Integrative Molecular Analysis of Patients With Advanced and Metastatic Cancer.

Abstract

We developed a precision medicine program for patients with advanced cancer using integrative whole-exome sequencing and transcriptome analysis. Five hundred fifteen patients with locally advanced/metastatic solid tumors were prospectively enrolled, and paired tumor/normal sequencing was performed. Seven hundred fifty-nine tumors from 515 patients were evaluated. Most frequent tumor types were prostate (19.4%), brain (16.5%), bladder (15.4%), and kidney cancer (9.2%). Most frequently altered genes were <i>TP53</i> (33%), <i>CDKN2A</i> (11%), <i>APC</i> (10%), <i>KTM2D</i> (8%), <i>PTEN</i> (8%), and <i>BRCA2</i> (8%). Pathogenic germline alterations were present in 10.7% of patients, most frequently <i>CHEK2</i> (1.9%), <i>BRCA1</i> (1.5%), <i>BRCA2</i> (1.5%), and <i>MSH6</i> (1.4%). Novel gene fusions were identified, including a <i>RBM47-CDK12</i> fusion in a metastatic prostate cancer sample. The rate of clinically relevant alterations was 39% by whole-exome sequencing, which was improved by 16% by adding RNA sequencing. In patients with more than one sequenced tumor sample (n = 146), 84.62% of actionable mutations were concordant. Integrative analysis may uncover informative alterations for an advanced pan-cancer patient population. These alterations are consistent in spatially and temporally heterogeneous samples.