Use of WGS for Diagnosis and Discovery in the Cancer Genetics Clinic

Despite the potential of whole-genome sequencing (WGS) to improve patient diagnosis and care, the empirical value of WGS in the cancer genetics clinic is unknown. We performed WGS on members of two cohorts of cancer genetics patients: those with BRCA1/2 mutations (n = 176) and those without (n = 82). Initial analysis of potentially pathogenic variants (PPVs, defined as nonsynonymous variants with allele frequency < 1% in ESP6500) in 163 clinically-relevant genes suggested that WGS will provide useful clinical results. This is despite the fact that a majority of PPVs were novel missense variants likely to be classified as variants of unknown significance (VUS). Furthermore, previously reported pathogenic missense variants did not always associate with their predicted diseases in our patients. This suggests that the clinical use of WGS will require large-scale efforts to consolidate WGS and patient data to improve accuracy of interpretation of rare variants. While loss-of-function (LoF) variants represented only a small fraction of PPVs, WGS identified additional cancer risk LoF PPVs in patients with known BRCA1/2 mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding our analysis to 3209 ClinVar genes. These data illustrate how WGS can be used to improve our ability to discover patients' cancer genetic risks. "Reprinted from doi:10.1016/j.ebiom.2014.12.003, with permission from EBioMedicine."]]>
Individuals from the cancer genetics clinics of the University of Texas Southwestern Medical Center (UTSW) and the Ohio State University (OSU) cancer genetics programs were recruited to the study following informed consent approved by the Institutional Review Boards of both institutions. Only unrelated individuals were included in this study. Blood samples were obtained and de-identified. Subsequent genetic results were not returned to participants.]]>
First samples collected March 2003. Additional patients recruited at Ohio State University, Columbus, OH, and University of Texas Southwestern Medical Center, Dallas, TX, continued through 2013. First samples submitted to Complete Genomics, Inc. in December 2012. Study ended October 2014.]]>