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The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine.

ABSTRACT: BACKGROUND:The diversity of clinical tumor profiling approaches (small panels to whole exomes with matched or unmatched germline analysis) may engender uncertainty about their benefits and liabilities, particularly in light of reported germline false positives in tumor-only profiling and use of global mutational and/or neoantigen data. The goal of this study was to determine the impact of genomic analysis strategies on error rates and data interpretation across contexts and ancestries. METHODS:We modeled common tumor profiling modalities-large (n?=?300 genes), medium (n?=?48 genes), and small (n?=?15 genes) panels-using clinical whole exomes (WES) from 157 patients with lung or colon adenocarcinoma. We created a tumor-only analysis algorithm to assess germline false positive rates, the impact of patient ancestry on tumor-only results, and neoantigen detection. RESULTS:After optimizing a germline filtering strategy, the germline false positive rate with tumor-only large panel sequencing was 14 % (144/1012 variants). For patients whose tumor-only results underwent molecular pathologist review (n?=?91), 50/54 (93 %) false positives were correctly interpreted as uncertain variants. Increased germline false positives were observed in tumor-only sequencing of non-European compared with European ancestry patients (p?

SUBMITTER: Garofalo A

PROVIDER: S-EPMC4962446 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine.

Garofalo Andrea A Sholl Lynette L Reardon Brendan B Taylor-Weiner Amaro A Amin-Mansour Ali A Miao Diana D Liu David D Oliver Nelly N MacConaill Laura L Ducar Matthew M Rojas-Rudilla Vanesa V Giannakis Marios M Ghazani Arezou A Gray Stacy S Janne Pasi P Garber Judy J Joffe Steve S Lindeman Neal N Wagle Nikhil N Garraway Levi A LA Van Allen Eliezer M EM

Genome medicine 20160726 1

<h4>Background</h4>The diversity of clinical tumor profiling approaches (small panels to whole exomes with matched or unmatched germline analysis) may engender uncertainty about their benefits and liabilities, particularly in light of reported germline false positives in tumor-only profiling and use of global mutational and/or neoantigen data. The goal of this study was to determine the impact of genomic analysis strategies on error rates and data interpretation across contexts and ancestries.<h ...[more]

PMID: 27460824

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Project description:BACKGROUND:Genomic profiling of colorectal cancer aims to identify actionable somatic mutations but can also discover incidental germline findings. OBJECTIVE:The purpose of this study was to report the detection of pathogenic germline variants that confer heritable cancer predisposition. DESIGN:This was a retrospective study. SETTINGS:The study was conducted at a tertiary-referral institution. PATIENTS:Between 2012 and 2015, 1000 patients with advanced cancer underwent targeted exome sequencing of a 202-gene panel. The subgroup of 151 patients with advanced colorectal cancer who underwent matched tumor-normal (blood) sequencing formed our study cohort. INTERVENTIONS:Germline variants in 46 genes associated with hereditary cancer predisposition were classified according to a defined algorithm based on in silico predictions of pathogenicity. Patients with presumed pathogenic variants were examined for type of mutation, as well as clinical, pedigree, and clinical genetic testing data. MAIN OUTCOME MEASURES:We measured detection of pathogenic germline variants. RESULTS:A total of 1910 distinct germline variants were observed in 151 patients. After filtering, 15 pathogenic germline variants (9.9%) were found in 15 patients, arising from 9 genes of varying penetrance for colorectal cancer (APC (n = 2; 13%), ATM (n = 1; 6%), BRCA1 (n = 2; 13%), CDH1 (n = 2; 13%), CHEK2 (n = 4; 27%), MSH2 (n = 1; 7%), MSH6 (n = 1; 7%), NF2 (n = 1; 7%), and TP53 (n = 1; 7%)). Patients with pathogenic variants were diagnosed at a younger age than those without (median, 45 vs 52 y; p = 0.03). Of the 15 patients, 7 patients (46.7%) with variants in low/moderate- penetrant genes for colorectal cancer would likely have not been tested based on clinical and pedigree criteria, where 2 harbored clinically actionable variants (CDH1 and NF2, 28.5% of 7). LIMITATIONS:This study was limited by its small sample size and advanced-stage patients. CONCLUSIONS:Tumor-normal sequencing can incidentally discover clinically unsuspected germline variants that confer cancer predisposition in 9.9% of patients with advanced colorectal cancer. Precision medicine should integrate clinical cancer genetics to inform and interpret the actionability of germline variants and to provide follow-up care to mutation carriers. See Video Abstract at http://links.lww.com/DCR/A906.

Dataset Information

The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine.

Publications

The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine.

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