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Comparative effectiveness of next generation genomic sequencing for disease diagnosis: design of a randomized controlled trial in patients with colorectal cancer/polyposis syndromes.

ABSTRACT: Whole exome and whole genome sequencing are applications of next generation sequencing transforming clinical care, but there is little evidence whether these tests improve patient outcomes or if they are cost effective compared to current standard of care. These gaps in knowledge can be addressed by comparative effectiveness and patient-centered outcomes research. We designed a randomized controlled trial that incorporates these research methods to evaluate whole exome sequencing compared to usual care in patients being evaluated for hereditary colorectal cancer and polyposis syndromes. Approximately 220 patients will be randomized and followed for 12 months after return of genomic findings. Patients will receive findings associated with colorectal cancer in a first return of results visit, and findings not associated with colorectal cancer (incidental findings) during a second return of results visit. The primary outcome is efficacy to detect mutations associated with these syndromes; secondary outcomes include psychosocial impact, cost-effectiveness and comparative costs. The secondary outcomes will be obtained via surveys before and after each return visit. The expected challenges in conducting this randomized controlled trial include the relatively low prevalence of genetic disease, difficult interpretation of some genetic variants, and uncertainty about which incidental findings should be returned to patients. The approaches utilized in this study may help guide other investigators in clinical genomics to identify useful outcome measures and strategies to address comparative effectiveness questions about the clinical implementation of genomic sequencing in clinical care.

SUBMITTER: Gallego CJ

PROVIDER: S-EPMC4175052 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Comparative effectiveness of next generation genomic sequencing for disease diagnosis: design of a randomized controlled trial in patients with colorectal cancer/polyposis syndromes.

Gallego Carlos J CJ Bennette Caroline S CS Heagerty Patrick P Comstock Bryan B Horike-Pyne Martha M Hisama Fuki F Amendola Laura M LM Bennett Robin L RL Dorschner Michael O MO Tarczy-Hornoch Peter P Grady William M WM Fullerton S Malia SM Trinidad Susan B SB Regier Dean A DA Nickerson Deborah A DA Burke Wylie W Patrick Donald L DL Jarvik Gail P GP Veenstra David L DL

Contemporary clinical trials 20140703 1

Whole exome and whole genome sequencing are applications of next generation sequencing transforming clinical care, but there is little evidence whether these tests improve patient outcomes or if they are cost effective compared to current standard of care. These gaps in knowledge can be addressed by comparative effectiveness and patient-centered outcomes research. We designed a randomized controlled trial that incorporates these research methods to evaluate whole exome sequencing compared to usu ...[more]

PMID: 24997220

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Project description:BackgroundGenetic screening in families with high risk to develop colorectal cancer (CRC) prevents incurable disease and permits personalized therapeutic and follow-up strategies. The advancement of next-generation sequencing (NGS) technologies has revolutionized the throughput of DNA sequencing.MethodsA series of 16 probands for either familial adenomatous polyposis (FAP; 8 cases) or hereditary nonpolyposis colorectal cancer (HNPCC; 8 cases) were investigated for intragenic mutations in five CRC familial syndromes-associated genes (APC, MUTYH, MLH1, MSH2, MSH6) applying both a custom multigene Ion AmpliSeq NGS panel and conventional Sanger sequencing.ResultsFourteen pathogenic variants were detected in 13/16 FAP/HNPCC probands (81.3 %); one FAP proband presented two co-existing pathogenic variants, one in APC and one in MUTYH. Thirteen of these 14 pathogenic variants were detected by both NGS and Sanger, while one MSH2 mutation (L280FfsX3) was identified only by Sanger sequencing. This is due to a limitation of the NGS approach in resolving sequences close or within homopolymeric stretches of DNA. To evaluate the performance of our NGS custom panel we assessed its capability to resolve the DNA sequences corresponding to 2225 pathogenic variants reported in the COSMIC database for APC, MUTYH, MLH1, MSH2, MSH6. Our NGS custom panel resolves the sequences where 2108 (94.7 %) of these variants occur. The remaining 117 mutations reside inside or in close proximity to homopolymer stretches; of these 27 (1.2 %) are imprecisely identified by the software but can be resolved by visual inspection of the region, while the remaining 90 variants (4.0 %) are blind spots. In summary, our custom panel would miss 4 % (90/2225) of pathogenic variants that would need a small set of Sanger sequencing reactions to be solved.ConclusionsThe multiplex NGS approach has the advantage of analyzing multiple genes in multiple samples simultaneously, requiring only a reduced number of Sanger sequences to resolve homopolymeric DNA regions not adequately assessed by NGS. The implementation of NGS approaches in routine diagnostics of familial CRC is cost-effective and significantly reduces diagnostic turnaround times.

Dataset Information

Comparative effectiveness of next generation genomic sequencing for disease diagnosis: design of a randomized controlled trial in patients with colorectal cancer/polyposis syndromes.

Publications

Comparative effectiveness of next generation genomic sequencing for disease diagnosis: design of a randomized controlled trial in patients with colorectal cancer/polyposis syndromes.

Similar Datasets

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