Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic

Samantha B Foley,Jonathan J Rios,Victoria E Mgbemena,Linda S Robinson,Heather L Hampel,Amanda E Toland,Leslie Durham,Theodora S Ross

doi:10.1016/j.ebiom.2014.12.003

Abstract

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.

Highlights

With the rapid development and decreasing cost of whole-genome sequencing (WGS) technologies, this genetic testing tool will soon be readily available for common use in the laboratory and clinic (Collins and Hamburg, 2013)
We sought to investigate the value of WGS in two cohorts of cancer genetics patients to begin to address the challenges associated with the identification and clinical interpretation of WGS and potentially pathogenic variants (PPVs) in the genetics clinic
WGS was performed on a series of patients from the cancer genetics clinic that included those found to have BRCA1 (n = 88; Supplementary Table 2) or BRCA2 (n = 88; Supplementary Table 3) mutations, as well as those that were not carriers of a BRCA1/2 mutation (n = 82; Supplementary Table 4)

Summary

Introduction

With the rapid development and decreasing cost of whole-genome sequencing (WGS) technologies, this genetic testing tool will soon be readily available for common use in the laboratory and clinic (Collins and Hamburg, 2013). WGS, and whole-exome sequencing, have already been used to provide genetic diagnoses that inform clinical care (Worthey et al, 2011; Bainbridge et al, 2011; Rios et al, 2010). These early successes in individual patients prompted expanded studies to investigate a more general use of WGS in clinical settings (Saunders et al, 2012). We sought to investigate the value of WGS in two cohorts of cancer genetics patients to begin to address the challenges associated with the identification and clinical interpretation of WGS and potentially pathogenic variants (PPVs) in the genetics clinic

Methods

Results

Conclusion