TY - JOUR
T1 - Homologous recombination DNA repair defects in PALB2-associated breast cancers
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 - Aghmesheh, Morteza
AU - Amor, David
AU - Andrews, Leslie
AU - Antill, Yoland
AU - Balleine, Rosemary
AU - Beesley, Jonathan
AU - Blackburn, Anneke
AU - Bogwitz, Michael
AU - Brown, Melissa
AU - Burgess, Matthew
AU - Burke, Jo
AU - Butow, Phyllis
AU - Caldon, Liz
AU - Campbell, Ian
AU - Christian, Alice
AU - Clarke, Christine
AU - Cohen, Paul
AU - Crook, Ashley
AU - Cui, James
AU - Cummings, Margaret
AU - Dawson, Sarah Jane
AU - De Fazio, Anna
AU - Delatycki, Martin
AU - Dobrovic, Alex
AU - Dudding, Tracy
AU - Duijf, Pascal
AU - Edkins, Edward
AU - Edwards, Stacey
AU - Farshid, Gelareh
AU - Fellows, Andrew
AU - Field, Michael
AU - Flanagan, James
AU - Forrest, Laura
AU - Mann, Graham
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85070388252&partnerID=8YFLogxK
U2 - 10.1038/s41523-019-0115-9
DO - 10.1038/s41523-019-0115-9
M3 - Article
SN - 2374-4677
VL - 5
JO - npj Breast Cancer
JF - npj Breast Cancer
IS - 1
M1 - 23
ER -