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Integrative clinical genomics of metastatic cancer.

ABSTRACT: Metastasis is the primary cause of cancer-related deaths. Although The Cancer Genome Atlas has sequenced primary tumour types obtained from surgical resections, much less comprehensive molecular analysis is available from clinically acquired metastatic cancers. Here we perform whole-exome and -transcriptome sequencing of 500 adult patients with metastatic solid tumours of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53, CDKN2A, PTEN, PIK3CA, and RB1. Putative pathogenic germline variants were present in 12.2% of cases of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing to identify gene fusions, pathway activation, and immune profiling. Our results show that integrative sequence analysis provides a clinically relevant, multi-dimensional view of the complex molecular landscape and microenvironment of metastatic cancers.

SUBMITTER: Robinson DR

PROVIDER: S-EPMC5995337 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Integrative clinical genomics of metastatic cancer.

Robinson Dan R DR Wu Yi-Mi YM Lonigro Robert J RJ Vats Pankaj P Cobain Erin E Everett Jessica J Cao Xuhong X Rabban Erica E Kumar-Sinha Chandan C Raymond Victoria V Schuetze Scott S Alva Ajjai A Siddiqui Javed J Chugh Rashmi R Worden Francis F Zalupski Mark M MM Innis Jeffrey J Mody Rajen J RJ Tomlins Scott A SA Lucas David D Baker Laurence H LH Ramnath Nithya N Schott Ann F AF Hayes Daniel F DF Vijai Joseph J Offit Kenneth K Stoffel Elena M EM Roberts J Scott JS Smith David C DC Kunju Lakshmi P LP Talpaz Moshe M Cieślik Marcin M Chinnaiyan Arul M AM

Nature 20170802 7667

Metastasis is the primary cause of cancer-related deaths. Although The Cancer Genome Atlas has sequenced primary tumour types obtained from surgical resections, much less comprehensive molecular analysis is available from clinically acquired metastatic cancers. Here we perform whole-exome and -transcriptome sequencing of 500 adult patients with metastatic solid tumours of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53, CDKN2A, PTE ...[more]

PMID: 28783718

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Project description:It is understood that cancer is a clonal disease initiated by a single cell, and that metastasis, which is the spread of cancer from the primary site, is also initiated by a single cell. The seemingly natural capability of cancer to adapt dynamically in a Darwinian manner is a primary reason for therapeutic failures. Survival advantages may be induced by cancer therapies and also occur as a result of inherent cell and microenvironmental factors. The selected "more fit" clones outmatch their competition and then become dominant in the tumor via propagation of progeny. This clonal expansion leads to relapse, therapeutic resistance and eventually death. The goal of this study is to develop and demonstrate a more detailed clonality approach by utilizing integrative genomics.Patient tumor samples were profiled by Whole Exome Sequencing (WES) and RNA-seq on an Illumina HiSeq 2500 and methylation profiling was performed on the Illumina Infinium 450K array. STAR and the Haplotype Caller were used for RNA-seq processing. Custom approaches were used for the integration of the multi-omic datasets.Reported are major enhancements to CloneViz, which now provides capabilities enabling a formal tumor multi-dimensional clonality analysis by integrating: i) DNA mutations, ii) RNA expressed mutations, and iii) DNA methylation data. RNA and DNA methylation integration were not previously possible, by CloneViz (previous version) or any other clonality method to date. This new approach, named iCloneViz (integrated CloneViz) employs visualization and quantitative methods, revealing an integrative genomic mutational dissection and traceability (DNA, RNA, epigenetics) thru the different layers of molecular structures.The iCloneViz approach can be used for analysis of clonal evolution and mutational dynamics of multi-omic data sets. Revealing tumor clonal complexity in an integrative and quantitative manner facilitates improved mutational characterization, understanding, and therapeutic assignments.

Dataset Information

Integrative clinical genomics of metastatic cancer.

Publications

Integrative clinical genomics of metastatic cancer.

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