- Title
- Homologous recombination DNA repair defects in PALB2-associated breast cancers
- Creator
- Li, Anqi; Mane, G; Marsh, D; Mclachlan, S-A; 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; Taylor, J; Thorne, H; Trainer, A; Trench, G; Tucker, K; Visvader, J; Walker, L; Wallis, M; Williams, R; Winship, I; Wu, K; Young, MA; Geyer, Felipe C.; Bi, Rui; Piscuoglio, Salvatore; Wen, Hannah Y.; Lozada, John R.; Gularte-Merida, Rodrigo; Cavallone, Luca; Rezoug, Zoulikha; Nguyen-Dumont, Tu; Peterlongo, Paolo; Tondini, Carlo; Blecua, Pedro; Terkelsen, Thorkild; Ronlund, K; Boonen, SE; Mannerma, A; Winqvist, R; Janatova, M; Rajadurai, P; Xia, B; Norton, L; Robson, ME; Lee, Ju Youn; Ng, P-S; Looi, L-M; Southey, MC; Weigelt, B; Soo-Hwang, T; Tischkowitz, M; Foulkes, WD; Reis-Filho, JS; Aghmesheh, M; Amor, D; Selenica, Pier; Andrews, L; Antill, Y; Balleine, R; Beesley, J; Blackburn, A; Bogwitz, M; Brown, M; Burgess, M; Burke, J; Butow, P; Brown, David N.; Caldon, L; Campbell, I; Christian, A; Clarke, C; Cohen, P; Crook, A; Cui, J; Cummings, M; Dawson, S-J; De Fazio, A; Pareja, Fresia; Delatycki, M; Dobrovic, A; Dudding, T; Duijf, P; Edkins, E; Edwards, S; Farshid, G; Fellows, A; Field, M; Flanagan, J; Lee, Simon S. K.; Fong, P; Forbes, John; Forrest, L; Fox, S; French, J; Friedlander, M; Ortega, DG; Gattas, M; Giles, G; Gill, G; Kumar, Rahul; Gleeson, M; Greening, S; Haan, E; Harris, M; Hayward, N; Hickie, I; Hopper, J; Hunt, C; James, P; Jenkins, M; Rivera, Barbara; Kefford, R; Kentwell, M; Kirk, J; Kollias, J; Lakhani, S; Lindeman, G; Lipton, L; Lobb, L; Lok, S; Macrea, F
- Relation
- NHMRC.1029974 http://purl.org/au-research/grants/nhmrc/1029974
- Relation
- NPJ Breast Cancer Vol. 5, no. 23
- Publisher Link
- http://dx.doi.org/10.1038/s41523-019-0115-9
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2019
- Description
- 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 biallelic 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, largescale 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.
- Subject
- breast cancer; genomic feature; germline mutations; mutational signatures; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1456486
- Identifier
- uon:45235
- Identifier
- ISSN:2374-4677
- Rights
- This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Language
- eng
- Full Text
- Reviewed
- Hits: 77618
- Visitors: 77396
- Downloads: 159
Collections
Goal 3: Good Health and Well-Being
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT02 | Publisher version (open access) | 2 MB | Adobe Acrobat PDF | View Details Download |