title: Exome sequencing reveals frequent deleterious germline variants in cancer susceptibility genes in women with invasive breast cancer undergoing neoadjuvant chemotherapy.
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.
authors: Center for Individualized Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors: Marissa S
authors: MS
authors: Ellingson
authors: Steven N
authors: SN
authors: Hart
authors: Krishna R
authors: KR
authors: Kalari
authors: Vera
authors: V
authors: Suman
authors: Kimberly A
authors: KA
authors: Schahl
authors: Travis J
authors: TJ
authors: Dockter
authors: Sara J
authors: SJ
authors: Felten
authors: Jason P
authors: JP
authors: Sinnwell
authors: Kevin J
authors: KJ
authors: Thompson
authors: Xiaojia
authors: X
authors: Tang
authors: Peter T
authors: PT
authors: Vedell
authors: Poulami
authors: P
authors: Barman
authors: Hugues
authors: H
authors: Sicotte
authors: Jeanette E
authors: JE
authors: Eckel-Passow
authors: Donald W
authors: DW
authors: Northfelt
authors: Richard J
authors: RJ
authors: Gray
authors: Sarah A
authors: SA
authors: McLaughlin
authors: Alvaro
authors: A
authors: Moreno-Aspitia
authors: James N
authors: JN
authors: Ingle
authors: Ann M
authors: AM
authors: Moyer
authors: Daniel W
authors: DW
authors: Visscher
authors: Katie
authors: K
authors: Jones
authors: Amy
authors: A
authors: Conners
authors: Michelle
authors: M
authors: McDonough
authors: Eric D
authors: ED
authors: Wieben
authors: Liewei
authors: L
authors: Wang
authors: Richard
authors: R
authors: Weinshilboum
authors: Judy C
authors: JC
authors: Boughey
authors: Matthew P
authors: MP
authors: Goetz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D030541:Databases, Genetic; D059472:Exome; D005260:Female; D005787:Gene Frequency; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor