Dataset Information

A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation.

ABSTRACT:

Purpose

Genome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder enables clinical interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource of information regarding the clinical relevance of genomic variation for use in precision medicine and research.

Methods

We developed a practical, standardized protocol to identify available evidence and generate qualitative summary reports of actionability for disorders and associated genes. We applied a semiquantitative metric to score actionability.

Results

We generated summary reports and actionability scores for the 56 genes and associated disorders recommended by the American College of Medical Genetics and Genomics for return as secondary findings from clinical genome-scale sequencing. We also describe the challenges that arose during the development of the protocol that highlight important issues in characterizing actionability across a range of disorders.

Conclusion

The ClinGen framework for actionability assessment will assist research and clinical communities in making clear, efficient, and consistent determinations of actionability based on transparent criteria to guide analysis and reporting of findings from clinical genome-scale sequencing.Genet Med 18 12, 1258-1268.

SUBMITTER: Hunter JE

PROVIDER: S-EPMC5085884 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Publications

A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation.

Hunter Jessica Ezzell JE Irving Stephanie A SA Biesecker Leslie G LG Buchanan Adam A Jensen Brian B Lee Kristy K Martin Christa Lese CL Milko Laura L Muessig Kristin K Niehaus Annie D AD O'Daniel Julianne J Piper Margaret A MA Ramos Erin M EM Schully Sheri D SD Scott Alan F AF Slavotinek Anne A Sobreira Nara N Strande Natasha N Weaver Meredith M Webber Elizabeth M EM Williams Marc S MS Berg Jonathan S JS Evans James P JP Goddard Katrina A B KA

Genetics in medicine : official journal of the American College of Medical Genetics 20160428 12

<h4>Purpose</h4>Genome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder enables clinical interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource of information regarding the ...[more]

PMID: 27124788

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Project description:BackgroundThe frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important.MethodsA prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board.ResultsOf the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0-10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing.ConclusionUse of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability.Implications for practiceIdentification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next-generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents.

Dataset Information

A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation.

Purpose

Methods

Results

Conclusion

Publications

A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation.

Similar Datasets

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