Integrative clinical genomics of metastatic cancer

Dan R Robinson; Yi-Mi Wu; Robert J Lonigro; Pankaj Vats; Erin Cobain; Jessica Everett; Xuhong Cao; Erica Rabban; Chandan Kumar-Sinha; Victoria Raymond; Scott Schuetze; Ajjai Alva; Javed Siddiqui; Rashmi Chugh; Francis Worden; Mark M Zalupski; Jeffrey Innis; Rajen J Mody; Scott A Tomlins; David Lucas; Laurence H Baker; Nithya Ramnath; Ann F Schott; Daniel F Hayes; Joseph Vijai; Kenneth Offit; Elena M Stoffel; J Scott Roberts; David C Smith; Lakshmi P Kunju; Moshe Talpaz; Marcin Cieślik; Arul M Chinnaiyan

doi:10.1038/nature23306

Integrative clinical genomics of metastatic cancer

Nature. 2017 Aug 17;548(7667):297-303. doi: 10.1038/nature23306. Epub 2017 Aug 2.

Authors

Dan R Robinson^{1

2}, Yi-Mi Wu^{1

2}, Robert J Lonigro¹, Pankaj Vats¹, Erin Cobain³, Jessica Everett³, Xuhong Cao¹, Erica Rabban¹, Chandan Kumar-Sinha^{1

2}, Victoria Raymond³, Scott Schuetze³, Ajjai Alva³, Javed Siddiqui^{1

2}, Rashmi Chugh³, Francis Worden³, Mark M Zalupski³, Jeffrey Innis⁴, Rajen J Mody⁴, Scott A Tomlins^{1

2}, David Lucas², Laurence H Baker³, Nithya Ramnath³, Ann F Schott³, Daniel F Hayes³, Joseph Vijai⁵, Kenneth Offit⁵, Elena M Stoffel³, J Scott Roberts⁶, David C Smith³, Lakshmi P Kunju^{1

2}, Moshe Talpaz⁷, Marcin Cieślik^{1

2}, Arul M Chinnaiyan^{1

2

7

8

9}

Affiliations

¹ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
² Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
³ Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁴ Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁵ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
⁶ Department of Health Behavior &Health Education, School of Public Health, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁷ Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁸ Department of Urology, University of Michigan, Ann Arbor, Michigan 48109, USA.
⁹ Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Class I Phosphatidylinositol 3-Kinases / genetics
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p18 / genetics
DNA Repair / genetics
Exome Sequencing
Female
Genetics, Medical*
Genomics*
Germ-Line Mutation / genetics
Humans
Male
Neoplasm Metastasis / genetics*
Neoplasm Metastasis / immunology
Neoplasm Metastasis / pathology
PTEN Phosphohydrolase / genetics
Retinoblastoma Binding Proteins / genetics
Transcriptome / genetics
Tumor Microenvironment / genetics
Tumor Microenvironment / immunology
Tumor Suppressor Protein p53 / genetics
Ubiquitin-Protein Ligases / genetics

Substances

CDKN2A protein, human
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p18
RB1 protein, human
Retinoblastoma Binding Proteins
TP53 protein, human
Tumor Suppressor Protein p53
Ubiquitin-Protein Ligases
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human
PTEN Phosphohydrolase
PTEN protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding