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Integrative Molecular Analysis of Patients With Advanced and Metastatic Cancer.

ABSTRACT: PURPOSE:We developed a precision medicine program for patients with advanced cancer using integrative whole-exome sequencing and transcriptome analysis. PATIENTS AND METHODS: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. RESULTS:Most frequent tumor types were prostate (19.4%), brain (16.5%), bladder (15.4%), and kidney cancer (9.2%). Most frequently altered genes were TP53 (33%), CDKN2A (11%), APC (10%), KTM2D (8%), PTEN (8%), and BRCA2 (8%). Pathogenic germline alterations were present in 10.7% of patients, most frequently CHEK2 (1.9%), BRCA1 (1.5%), BRCA2 (1.5%), and MSH6 (1.4%). Novel gene fusions were identified, including a RBM47-CDK12 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. CONCLUSION:Integrative analysis may uncover informative alterations for an advanced pan-cancer patient population. These alterations are consistent in spatially and temporally heterogeneous samples.

SUBMITTER: Sailer V

PROVIDER: S-EPMC6778956 | biostudies-other | 2019

REPOSITORIES: biostudies-other

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Integrative Molecular Analysis of Patients With Advanced and Metastatic Cancer.

Sailer Verena V Eng Kenneth Wa KW Zhang Tuo T Bareja Rohan R Pisapia David J DJ Sigaras Alexandros A Bhinder Bhavneet B Romanel Alessandro A Wilkes David D Sticca Evan E Cyrta Joanna J Rao Rema R Sahota Sheena S Pauli Chantal C Beg Shaham S Motanagh Samaneh S Kossai Myriam M Fontunge Jacqueline J Puca Loredana L Rennert Hanna H Zhaoying Xiang Jenny J Greco Noah N Kim Rob R MacDonald Theresa Y TY McNary Terra T Blattner-Johnson Mirjam M Schiffman Marc H MH Faltas Bishoy M BM Greenfield Jeffrey P JP Rickman David D Andreopoulou Eleni E Holcomb Kevin K Vahdat Linda T LT Scherr Douglas S DS van Besien Koen K Barbieri Christopher E CE Robinson Brian D BD Fine Howard Alan HA Ocean Allyson J AJ Molina Ana A Shah Manish A MA Nanus David M DM Pan Qiulu Q Demichelis Francesca F Tagawa Scott T ST Song Wei W Mosquera Juan Miguel JM Sboner Andrea A Rubin Mark A MA Elemento Olivier O Beltran Himisha H

JCO precision oncology 20190920

<h4>Purpose</h4>We developed a precision medicine program for patients with advanced cancer using integrative whole-exome sequencing and transcriptome analysis.<h4>Patients and methods</h4>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.<h4>Results</h4>Most frequent tumor types were prostate (19.4%), brain (16.5%), bladder (15 ...[more]

PMID: 31592503

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Project description:BACKGROUND:Hepatocellular carcinoma (HCC) is the major type of primary liver cancer. Intrahepatic metastasis, such as portal vein tumor thrombosis (PVTT), strongly indicates poor prognosis of HCC. But now, there are limited understandings of the molecular features and mechanisms of those metastatic HCCs. METHODS:To characterize the molecular alterations of the metastatic HCCs, we implemented an integrative analysis of the copy number variations (CNVs), DNA methylations and transcriptomes of matched adjacent normal, primary tumor and PVTT samples from 19 HCC patients. RESULTS:CNV analysis identified a frequently amplified focal region chr11q13.3 and a novel deletion peak chr19q13.41 containing three miRNAs. The integrative analysis with RNA-seq data suggests that CNVs and differential promoter methylations regulate distinct oncogenic processes. Then, we used individualized differential analysis to identify the differentially expressed genes between matched primary tumor and PVTT of each patient. Results show that 5 out of 19 studied patients acquire evidential progressive alterations of gene expressions (more than 1000 differentially expressed genes were identified in each patient). While, another subset of eight patients have nearly identical gene expressions between the corresponding matched primary tumor and PVTT. Twenty genes were found to be recurrently and progressively differentially expressed in multiple patients. These genes are mainly associated with focal adhesion, xenobiotics metabolism by cytochrome P450 and amino acid metabolism. For several differentially expressed genes in metabolic pathways, their expressions are significantly associated with overall survivals and vascular invasions of HCC patients. The following transwell assay experiments validate that they can regulate invasive phenotypes of HCC cells. CONCLUSIONS:The metastatic HCCs with PVTTs have significant molecular alterations comparing with adjacent normal tissues. The recurrent alteration patterns are similar to several previously published general HCC cohorts, but usually with higher severity. By an individualized differential analysis strategy, the progressively differentially expressed genes between the primary tumor and PVTT were identified for each patient. A few patients aquire evidential progressive alterations of gene expressions. And, experiments show that several recurrently differentially expressed genes can strongly regulate HCC cell invasions.

Dataset Information

Integrative Molecular Analysis of Patients With Advanced and Metastatic Cancer.

Publications

Integrative Molecular Analysis of Patients With Advanced and Metastatic Cancer.

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