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

Genet Med. 2017 Jul;19(7):787-795. doi: 10.1038/gim.2016.191. Epub 2017 Jan 26.


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.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma of Lung
  • Adult
  • Colorectal Neoplasms / genetics
  • Databases, Genetic
  • Exome / genetics*
  • Genomics / methods
  • Germ-Line Mutation / genetics
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Lung Neoplasms / genetics
  • Mutation / genetics
  • Precision Medicine / methods*
  • Prospective Studies
  • Sequence Analysis, DNA / methods
  • Whole Exome Sequencing / methods*