302PD Targeted sequencing of a specific gene panel detects a high frequency of ARID1A and PIK3CA mutations in endometrioid and clear cell ovarian cancer

5582 Background: The prediction of tumor chemoresponse and treatment toxicity is crucial for optimal patient care in high grade serous ovarian cancer (HGSC). We employed a targeted sequencing panel of 508 clinically annotated cancer genes to screen for actionable genetic variants in tumor tissue and ctDNA of patients with advanced HGSC. Methods: Tumor tissue, and serial plasma samples at diagnosis and during primary therapy were obtained from five patients with FIGO Stage IIIc HGSC. All patients were surgically debulked and received standard carboplatin and paclitaxel chemotherapy. DNA isolated from tumor tissue and plasma was analyzed for genetic alterations by targeted deep-sequencing of 508 previously annotated cancer genes. Somatic variants were systematically reported for alterations related to drug sensitivity and treatment toxicity, and analyzed with respect to clinical parameters and primary therapy outcomes. Results: In tumor tissues, and the corresponding pre-treatment ctDNA, oncogenic mutations were detected at a median of 13.0 and 1.6 allelic frequencies, respectively. The mutation frequency was higher, and also more unique mutations were detected in ctDNA of patients presenting with high tumor spread. Interestingly, a de-novo ctDNA MAPK1 mutation was detected in a sample taken during chemotherapy with partial response, while, no new mutations emerged in a patient with complete response. Analysis of the pretreatment plasma ctDNA revealed profiles of low and high drug sensitivities consistent with the clinical course of the patients. In two patients, increased risk profiles for treatment toxicities were identified via e.g. GSTP1. Consistently, these two patients were forced to discontinue standard therapy. Conclusions: Panel-based targeted sequencing of ctDNA identified potentially actionable mutations, and reflected tumor heterogeneity of HGSC. Further, the ctDNA gene panel annotations showed concordance with the chemoresponse- and treatment toxicity profiles, suggesting that ctDNA gene panel maybe a feasible approach to individualize treatment of HGSC patients.

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Combination of gene set signatures correlates with response to nivolumab in platinum-resistant ovarian cancer

10.21203/rs.3.rs-371906/v1 ◽

2021 ◽

Author(s):

Ryusuke Murakami ◽

Junzo Hamanishi ◽

J. B. Brown ◽

Kaoru Abiko ◽

Koji Yamanoi ◽

...

Keyword(s):

Ovarian Cancer ◽

Clinical Response ◽

Clear Cell ◽

Gene Signature ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Specific Gene ◽

Gene Signatures ◽

Gene Set ◽

Platinum Resistant

Abstract Background Based on our previous phase II clinical trial of anti-programmed death-1 (PD-1) antibody nivolumab for platinum-resistant ovarian cancer (n=19, UMIN000005714), we aimed to identify the therapeutic response biomarkers to nivolumab in ovarian cancer. Methods Tumor gene expressions were evaluated by proliferative, mesenchymal, differentiated, and immunoreactive gene signatures derived from high-grade serous carcinomas in The Cancer Genome Atlas and a signature established prior to ovarian clear cell carcinoma. Gene sets were scored using the single-sample gene set enrichment analysis, and resulting scores were used to assess the correlation between each gene set and the clinical response to nivolumab therapy. Statistical analyses were performed to identify pathways differentially expressed by either the complete response (CR) or progressive disease (PD) groups. Results The clear cell gene signature significantly had higher score in the CR group, and the proliferative gene signature had significantly higher score in the PD group where nivolumab was not effective (respective p-values 0.005 and 0.026). Combinations of gene signatures improved correlation with response, where a projection of immunoreactive, proliferative, and clear cell signatures differentiated clinical response. Conclusion Ovarian cancer-specific gene signature and related pathway scores provide a preliminary indicator for ovarian cancer prior to receiving anti-PD-1 antibody therapy.

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Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel

Scientific Reports ◽

10.1038/srep23910 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 29

Author(s):

Nereida Bravo-Gil ◽

Cristina Méndez-Vidal ◽

Laura Romero-Pérez ◽

María González-del Pozo ◽

Enrique Rodríguez-de la Rúa ◽

...

Keyword(s):

Gene Panel ◽

Targeted Sequencing ◽

Specific Gene ◽

Inherited Retinal Dystrophies ◽

Retinal Dystrophies

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Detection of high frequency of mutations in a breast and/or ovarian cancer cohort: implications of embracing a multi-gene panel in molecular diagnosis in India

Journal of Human Genetics ◽

10.1038/jhg.2016.4 ◽

2016 ◽

Vol 61 (6) ◽

pp. 515-522 ◽

Cited By ~ 30

Author(s):

Ashraf U Mannan ◽

Jaya Singh ◽

Ravikiran Lakshmikeshava ◽

Nishita Thota ◽

Suhasini Singh ◽

...

Keyword(s):

Ovarian Cancer ◽

Molecular Diagnosis ◽

High Frequency ◽

Gene Panel

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Combination of gene set signatures correlates with response to nivolumab in platinum-resistant ovarian cancer

Scientific Reports ◽

10.1038/s41598-021-91012-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ryusuke Murakami ◽

Junzo Hamanishi ◽

J. B. Brown ◽

Kaoru Abiko ◽

Koji Yamanoi ◽

...

Keyword(s):

Ovarian Cancer ◽

Clinical Response ◽

Clear Cell ◽

Response Prediction ◽

Complete Response ◽

Gene Signature ◽

Specific Gene ◽

Gene Signatures ◽

Platinum Resistant ◽

Visual Projection

AbstractBased on our previous phase II clinical trial of anti-programmed death-1 (PD-1) antibody nivolumab for platinum-resistant ovarian cancer (n = 19, UMIN000005714), we aimed to identify the biomarkers predictive of response. Tumor gene expression was evaluated by proliferative, mesenchymal, differentiated, and immunoreactive gene signatures derived from high-grade serous carcinomas and a signature established prior for ovarian clear cell carcinoma. Resulting signature scores were statistically assessed with both univariate and multivariate approaches for correlation to clinical response. Analyses were performed to identify pathways differentially expressed by either the complete response (CR) or progressive disease (PD) patient groups. The clear cell gene signature was scored significantly higher in the CR group, and the proliferative gene signature had significantly higher scores in the PD group where nivolumab was not effective (respective p values 0.005 and 0.026). Combinations of gene signatures improved correlation with response, where a visual projection of immunoreactive, proliferative, and clear cell signatures differentiated clinical response. An applicable clinical response prediction formula was derived. Ovarian cancer-specific gene signatures and related pathway scores provide a robust preliminary indicator for ovarian cancer patients prior to anti-PD-1 therapy decisions.

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Identification of Survival-Specific Genes in Clear Cell Renal Cell Carcinoma Using a Customized Next-Generation Sequencing Gene Panel

Journal of Personalized Medicine ◽

10.3390/jpm12010113 ◽

2022 ◽

Vol 12 (1) ◽

pp. 113

Author(s):

Jia Hwang ◽

Heeeun Kim ◽

Jinseon Han ◽

Jieun Lee ◽

Sunghoo Hong ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Gene Panel ◽

Specific Gene ◽

Cell Renal Cell Carcinoma ◽

Clinicopathological Findings ◽

Generation Sequencing

Purpose: Although mutations are associated with carcinogenesis, little is known about survival-specific genes in clear cell renal cell carcinoma (ccRCC). We developed a customized next-generation sequencing (NGS) gene panel with 156 genes. The purpose of this study was to investigate whether the survival-specific genes we found were present in Korean ccRCC patients, and their association with clinicopathological findings. Materials and Methods: DNA was extracted from the formalin-fixed, paraffin-embedded tissue of 22 ccRCC patients. NGS was performed using our survival-specific gene panel with an Illumina MiSeq. We analyzed NGS data and the correlations between mutations and clinicopathological findings and also compared them with data from the Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) and Renal Cell Cancer-European Union (RECA-EU). Results: We found a total of 100 mutations in 37 of the 156 genes (23.7%) in 22 ccRCC patients. Of the 37 mutated genes, 11 were identified as clinicopathologically significant. Six were novel survival-specific genes (ADAMTS10, CARD6, NLRP2, OBSCN, SECISBP2L, and USP40), and five were top-ranked mutated genes (AKAP9, ARID1A, BAP1, KDM5C, and SETD2). Only CARD6 was validated as an overall survival-specific gene in this Korean study (p = 0.04, r = −0.441), TCGA-KIRC cohort (p = 0.0003), RECA-EU (p = 0.0005). The 10 remaining gene mutations were associated with clinicopathological findings; disease-free survival, mortality, nuclear grade, sarcomatoid component, N-stage, sex, and tumor size. Conclusions: We discovered 11 survival-specific genes in ccRCC using data from TCGA-KIRC, RECA-EU, and Korean patients. We are the first to find a correlation between CARD6 and overall survival in ccRCC. The 11 genes, including CARD6, NLRP2, OBSCN, and USP40, could be useful diagnostic, prognostic, and therapeutic markers in ccRCC.

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