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

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)74-81
Number of pages8
JournalEBioMedicine
Volume2
Issue number1
DOIs
StatePublished - 2015

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Genes
Genome
Neoplasms
Mutation
Genetics
Gene Frequency
Patient Care

Keywords

  • BRCA1/2
  • Cancer genetics
  • ClinVar
  • Pathogenic variants
  • Single nucleotide variant
  • Whole-genome sequence

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic. / Foley, Samantha B.; Rios, Jonathan J.; Mgbemena, Victoria E.; Robinson, Linda S.; Hampel, Heather L.; Toland, Amanda E.; Durham, Leslie; Ross, Theodora S.

In: EBioMedicine, Vol. 2, No. 1, 2015, p. 74-81.

Research output: Contribution to journalArticle

Foley, SB, Rios, JJ, Mgbemena, VE, Robinson, LS, Hampel, HL, Toland, AE, Durham, L & Ross, TS 2015, 'Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic', EBioMedicine, vol. 2, no. 1, pp. 74-81. https://doi.org/10.1016/j.ebiom.2014.12.003
Foley, Samantha B. ; Rios, Jonathan J. ; Mgbemena, Victoria E. ; Robinson, Linda S. ; Hampel, Heather L. ; Toland, Amanda E. ; Durham, Leslie ; Ross, Theodora S. / Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic. In: EBioMedicine. 2015 ; Vol. 2, No. 1. pp. 74-81.
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