TY - JOUR
T1 - Homologous recombination DNA repair defects in PALB2-associated breast cancers
AU - kConFab Investigators
AU - Li, Anqi
AU - Geyer, Felipe C
AU - Blecua, Pedro
AU - Lee, Ju Youn
AU - Selenica, Pier
AU - Brown, David N
AU - Pareja, Fresia
AU - Lee, Simon S K
AU - Kumar, Rahul
AU - Rivera, Barbara
AU - Bi, Rui
AU - Piscuoglio, Salvatore
AU - Wen, Hannah Y
AU - Lozada, John R
AU - Gularte-Mérida, Rodrigo
AU - Cavallone, Luca
AU - Rezoug, Zoulikha
AU - Nguyen-Dumont, Tu
AU - Peterlongo, Paolo
AU - Tondini, Carlo
AU - Terkelsen, Thorkild
AU - Rønlund, Karina
AU - Boonen, Susanne E
AU - Mannerma, Arto
AU - Winqvist, Robert
AU - Janatova, Marketa
AU - Rajadurai, Pathmanathan
AU - Xia, Bing
AU - Norton, Larry
AU - Robson, Mark E
AU - Ng, Pei-Sze
AU - Looi, Lai-Meng
AU - Southey, Melissa C
AU - Weigelt, Britta
AU - Soo-Hwang, Teo
AU - Tischkowitz, Marc
AU - Foulkes, William D
AU - Reis-Filho, Jorge S
PY - 2019/8/8
Y1 - 2019/8/8
N2 - Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n?=?16) or targeted capture massively parallel sequencing (410 cancer genes, n?=?8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n?=?11) or second somatic mutations (n?=?5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.
AB - Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n?=?16) or targeted capture massively parallel sequencing (410 cancer genes, n?=?8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n?=?11) or second somatic mutations (n?=?5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.
U2 - 10.1038/s41523-019-0115-9
DO - 10.1038/s41523-019-0115-9
M3 - Article
C2 - 31428676
VL - 5
SP - 23
JO - npj Breast Cancer
JF - npj Breast Cancer
SN - 2374-4677
ER -