Back to Search
Start Over
Pan-cancer landscape of homologous recombination deficiency.
- Source :
-
Nature communications [Nat Commun] 2020 Nov 04; Vol. 11 (1), pp. 5584. Date of Electronic Publication: 2020 Nov 04. - Publication Year :
- 2020
-
Abstract
- Homologous recombination deficiency (HRD) results in impaired double strand break repair and is a frequent driver of tumorigenesis. Here, we develop a genome-wide mutational scar-based pan-cancer Classifier of HOmologous Recombination Deficiency (CHORD) that can discriminate BRCA1- and BRCA2-subtypes. Analysis of a metastatic (nā=ā3,504) and primary (nā=ā1,854) pan-cancer cohort reveals that HRD is most frequent in ovarian and breast cancer, followed by pancreatic and prostate cancer. We identify biallelic inactivation of BRCA1, BRCA2, RAD51C or PALB2 as the most common genetic cause of HRD, with RAD51C and PALB2 inactivation resulting in BRCA2-type HRD. We find that while the specific genetic cause of HRD is cancer type specific, biallelic inactivation is predominantly associated with loss-of-heterozygosity (LOH), with increased contribution of deep deletions in prostate cancer. Our results demonstrate the value of pan-cancer genomics-based HRD testing and its potential diagnostic value for patient stratification towards treatment with e.g. poly ADP-ribose polymerase inhibitors (PARPi).
- Subjects :
- Alleles
Breast Neoplasms diagnosis
DNA-Binding Proteins genetics
Databases, Genetic
Fanconi Anemia Complementation Group N Protein genetics
Female
Humans
Incidence
Loss of Heterozygosity
Male
Multigene Family
Mutation
Ovarian Neoplasms diagnosis
Pancreatic Neoplasms diagnosis
Pancreatic Neoplasms genetics
Prostatic Neoplasms diagnosis
Prostatic Neoplasms genetics
BRCA1 Protein genetics
BRCA2 Protein genetics
Breast Neoplasms genetics
Genomics methods
Homologous Recombination
Ovarian Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33149131
- Full Text :
- https://doi.org/10.1038/s41467-020-19406-4