Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

RNA-seq of pre-treatment and post-relapse matched samples from melanoma patients

ABSTRACT: RNA-seq of pre-treatment and post-relapse matched samples from melanoma patients RNA-seq was performed for matched samples before treatment and after relapse from six patients that have been treated with RAF or RAF+MEK inhibitors. Submitter declares that raw sequence data will be submitted to dbGaP due to patient privacy concerns.

ORGANISM(S): Homo sapiens

SUBMITTER: Itay Tirosh

PROVIDER: E-GEOD-77940 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition.

Wagle Nikhil N Van Allen Eliezer M EM Treacy Daniel J DJ Frederick Dennie T DT Cooper Zachary A ZA Taylor-Weiner Amaro A Rosenberg Mara M Goetz Eva M EM Sullivan Ryan J RJ Farlow Deborah N DN Friedrich Dennis C DC Anderka Kristin K Perrin Danielle D Johannessen Cory M CM McKenna Aaron A Cibulskis Kristian K Kryukov Gregory G Hodis Eran E Lawrence Donald P DP Fisher Sheila S Getz Gad G Gabriel Stacey B SB Carter Scott L SL Flaherty Keith T KT Wargo Jennifer A JA Garraway Levi A LA

Cancer discovery 20131121 1

Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP-ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired res ...[more]

PMID: 24265154

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Project description:Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer with high intra-tumoral heterogeneity, frequently resistant to treatment and no known targeted therapy available to improve patient outcomes. It has been hypothesized that the genomic architecture of a TNBC tumour evolves over time, both before, and during therapy, leading to therapy resistance and a high propensity to relapse. Whether this is an inherent property of the tumour or acquired over time is not well characterized. Despite this important clinical implication, limited studies have been carried out to unravel temporal evolution of TNBC over time. Herein, we report an OMICS based analysis of three TNBC patients who were longitudinally sampled during their treatment at different times of relapse. We recruited three TNBC patients at the time of their first relapse who were then followed-up through the course of their treatment. We obtained retrospective samples (tumour samples) from patient tumours at diagnosis (before neo-adjuvant chemotherapy - NACT) at surgery (post NACT) and prospectively sampled them at each subsequent relapse (tumour, blood plasma, and buffy coat) as determined by RECIST criteria. Tumor and buffy coat DNA were subjected to whole exome sequencing (WES) at 200x, and SNP arrays for copy number variation (CNV) analysis. RNA from tumour samples at relapse was subjected to whole transcriptome sequencing. Pathogenic germline BRCA1 variants identified in WES were validated using Sanger sequencing. 1084 somatic mutations identified in whole exome sequencing of all tumour tissues (n=13) from three patients, were subjected to a custom amplicon ultra-deep sequencing assay at 30,000X in their germline DNA (n=3), tumour DNA (n=10), and cfDNA from plasma samples at relapse (n=8). Copy number corrected allele frequencies, tumour ploidy, tumour purity, and ultra-deep sequencing assay derived variant allele frequencies were used to infer clonal and phylogenetic architecture of each patient as it evolved under selective pressure of therapy over time. Clonality analysis incorporating allele fractions from ultra-deep sequencing identified clones comprising of mutations that are present throughout the course of therapy which we term as founding clones and stem mutations respectively. Such founding clones comprising of stem mutations in all 3 patients were present throughout the course of treatment, irrespective of change in treatment modalities. These stem clones included well characterized cancer related genes like PDGFRB & ARID2 (Patient 02), TP53, BRAF & CSF3R (Patient 04) and ESR1, APC, EZH2 & TP53 (Patient 07). Such branching evolution is seen in all three patients wherein the dominant clone (stem clone) acquires additional mutations to form sub-clones, while persisting over time. These sub-clones may be chemo and radio resistant, while also providing for organ specific metastatic potential. Allele fractions of expressed variants inferred from RNA-Seq data co-related with allele fractions from WES data indicating that all somatic.

Dataset Information

RNA-seq of pre-treatment and post-relapse matched samples from melanoma patients

Publications

MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition.

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