Dataset Information

Development and clinical application of an integrative genomic approach to personalized cancer therapy.

ABSTRACT:

Background

Personalized therapy provides the best outcome of cancer care and its implementation in the clinic has been greatly facilitated by recent convergence of enormous progress in basic cancer research, rapid advancement of new tumor profiling technologies, and an expanding compendium of targeted cancer therapeutics.

Methods

We developed a personalized cancer therapy (PCT) program in a clinical setting, using an integrative genomics approach to fully characterize the complexity of each tumor. We carried out whole exome sequencing (WES) and single-nucleotide polymorphism (SNP) microarray genotyping on DNA from tumor and patient-matched normal specimens, as well as RNA sequencing (RNA-Seq) on available frozen specimens, to identify somatic (tumor-specific) mutations, copy number alterations (CNAs), gene expression changes, gene fusions, and also germline variants. To provide high sensitivity in known cancer mutation hotspots, Ion AmpliSeq Cancer Hotspot Panel v2 (CHPv2) was also employed. We integrated the resulting data with cancer knowledge bases and developed a specific workflow for each cancer type to improve interpretation of genomic data.

Results

We returned genomics findings to 46 patients and their physicians describing somatic alterations and predicting drug response, toxicity, and prognosis. Mean 17.3 cancer-relevant somatic mutations per patient were identified, 13.3-fold, 6.9-fold, and 4.7-fold more than could have been detected using CHPv2, Oncomine Cancer Panel (OCP), and FoundationOne, respectively. Our approach delineated the underlying genetic drivers at the pathway level and provided meaningful predictions of therapeutic efficacy and toxicity. Actionable alterations were found in 91 % of patients (mean 4.9 per patient, including somatic mutations, copy number alterations, gene expression alterations, and germline variants), a 7.5-fold, 2.0-fold, and 1.9-fold increase over what could have been uncovered by CHPv2, OCP, and FoundationOne, respectively. The findings altered the course of treatment in four cases.

Conclusions

These results show that a comprehensive, integrative genomic approach as outlined above significantly enhanced genomics-based PCT strategies.

SUBMITTER: Uzilov AV

PROVIDER: S-EPMC4888213 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Publications

Development and clinical application of an integrative genomic approach to personalized cancer therapy.

Uzilov Andrew V AV Ding Wei W Fink Marc Y MY Antipin Yevgeniy Y Brohl Andrew S AS Davis Claire C Lau Chun Yee CY Pandya Chetanya C Shah Hardik H Kasai Yumi Y Powell James J Micchelli Mark M Castellanos Rafael R Zhang Zhongyang Z Linderman Michael M Kinoshita Yayoi Y Zweig Micol M Raustad Katie K Cheung Kakit K Castillo Diane D Wooten Melissa M Bourzgui Imane I Newman Leah C LC Deikus Gintaras G Mathew Bino B Zhu Jun J Glicksberg Benjamin S BS Moe Aye S AS Liao Jun J Edelmann Lisa L Dudley Joel T JT Maki Robert G RG Kasarskis Andrew A Holcombe Randall F RF Mahajan Milind M Hao Ke K Reva Boris B Longtine Janina J Starcevic Daniela D Sebra Robert R Donovan Michael J MJ Li Shuyu S Schadt Eric E EE Chen Rong R

Genome medicine 20160601 1

<h4>Background</h4>Personalized therapy provides the best outcome of cancer care and its implementation in the clinic has been greatly facilitated by recent convergence of enormous progress in basic cancer research, rapid advancement of new tumor profiling technologies, and an expanding compendium of targeted cancer therapeutics.<h4>Methods</h4>We developed a personalized cancer therapy (PCT) program in a clinical setting, using an integrative genomics approach to fully characterize the complexi ...[more]

PMID: 27245685

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Project description:ImportanceGreater understanding of molecular features of conjunctival melanoma (CM) may improve its clinical management.ObjectiveTo evaluate molecular features of CM and application of this information into clinical care.Design, setting, and participantsIn a prospective case series of CM with integrative exome and transcriptome analysis, 8 patients at an academic ocular oncology setting were evaluated. The study was conducted from November 2015 to March 2018.Interventions/exposuresIntegrative exome and transcriptome analysis of CMs and clinical management of a patient's care by using this information.Main outcomes and measuresMolecular characterization of CM and its potential clinical application.ResultsIn the 8 patients (4 men) included in analysis, 4 subgroups of CM were observed, including the BRAF V600E mutation in 1 tumor, NRAS Q61R mutation in 3 tumors, NF1 mutations (Q1188X, R440X, or M1215K+ S15fs) in 3 tumors, and triple-wild type (triple-WT) in 1 tumor. The triple-WT case had CCND1 amplification and mutation in the CIC gene (Q1508X). Five tumors, including the triple-WT, also harbored mutations in MAPK genes. In addition to the genes linked to mitogen-activated protein kinase and phosphoinositol 3-kinase pathways, those involved in cell cycle and/or survival, ubiquitin-mediated protein degradation, and chromatin remodeling/epigenetic regulation (ATRX being the most frequently mutated: noted in 5 tumors) may play an important role. Other frequently mutated genes included PREX2 (n = 3), APOB (n = 4), and RYR1/2 (n = 4), although their relevance remains to be determined. The mutation burden ranged from 1.1 to 15.6 mutations per megabase (Mut/Mb) and was 3.3 Mut/Mb or less in 3 tumors and more than 10 Mut/Mb in 2 tumors. A patient with a large tumor and BRAF V600E mutation was treated with combined systemic BRAF (dabrafenib) and MEK (trametinib) inhibitors. After 3 months of therapy, her CM responded substantially and the residual tumor was removed by local surgical excision.Conclusions and relevanceThe NRAS Q61R and NF1 mutations were more common than the BRAF V600E mutation in this series. Although small tumors (where incisional biopsy is not indicated) are treated with surgical excision regardless of mutational profile, in large tumors carrying the BRAF V600E mutation, neoadjuvant therapy with combined systemic BRAF and MEK inhibitors followed by local excision may be used as an alternative to exenteration. Integrative omics analysis of CM may be informative and guide clinical management and treatment in selected cases.

Dataset Information

Development and clinical application of an integrative genomic approach to personalized cancer therapy.

Background

Methods

Results

Conclusions

Publications

Development and clinical application of an integrative genomic approach to personalized cancer therapy.

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