Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer.
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.
['Mutter|Robert W|RW|', 'Riaz|Nadeem|N|0000-0001-9873-5862', 'Ng|Charlotte Ky|CK|0000-0002-6100-0026', 'Delsite|Rob|R|', 'Piscuoglio|Salvatore|S|', 'Edelweiss|Marcia|M|', 'Martelotto|Luciano G|LG|0000-0002-9625-1183', 'Sakr|Rita A|RA|', 'King|Tari A|TA|', 'Giri|Dilip D|DD|', 'Drobnjak|Maria|M|', 'Brogi|Edi|E|', 'Bindra|Ranjit|R|', 'Bernheim|Giana|G|', 'Lim|Raymond S|RS|', 'Blecua|Pedro|P|', 'Desrichard|Alexis|A|', 'Higginson|Dan|D|', 'Towers|Russell|R|', 'Jiang|Ruomu|R|', 'Lee|William|W|', 'Weigelt|Britta|B|', 'Reis-Filho|Jorge S|JS|', 'Powell|Simon N|SN|']
D000328:Adult D000368:Aged D000369:Aged, 80 and over D019313:BRCA1 Protein D024682:BRCA2 Protein D001943:Breast Neoplasms D018567:Breast Neoplasms, Male D049914:DNA Repair-Deficiency Disorders 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 D059767:Recombinational DNA Repair D055815:Young Adult
DNA repair mutation BRCAness RAD51 homologous recombination-deficient