Homologous recombination DNA repair defects in PALB2-associated breast cancers
Li, A
Geyer, FC
Blecua, P
Lee, JY
Selenica, P
Brown, DN
Pareja, F
Lee, SSK
Kumar, R
Rivera, B
Bi, R
Piscuoglio, S
Wen, HY
Lozada, JR
Gularte-Mérida, R
Cavallone, L
Aghmesheh, M
Amor, D
Andrews, L
Antill, Y
Balleine, R
Beesley, J
Blackburn, A
Bogwitz, M
Brown, M
Burgess, M
Burke, J
Butow, P
Caldon, L
Campbell, I
Christian, A
Clarke, C
Cohen, P
Crook, A
Cui, J
Cummings, M
Dawson, SJ
De Fazio, A
Delatycki, M
Dobrovic, A
Dudding, T
Duijf, P
Edkins, E
Edwards, S
Farshid, G
Fellows, A
Field, M
Flanagan, J
Fong, P
Forbes, J
Forrest, L
Fox, S
French, J
Friedlander, M
Ortega, DG
Gattas, M
Giles, G
Gill, G
Gleeson, M
Greening, S
Haan, E
Harris, M
Hayward, N
Hickie, I
Hopper, J
Hunt, C
James, P
Jenkins, M
Kefford, R
Kentwell, M
Kirk, J
Kollias, J
Lakhani, S
Lindeman, G
Lipton, L
Lobb, L
Lok, S
Macrea, F
Mann, G
Marsh, D
McLachlan, SA
Meiser, B
Milne, R
Nightingale, S
O’Connell, S
Pachter, N
Patterson, B
Phillips, K
Saleh, M
Salisbury, E
Saunders, C
Saunus, J
Scott, C
Scott, R
Sexton, A
Shelling, A
Simpson, P
Spigelman, A
Spurdle, M
Stone, J
Cui, J
Cummings, M
Dawson, SJ
De Fazio, A
Delatycki, M
Dobrovic, A
Dudding, T
Duijf, P
Edkins, E
Edwards, S
Farshid, G
Fellows, A
Field, M
Flanagan, J
Fong, P
Forbes, J
Forrest, L
Fox, S
French, J
Friedlander, M
Ortega, DG
Gattas, M
Giles, G
Gill, G
Gleeson, M
Greening, S
Haan, E
Harris, M
Hayward, N
Hickie, I
Hopper, J
Hunt, C
James, P
Jenkins, M
Kefford, R
Kentwell, M
Kirk, J
Kollias, J
Lakhani, S
Lindeman, G
Lipton, L
Lobb, L
Lok, S
Macrea, F
Mann, G
Marsh, D
McLachlan, SA
Meiser, B
Milne, R
Nightingale, S
O’Connell, S
Pachter, N
Patterson, B
Phillips, K
Saleh, M
Salisbury, E
Saunders, C
Saunus, J
Scott, C
Scott, R
Sexton, A
Shelling, A
Simpson, P
Spigelman, A
Spurdle, M
Stone, J
- Publication Type:
- Journal Article
- Citation:
- npj Breast Cancer, 2019, 5 (1)
- Issue Date:
- 2019-12-01
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© 2019, The Author(s). 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.
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