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HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.

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Date
2017-04
ICR Author
Tutt, Andrew
Author
Davies, H
Glodzik, D
Morganella, S
Yates, LR
Staaf, J
Zou, X
Ramakrishna, M
Martin, S
Boyault, S
Sieuwerts, AM
Simpson, PT
King, TA
Raine, K
Eyfjord, JE
Kong, G
Borg, Å
Birney, E
Stunnenberg, HG
van de Vijver, MJ
Børresen-Dale, A-L
Martens, JWM
Span, PN
Lakhani, SR
Vincent-Salomon, A
Sotiriou, C
Tutt, A
Thompson, AM
Van Laere, S
Richardson, AL
Viari, A
Campbell, PJ
Stratton, MR
Nik-Zainal, S
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Type
Journal Article
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Abstract
Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition.
URI
https://repository.icr.ac.uk/handle/internal/798
DOI
https://doi.org/10.1038/nm.4292
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  • Other ICR Research
Subject
Humans
Breast Neoplasms
Breast Neoplasms, Male
Pancreatic Neoplasms
Ovarian Neoplasms
BRCA1 Protein
BRCA2 Protein
Area Under Curve
Logistic Models
DNA Mutational Analysis
Mutation
Models, Genetic
Female
Male
Poly(ADP-ribose) Polymerase Inhibitors
Language
eng
Date accepted
2017-01-24
License start date
2017-04
Citation
Nature medicine, 2017, 23 (4), pp. 517 - 525

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