TY - JOUR
T1 - Pan-cancer landscape of homologous recombination deficiency
AU - Nguyen, Luan
AU - W M Martens, John
AU - Van Hoeck, Arne
AU - Cuppen, Edwin
N1 - Funding Information:
This publication and the underlying study have been made possible partly on the basis of the data that Hartwig Medical Foundation and the Center of Personalised Cancer Treatment (CPCT, The Netherlands) have made available to the study. We thank Neeltje Steeghs (Netherlands Cancer Institute), Martijn Lolkema (Erasmus Medical Center Rotterdam), Geert Cirkel (Meander Medical Center), Els Witteveen (UMC Utrecht), Mariette Labots (Amsterdam UMC, location VUmc) and Laurens Beerepoot (Elisabeth-TweeSteden Ziekenhuis, Tilburg) for study inclusion of a significant part of the patients that were used in this study and Peter Bouwman (Netherlands Cancer Institute, Amsterdam) for critically reading the manuscript. This work was financially supported by the gravitation program CancerGenomiCs.nl from the Netherlands Organisation for Scientific Research (NWO) and Oncode Institute to E.C.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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 (n = 3,504) and primary (n = 1,854) 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).
AB - 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 (n = 3,504) and primary (n = 1,854) 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).
UR - https://www.scopus.com/pages/publications/85094978631
U2 - 10.1038/s41467-020-19406-4
DO - 10.1038/s41467-020-19406-4
M3 - Article
C2 - 33149131
SN - 2041-1723
VL - 11
SP - 1
EP - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5584
ER -