Library Prep Kit, Illumina’s NovaSeq platform) was performed in matched BM, primary tumors (PT) and normal tissue. DNA was extracted from FFPE samples using QIAamp DNA FFPE Tissue Kit (Qiagen, Germany). All mutations were checked with Catalogue of Somatic Mutations in Cancer (COSMIC) and Integrative Genomics Viewer (IGV). Results: Study group included 10 HGSOC patients (International Federation of Gynecology and Obstetrics classification (FIGO) II-IV, mean age at diagnosis 48 years, range 35-59). Median time from primary HGSOC diagnosis to BM was 38 months (range, 18 to 149). TP53 somatic mutations were found in both primary tumor (PT) and BM in 8 patients. The other 2 cases harbored TP53 mutations not reported in COSMIC catalogue: p.S60L and intronic TP53 mutation preceding p.I322 (IGV). In 9 cases TP53 mutations coexisted with germline or somatic DNA damage repair deficiency. Four cases contained BRCA1 mutations (all germline), and none harbored germline BRCA2 mutation. Other mutated genes included MLH1 (2 somatic, 2 germline), ATR (4 germline, 1 somatic), AMT (1 somatic), RAD50 (1 somatic), ERCC4 (1 somatic), FANCD2 (1 somatic) and RPA1 (1 germline). Three mutation signatures defined in the COSMIC database were indentified in BM: 6, 20 and 30. In 6 cases these mutations were shared in PT, and in another 4 their presence in PT could not be determined due to technical reasons. Median survival from BM was 31 months (range, 5 to 184). Conclusions: Genomic analysis of BM provides an opportunity to identify potentially clinically informative alterations. Mutational profiles in PT are generally reflected in BM. Detected genetic alterations suggest their potential sensitivity to PARP inhibitors and immunotherapy.

Abstract AP23: A PLATINUM–RESISTANT SUBTYPE OF HIGH–GRADE SEROUS OVARIAN CANCER IDENTIFIED BY A NETWORK OF SOMATIC MUTATIONS

2017 ◽  
Author(s):  
John Paul Shen ◽  
Ana Bojorquez-Gomez ◽  
Justin Huang ◽  
Matan Hofree ◽  
Kristin Klepper ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Somatic Mutations ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Platinum Resistant

scholarly journals HIST1H2BB and MAGI2 Methylation and Somatic Mutations as Precision Medicine Biomarkers for Diagnosis and Prognosis of High-grade Serous Ovarian Cancer

2020 ◽  
Vol 13 (9) ◽  
pp. 783-794
Author(s):  
Blanca L. Valle ◽  
Sebastian Rodriguez-Torres ◽  
Elisabetta Kuhn ◽  
Teresa Díaz-Montes ◽  
Edgardo Parrilla-Castellar ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Precision Medicine ◽  
Somatic Mutations ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Diagnosis And Prognosis

scholarly journals Abnormal methylation characteristics predict chemoresistance and poor prognosis in advanced high-grade serous ovarian cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Li-yuan Feng ◽  
Bing-bing Yan ◽  
Yong-zhi Huang ◽  
Li Li
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Roc Analysis ◽  
Bioinformatics Analysis ◽  
Kegg Pathway ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Chemotherapy Sensitivity ◽  
Kaplan Meier ◽  
Sensitivity Specificity

Abstract Background Primary or acquired chemoresistance is a key link in the high mortality rate of ovarian cancer. There is no reliable method to predict chemoresistance in ovarian cancer. We hypothesized that specific methylation characteristics could distinguish chemoresistant and chemosensitive ovarian cancer patients. Methods In this study, we used 450 K Infinium Methylation BeadChip to detect the different methylation CpGs between ovarian cancer patients. The differential methylation genes were analyzed by GO and KEGG Pathway bioinformatics analysis. The candidate CpGs were confirmed by pyrosequencing. The expression of abnormal methylation gene was identified by QRT-PCR and IHC. ROC analysis confirmed the ability to predict chemotherapy outcomes. Prognosis was evaluated using Kaplan–Meier. Results In advanced high-grade serous ovarian cancer, 8 CpGs (ITGB6:cg21105318, cg07896068, cg18437633; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934, cg13270625) remained hypermethylated in chemoresistant patients. The sensitivity, specificity and AUC of 8 CpGs (ITGB6:cg21105318, cg07896068, cg18437633; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934, cg13270625) methylation to predict chemotherapy sensitivity were 63.60–97.00%, 46.40–89.30% and 0.774–0.846. PFS of 6 candidate genes (ITGB6:cg21105318, cg07896068; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934) hypermethylation patients was significantly shorter. The expression of NCALD and LAMA3 in chemoresistant patients was lower than that of chemosensitive patients. Spearman analysis showed that NCALD and LAMA3 methylations were negatively correlated with their expression. Conclusions As a new biomarker of chemotherapy sensitivity, hypermethylation of NCALD and LAMA3 is associated with poor PFS in advanced high-grade serous ovarian cancer. In the future, further research on NCALD and LAMA3 will be needed to provide guidance for clinical stratification of demethylation therapy.

scholarly journals Model constructions of chemosensitivity and prognosis of high grade serous ovarian cancer based on evaluation of immune microenvironment and immune response

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Han Zhang ◽  
Yijun Wu ◽  
Hao Li ◽  
Liping Sun ◽  
Xiangkai Meng
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
Prediction Models ◽  
Interaction Network ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Immune Microenvironment ◽  
Chemotherapy Sensitivity ◽  
Protein Protein Interaction ◽  
Sensitivity Score

Abstract Background The prognosis of high grade serous ovarian cancer (HGSOC) patients is closely related to the immune microenvironment and immune response. Based on this, the purpose of this study was to construct a model to predict chemosensitivity and prognosis, and provide novel biomarkers for immunotherapy and prognosis evaluation of HGSOC. Methods GSE40595 (38 samples), GSE18520 (63 samples), GSE26712 (195 samples), TCGA (321 samples) and GTEx (88 samples) were integrated to screen differential expressed genes (DEGs) of HGSOC. The prognosis related DEGs (DEPGs) were screened through overall survival analysis. The DEGs-encoded protein–protein interaction network was constructed and hub genes of DEPGs (DEPHGs) were generated by STRING. Immune characteristics of the samples were judged by ssGSEA, ESTIMATE and CYBERSORT. TIMER was used to analyze the relationship between DEPHGs and tumor-infiltrating immunocytes, as well as the immune checkpoint genes, finally immune-related DEPHGs (IDEPHGs) were determined, and whose expression in 12 pairs of HGSOC tissues and tumor-adjacent tissues were analyzed by histological verification. Furthermore, the chemosensitivity genes in IDEPHGs were screened according to GSE15622 (n = 65). Finally, two prediction models of paclitaxel sensitivity score (PTX score) and carboplatin sensitivity score (CBP score) were constructed by lasso algorithm. The area under curve was calculated to estimate the accuracy of candidate gene models in evaluating chemotherapy sensitivity. Results 491 DEGs were screened and 37 DEGs were identified as DEPGs, and 11 DEPHGs were further identified. Among them, CXCL13, IDO1, PI3, SPP1 and TRIM22 were screened as IDEPHGs and verified in the human tissues. Further analysis showed that IDO1, PI3 and TRIM22 could independently affect the chemotherapy sensitivity of HGSOC patients. The PTX score was significantly better than TRIM22, PI3, SPP1, IDO1 and CXCL13 in predicting paclitaxel sensitivity, so was CBP score in predicting carboplatin sensitivity. What’s more, both of the HGSOC patients with high PTX score or high CBP score had longer survival time. Conclusions Five IDEPHGs identified through comprehensive bioinformatics analysis were closely related with the prognosis, immune microenvironment and chemotherapy sensitivity of HGSOC. Two prediction models based on IDEPHGs might have potential application of chemotherapy sensitivity and prognosis for patients with HGSOC.

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