title: Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer.
abstract: Homologous recombination (HR) DNA repair-deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51-based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression, and whole-exome sequencing was employed to ascertain the aetiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large-scale state transitions and specific mutational signatures. Somatic and/or germline genetic alterations resulting in bi-allelic loss-of-function of HR genes underpinned functional HRD in 89% of cases, and were observed in only one of the 15 HR-proficient samples tested. These findings indicate the importance of a comprehensive genetic assessment of bi-allelic alterations in the HR pathway to deliver a precision medicine-based approach to select patients for therapies targeting tumour-specific DNA repair defects. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Mutter
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Nadeem
authors.identifier: 0000-0001-9873-5862
authors.initials: N
authors.lastname: Riaz
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Charlotte Ky
authors.identifier: 0000-0002-6100-0026
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Rob
authors.initials: R
authors.lastname: Delsite
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piscuoglio
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Edelweiss
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Luciano G
authors.identifier: 0000-0002-9625-1183
authors.initials: LG
authors.lastname: Martelotto
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Rita A
authors.initials: RA
authors.lastname: Sakr
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Tari A
authors.initials: TA
authors.lastname: King
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Dilip D
authors.initials: DD
authors.lastname: Giri
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Drobnjak
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Edi
authors.initials: E
authors.lastname: Brogi
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Radiation Oncology, Yale, New Haven, CT, USA.
authors.forename: Ranjit
authors.initials: R
authors.lastname: Bindra
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Giana
authors.initials: G
authors.lastname: Bernheim
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Lim
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Blecua
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Alexis
authors.initials: A
authors.lastname: Desrichard
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Higginson
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Towers
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
authors.forename: Ruomu
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: William
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Powell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000175:diagnosis / Q000235:genetics; D049914:DNA Repair-Deficiency Disorders / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D059765:Homologous Recombination; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051135:Rad51 Recombinase / Q000235:genetics*; D059767:Recombinational DNA Repair; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C495153:RAD51 protein, human; D051135:Rad51 Recombinase
keywords: BRCAness; DNA repair; RAD51; homologous recombination-deficient; mutation