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Journal Article

Assigning clinical meaning to somatic and germ-line whole-exome sequencing data in a prospective cancer precision medicine study

PURPOSE: Implementing cancer precision medicine in the clinic requires assessing the therapeutic relevance of genomic alterations. A main challenge is the systematic interpretation of whole-exome sequencing (WES) data for clinical care.

METHODS: One hundred sixty-five adults with metastatic colorectal and lung adenocarcinomas were prospectively enrolled in the CanSeq study. WES was performed on DNA extracted from formalin-fixed paraffin-embedded tumor biopsy samples and matched blood samples. Somatic and germ-line alterations were ranked according to therapeutic or clinical relevance. Results were interpreted using an integrated somatic and germ-line framework and returned in accordance with patient preferences.

RESULTS: At the time of this analysis, WES had been performed and results returned to the clinical team for 165 participants. Of 768 curated somatic alterations, only 31% were associated with clinical evidence and 69% with preclinical or inferential evidence. Of 806 curated germ-line variants, 5% were clinically relevant and 56% were classified as variants of unknown significance. The variant review and decision-making processes were effective when the process was changed from that of a Molecular Tumor Board to a protocol-based approach.

CONCLUSION: The development of novel interpretive and decision-support tools that draw from scientific and clinical evidence will be crucial for the success of cancer precision medicine in WES studies.Genet Med advance online publication 26 January 2017.

Arezou A Ghazani
Nelly M Oliver
Joseph P St. Pierre
Andrea Garofalo
Irene R Rainville
Elaine Hiller
Daniel J Treacy
Vanesa Rojas-Rudilla
Sam Wood
Elizabeth Bair
Michael Parello
Franklin Huang
Marios Giannakis
Frederick H Wilson
Elizabeth H Stover
Steven M Corsello
Tom Nguyen
Huma Q Rana
Alanna J Church
Carol Lowenstein
Carrie Cibulskis
Ali Amin-Mansour
Jennifer Heng
Lauren Brais
Abigail Santos
Patrick Bauer
Amanda Waldron
Peter Lo
Megan Gorman
Christine A Lydon
Marisa Welch
Philip McNamara
Stacey Gabriel
Lynette M Sholl
Neal I Lindeman
Judy E Garber
Steven Joffe
Eliezer M Van Allen
Stacy W Gray
Pasi A Jänne
Levi A Garraway
Nikhil Wagle
Journal Name
Genetics In Medicine
Publication Date
July, 2017