Clinical genomics of metastatic cancer


Recently, we carried out a comprehensive molecular analysis of metastatic solid tumors of diverse lineage and biopsy site from 500 adult patients (MET500 cohort) by performing clinical-grade integrative whole exome (tumor/normal) and transcriptome sequencing. Sequencing matched tumor and normal samples from patients identified potentially pathogenic germline alterations as well as provided high resolution copy number landscapes. RNA sequencing analysis provided insights into the tumor lineage, functional gene fusions, transcriptional pathway activation, viral pathogen, and immune cell landscape. We found that 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 genes, most commonly occurring in BRCA1, BRCA2, CHEK2 and MUTYH. Tiering of the molecular alterations identified in metastatic cancers provided a rationale for clinical trial or registry study enrollment in 72% of cases and guideline based recommendations in 16% of cases. Our results demonstrate that integrative sequence analysis provides clinically relevant, multidimensional view of the complex molecular landscape and microenvironment of metastatic cancers. The manuscript presenting the analysis of the MET500 cohort has been published in Nature (2017 Aug 2. doi: 10.1038/nature23306).

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