Exome sequencing reveals frequent deleterious germline variants in cancer susceptibility genes in women with invasive breast cancer undergoing neoadjuvant chemotherapy

Marissa S. Ellingson, Steven N. Hart, Krishna R. Kalari, Vera Suman, Kimberly A. Schahl, Travis J. Dockter, Sara J. Felten, Jason P. Sinnwell, Kevin J. Thompson, Xiaojia Tang, Peter T. Vedell, Poulami Barman, Hugues Sicotte, Jeanette E. Eckel-Passow, Donald W. Northfelt, Richard J. Gray, Sarah A. McLaughlin, Alvaro Moreno-Aspitia, James N. Ingle, Ann M. MoyerDaniel W. Visscher, Katie Jones, Amy Conners, Michelle McDonough, Eric D. Wieben, Liewei Wang, Richard Weinshilboum, Judy C. Boughey, Matthew P. Goetz

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

When sequencing blood and tumor samples to identify targetable somatic variants for cancer therapy, clinically relevant germline variants may be uncovered. We evaluated the prevalence of deleterious germline variants in cancer susceptibility genes in women with breast cancer referred for neoadjuvant chemotherapy and returned clinically actionable results to patients. Exome sequencing was performed on blood samples from women with invasive breast cancer referred for neoadjuvant chemotherapy. Germline variants within 142 hereditary cancer susceptibility genes were filtered and reviewed for pathogenicity. Return of results was offered to patients with deleterious variants in actionable genes if they were not aware of their result through clinical testing. 124 patients were enrolled (median age 51) with the following subtypes: triple negative (n = 43, 34.7 %), HER2+ (n = 37, 29.8 %), luminal B (n = 31, 25 %), and luminal A (n = 13, 10.5 %). Twenty-eight deleterious variants were identified in 26/124 (21.0 %) patients in the following genes: ATM (n = 3), BLM (n = 1), BRCA1 (n = 4), BRCA2 (n = 8), CHEK2 (n = 2), FANCA (n = 1), FANCI (n = 1), FANCL (n = 1), FANCM (n = 1), FH (n = 1), MLH3 (n = 1), MUTYH (n = 2), PALB2 (n = 1), and WRN (n = 1). 121/124 (97.6 %) patients consented to return of research results. Thirteen (10.5 %) had actionable variants, including four that were returned to patients and led to changes in medical management. Deleterious variants in cancer susceptibility genes are highly prevalent in patients with invasive breast cancer referred for neoadjuvant chemotherapy undergoing exome sequencing. Detection of these variants impacts medical management.

Original languageEnglish (US)
Pages (from-to)435-443
Number of pages9
JournalBreast Cancer Research and Treatment
Volume153
Issue number2
DOIs
StatePublished - Sep 7 2015

Keywords

  • Breast cancer
  • Exome sequencing
  • Germline mutation/pathogenic germline variant
  • High-risk breast cancer
  • Neoadjuvant chemotherapy
  • Return of results

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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