Management of Germline Findings Revealed throughout the Course of Tumor-normal Whole Genome Sequencing in Oncology

Lim, Howard*; Fok, Alexandra*; Schrader, Kasmintan; Armstrong, Linlea; Young, Sean; Virani, Alice; Karsan, Aly; Yip, Stephen; Rassekh, S. Rod; Deyell, Rebecca; Roscoe, Robyn; Jones, Martin; Pleasance, Erin; Marra, Marco; Laskin, Janessa

Background: The Personalized OncoGenomics (POG) project utilizes tumor-normal whole genome sequencing (WGS) to understand key driver pathways and guide personalized treatment decisions. Analysis of the germline data can reveal variants; these may be presumed pathogenic, presumed benign or of unknown significance (VUS). We have developed a process for evaluating, and returning presumed pathogenic variants to patients, after counseling and verification in a clinically-accredited laboratory.

Methods: Patients are given the option of receiving germline information as part of the consent process for participation in the POG program. A sub-committee comprised of medical geneticists, bioinformaticians, genomic pathologists, oncologists, and a genomics ethicist review the germline results. Variant verification in the clinically accredited BCCA Cancer Genetics Laboratory, and genetic counseling within the Hereditary Cancer Program of BC enables seamless return of POG-generated clinically relevant germline results to affected subjects.

Results: Presumed pathogenic variants in known cancer susceptibility genes are validated and returned to the patient via the oncologist with an appointment with a medical geneticist and counselor in the Hereditary Cancer Program. VUS are reviewed by the sub-committee. These are determined to be pathogenic, benign, or remain of unknown clinical significance after a review of the available literature, local frequency data, as well as publicly available databases. VUS are then catalogued in the event that a variant is reclassified as pathogenic or likely pathogenic during the time course of the POG program. If a VUS is thought to be likely pathogenic, the above process is followed.

Conclusion: Whole genome sequencing has provided a wealth of research information, some of which can have a profound impact on treatment choices as well as patients and their families. We have created a process to manage clinically relevant germline findings that identified during the course of genomic research to ensure appropriate care for patients.