Dataset Information

Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma.

ABSTRACT:

Background

Ovarian clear cell carcinoma (OCCC) is mostly resistant to standard chemotherapy that results in poor patient survival. To understand the genetic background of these tumours, we performed whole-genome sequencing of OCCC tumours.

Methods

Tumour tissue samples and matched blood samples were obtained from 55 Japanese women diagnosed with OCCC. Whole-genome sequencing was performed using the Illumina HiSeq platform according to standard protocols.

Results

Alterations to the switch/sucrose non-fermentable (SWI/SNF) subunit, the phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway, and the receptor tyrosine kinase (RTK)/Ras signalling pathway were found in 51%, 42%, and 29% of OCCC tumours, respectively. The 3-year overall survival (OS) rate for patients with an activated PI3K/Akt signalling pathway was significantly higher than that for those with inactive pathway (91 vs 40%, hazard ratio 0.24 (95% confidence interval (CI) 0.10-0.56), P=0.0010). Similarly, the OS was significantly higher in patients with the activated RTK/Ras signalling pathway than in those with the inactive pathway (91 vs 53%, hazard ratio 0.35 (95% CI 0.13-0.94), P=0.0373). Multivariable analysis revealed that activation of the PI3K/Akt and RTK/Ras signalling pathways was an independent prognostic factor for patients with OCCC.

Conclusions

The PI3K/Akt and RTK/Ras signalling pathways may be potential prognostic biomarkers for OCCC patients. Furthermore, our whole-genome sequencing data highlight important pathways for molecular and biological characterisations and potential therapeutic targeting in OCCC.

SUBMITTER: Itamochi H

PROVIDER: S-EPMC5572180 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma.

Itamochi Hiroaki H Oishi Tetsuro T Oumi Nao N Takeuchi Satoshi S Yoshihara Kosuke K Mikami Mikio M Yaegashi Nobuo N Terao Yasuhisa Y Takehara Kazuhiro K Ushijima Kimio K Watari Hidemichi H Aoki Daisuke D Kimura Tadashi T Nakamura Toshiaki T Yokoyama Yoshihito Y Kigawa Junzo J Sugiyama Toru T

British journal of cancer 20170720 5

<h4>Background</h4>Ovarian clear cell carcinoma (OCCC) is mostly resistant to standard chemotherapy that results in poor patient survival. To understand the genetic background of these tumours, we performed whole-genome sequencing of OCCC tumours.<h4>Methods</h4>Tumour tissue samples and matched blood samples were obtained from 55 Japanese women diagnosed with OCCC. Whole-genome sequencing was performed using the Illumina HiSeq platform according to standard protocols.<h4>Results</h4>Alterations ...[more]

PMID: 28728166

Similar Datasets

Project description:IntroductionOvarian clear cell carcinoma (OCCC) has distinct clinical and molecular features and heterogeneous prognosis. Insights into the somatic genomic abnormalities of OCCC provide the basis for deeper understanding and potential therapeutic avenues. Herein, we performed extensive genomic profiling in Chinese patients to illustrate the mutation landscape and genetic prognostic biomarkers of OCCC.Patients and methodsWe used targeted DNA sequencing on 61 OCCC cases with a panel of 520 cancer-related genes. Correlations between clinicopathological features and survival were evaluated. Nomogram-based models were constructed to predict progress-free survival (PFS).ResultsWe detected 763 somatic mutations spanning 286 genes. The most frequent genetic alterations, ARID1A (49%) and PIK3CA (48%), were concurrently mutated. Comprehensive copy number alterations (CNAs) were identified in chromosomes 20q13.2 and 8q. Most (73.7%) patients harboured potentially targetable driver mutations. The mean and median tumour mutational burden were 7.0 and 3.0 mutations/Mb, respectively. Microsatellite instability (high) was identified in 8.2% of patients. Mutation of the base-excision repair pathway was significantly higher in patients of stage II/III/IV. ATM mutation was associated with platinum sensitivity (p < .05). Survival analysis identified chr8q CNAs in all patients, PIK3CA mutations in stage I patients and SWI/SNF complex (ARID1A and SMARCA4) mutations in stage II/III/IV patients as potential prognosticators (p < .05). Integration of genetic alterations (SWI/SNF complex mutations, ATM mutations and chr8q CNAs) improved the performance of a nomogram based on tumour stage and residual disease (concordance index 0.75 vs. 0.70, p < .05).ConclusionsWe described somatic genomic alterations in Chinese OCCC patients and observed different genomic alterations between stage I and stage II/III/IV tumours. Genetic factors may supplement clinical factors in nomogram modelling for PFS prediction.Key MessagesWe performed extensive genomic profiling in a well-annotated cohort of 61 Chinese ovarian clear cell carcinoma (OCCC) patients.PIK3CA mutations were associated with worse overall survival (OS) in stage I OCCC, and SWI/SNF gene mutations were associated with improved OS in stage II/III/IV disease.We propose an easy-to-use nomogram using clinical factors (tumour stage and residual disease) and genetic alterations (SWI/SNF complex mutations, ATM mutations and chr8q CNAs) to predict the progress-free survival (PFS) of OCCC.

Project description:Objective: The aim of the present study was to determine the prognostic significances of markers of preoperative systemic inflammatory response (SIR) in patients with ovarian clear cell carcinoma (OCCC). Methods: A total of 109 patients diagnosed with OCCC that underwent primary cytoreductive surgery and adjuvant platinum-based chemotherapy from 2009 to 2012 were enrolled in this retrospective study. SIR markers were calculated from complete blood cell counts determined before surgery. Receiver operating characteristic (ROC) curve analysis was used to determine optimal cut-off values for neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR). Prognostic significances with respect to overall survival (OS) and progression-free survival (PFS) were determined by Kaplan-Meier curve and multivariate Cox regression analysis. Results: The optimized NLR, LMR and PLR cut-off values as determined by ROC curve analysis for PFS and OS were 2.3, 4.2, and 123.6, respectively. When the cohort was divided using these optimized cut-offs, NLR and LMR were found to be significantly associated with clinicopathologic factors, NLR with FIGO stage, the presence of malignant ascites, and platinum response, and LMR with FIGO stage, lymph node metastasis, malignant ascites, and platinum response. Kaplan-Meier analysis revealed a high NLR (> 2.3) was significantly associated with low 5-year PFS and OS rates and that a high LMR was significantly associated with high 5-year PFS and OS rates. Multivariate analysis identified FIGO stage, residual mass, and platinum response as independent prognostic factors of PFS, and FIGO stage, residual mass, platinum response, and LMR as independent prognostic factors of OS. Conclusions: Markers of systemic inflammatory response provide useful prognostic information and lymphocyte-to-monocyte ratio is the most reliable independent prognostic factor of overall survival in patients with ovarian clear cell carcinoma.

Dataset Information

Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma.

Background

Methods

Results

Conclusions

Publications

Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets