Abstract

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.

Details

Title
Homologous recombination DNA repair defects in PALB2-associated breast cancers
Author
Li, Anqi 1   VIAFID ORCID Logo  ; Geyer, Felipe C 2 ; Blecua, Pedro 3 ; Ju Youn Lee 2 ; Selenica, Pier 2 ; Brown, David N 2 ; Pareja, Fresia 2 ; Lee, Simon S K 2 ; Kumar, Rahul 2   VIAFID ORCID Logo  ; Rivera, Barbara 4   VIAFID ORCID Logo  ; Bi, Rui 1 ; Piscuoglio, Salvatore 5   VIAFID ORCID Logo  ; Wen, Hannah Y 2 ; Lozada, John R 2   VIAFID ORCID Logo  ; Gularte-Mérida, Rodrigo 2   VIAFID ORCID Logo  ; Cavallone, Luca 4 ; Rezoug, Zoulikha 6 ; Nguyen-Dumont, Tu 7 ; Peterlongo, Paolo 8   VIAFID ORCID Logo  ; Tondini, Carlo 9 ; Terkelsen, Thorkild 10 ; Rønlund, Karina 11 ; Boonen, Susanne E 12 ; Mannerma, Arto 13 ; Winqvist, Robert 14 ; Janatova, Marketa 15 ; Pathmanathan Rajadurai 16 ; Xia, Bing 17 ; Norton, Larry 18 ; Robson, Mark E 18   VIAFID ORCID Logo  ; Pei-Sze Ng 19 ; Lai-Meng Looi 20   VIAFID ORCID Logo  ; Southey, Melissa C 21 ; Weigelt, Britta 2 ; Soo-Hwang, Teo 22 ; Tischkowitz, Marc 23 ; Foulkes, William D 24   VIAFID ORCID Logo  ; Reis-Filho, Jorge S 2 ; Aghmesheh, Morteza 25 ; Amor, David 26 ; Andrews, Leslie 27 ; Antill, Yoland 28 ; Balleine, Rosemary 29 ; Beesley, Jonathan 30 ; Blackburn, Anneke 31 ; Bogwitz, Michael 32 ; Brown, Melissa 33 ; Burgess, Matthew 34 ; Burke, Jo 35 ; Butow, Phyllis 36 ; Caldon, Liz 37 ; Campbell, Ian 38 ; Christian, Alice 39 ; Clarke, Christine 40 ; Cohen, Paul 41 ; Crook, Ashley 42 ; Cui, James 43 ; Cummings, Margaret 44 ; Dawson, Sarah-Jane 45 ; De Fazio, Anna 46 ; Delatycki, Martin 26 ; Dobrovic, Alex 45 ; Dudding, Tracy 47 ; Duijf, Pascal 48 ; Edkins, Edward 49 ; Edwards, Stacey 30 ; Gelareh Farshid 50 ; Fellows, Andrew 38 ; Field, Michael 42 ; Flanagan, James 51 ; Fong, Peter 52 ; Forbes, John 53 ; Forrest, Laura 54 ; Fox, Stephen 38 ; French, Juliet 55 ; Friedlander, Michael 56 ; David Gallego Ortega 57 ; Gattas, Michael 58 ; Giles, Graham 59 ; Gill, Grantley 60 ; Gleeson, Margaret 61 ; Greening, Sian 25 ; Haan, Eric 62 ; Harris, Marion 63 ; Hayward, Nick 30 ; Hickie, Ian 64 ; Hopper, John 65 ; Hunt, Clare 63 ; James, Paul 38 ; Jenkins, Mark 65 ; Kefford, Rick 29 ; Kentwell, Maira 32 ; Kirk, Judy 66 ; Kollias, James 67 ; Lakhani, Sunil 68 ; Lindeman, Geoff 69 ; Lipton, Lara 70 ; Lobb, Lizz 71 ; Lok, Sheau 72 ; Finlay Macrea 32 ; Mann, Graham 40 ; Marsh, Deb 73 ; Sue-Anne McLachlan 74 ; Meiser, Bettina 27 ; Milne, Roger 59 ; Nightingale, Sophie 75 ; Shona O’Connell 63 ; Pachter, Nick 76 ; Patterson, Briony 35 ; Phillips, Kelly 45 ; Saleh, Mona 77 ; Salisbury, Elizabeth 78 ; Saunders, Christobel 79 ; Saunus, Jodi 80 ; Scott, Clare 69 ; Scott, Rodney 81 ; Sexton, Adrienne 32 ; Shelling, Andrew 82 ; Simpson, Peter 68 ; Spigelman, Allan 83 ; Spurdle, Mandy 30 ; Stone, Jennifer 84 ; Taylor, Jessica 32 ; Thorne, Heather 38 ; Trainer, Alison 39 ; Trench, Georgia 30 ; Tucker, Kathy 27 ; Visvader, Jane 69 ; Walker, Logan 85 ; Wallis, Mathew 34 ; Williams, Rachael 83 ; Winship, Ingrid 86 ; Wu, Kathy 83 ; Young, Mary Anne 37 

1  Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pathology, Fudan University Shanghai Cancer Center and Shanghai Medical College, Fudan University, Shanghai, P.R. China 
2  Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 
3  Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 
4  Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada; Cancer Axis, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada 
5  Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Institute of Pathology, University Hospital Basel, Basel, Switzerland 
6  Cancer Prevention Center, Jewish General Hospital, Montreal, Quebec, Canada 
7  Genetic Epidemiology Laboratory, Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Victoria, Australia 
8  IFOM, The Italian Foundation for Cancer Research Institute of Molecular Oncology, Milan, Italy 
9  Ospedale Papa Giovanni XXIII, Bergamo, Italy 
10  Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark 
11  Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark 
12  Clinical Genetics Unit, Department of Pediatrics, Zealand University Hospital, Roskilde, Denmark 
13  Biocenter Kuopio and Cancer Center of Easter Finland, University of Eastern Finland, Kuopio, Finland 
14  Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland 
15  Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic 
16  Department of Pathology, Subang Jaya Medical Centre, Subang Jaya, Selangor, Malaysia 
17  Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA 
18  Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA 
19  Cancer Research Malaysia, Subang Jaya, Malaysia 
20  Department of Pathology, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia 
21  Genetic Epidemiology Laboratory, Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia 
22  Cancer Research Malaysia, Subang Jaya, Malaysia; University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia 
23  Department of Medical Genetics, University of Cambridge, Cambridge, UK 
24  Cancer Axis, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada; Cancer Prevention Center, Jewish General Hospital, Montreal, Quebec, Canada; Cancer Program, Research Institute McGill University Health Centre, Montreal, Quebec, Canada 
25  Illawarra Cancer Care Centre, Wollongong Hospital, Wollongong, NSW, Australia 
26  Genetic Health Services Victoria, Royal Children’s Hospital, Melbourne, VIC, Australia 
27  Prince of Wales Hospital, Randwick, NSW, Australia 
28  The Family Cancer Clinic, Cabrini Hospital, Malvern, VIC, Australia 
29  Department of Medical Oncology, Westmead Hospital, Westmead, NSW, Australia 
30  Queensland Institute of Medical Research, Herston Qld, Australia 
31  Australian National University, Canberra ACT, Canberra, Australia 
32  Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, VIC, Australia 
33  University of Queensland, St. Lucia, QLD, Australia 
34  Clinical Genetics Service, Austin Health, Vic, Australia 
35  Royal Hobart Hospital, Hobart, Tasmania, Australia 
36  Medical Psychology Unit, Royal Prince Alfred Hospital, Camperdown NSW, Australia 
37  Garvan Institute of Medical Research, Darlinghurst, NSW, Australia 
38  Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia 
39  Genetics Department, Central Region Genetics Service, Wellington Hospital, Wellington, New Zealand 
40  Westmead Institute for Cancer Research, University of Sydney, Westmead Hospital, Westmead, NSW, Australia 
41  Gynaecological Cancer Research, St John of God Subiaco Hospital, Subiaco, WA, Australia 
42  Department of Clinical Genetics, Royal North Shore Hospital, St Leonards, NSW, Australia 
43  Epidemiology and Preventive Medicine, Monash University, Prahan, Vic, Australia 
44  Department of Pathology, University of Queensland Medical School, Herston, Qld, Australia 
45  Sir Peter MacCallum Department of Oncology, Melbourne, VIC, Australia 
46  Department of Gynaecological Oncology, Westmead Institute for Cancer Research, Westmead Hospital, Westmead, NSW, Australia 
47  Hunter Genetics, Hunter Area Health Service, Waratah, Australia 
48  The University of Queensland Diamantina Institute, Brisbane, QLD, Australia 
49  Clinical Chemistry, Princess Margaret Hospital for Children, Perth, WA, Australia 
50  SA Tissue Pathology, IMVS, Adelaide, SA, Australia 
51  Epigenetics Unit, Department of Surgery and Oncology, Imperial College London, London, UK 
52  Regional Cancer and Blood Services, Auckland City Hospital, Auckland, New Zealand 
53  Surgical Oncology, University of Newcastle, Newcastle Mater Hospital, Waratah, NSW, Australia 
54  Psychosocial Cancer Genetics Research Group, Parkville Familial Cancer Centre, Melbourne, Vic, Australia 
55  School of Molecular and Microbial Sciences, University of Queensland, St Lucia, Qld, Australia 
56  Department of Medical Oncology, Prince of Wales Hospital, Randwick, NSW, Australia 
57  Tumour Development Group, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSDW, Australia 
58  Queensland Clinical Genetic Service, Royal Children’s Hospital, Herston, QLD, Australia 
59  Anti-Cancer Council of Victoria, Melbourne, VIC, Australia 
60  Department of Surgery, Royal Adelaide Hospital, Adelaide, Australia 
61  Hunter Family Cancer Service, Waratah, NSW, Australia 
62  Department of Medical Genetics, Women’s and Children’s Hospital, North Adelaide, SA, Australia 
63  Family Cancer Clinic, Monash Medical Centre, Clayton, Australia 
64  Brain and Mind Centre, Camperdown, NSW, Australia 
65  Centre for M.E.G.A. Epidemiology, University of Melbourne, Carlton, VIC, Australia 
66  Familial Cancer Service, Department of Medicine, Westmead Hospital, Westmead, NSW, Australia 
67  Breast Endocrine and Surgical Unit, Royal Adelaide Hospital, North Terrace, SA, Australia 
68  University of Queensland, The Royal Brisbane & Women’s Hospital, Herston, QLD, Australia 
69  Walter and Eliza Hall Institute, PO Royal Melbourne, Hospital, Parkville, VIC, Australia 
70  Medical Oncology and Clinical Haematology Unit, Western Hospital, Footscray, VIC, Australia 
71  School of Medicine, University of Notre Dame, Kogarah, NSW, Australia 
72  Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Vic, Australia 
73  Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, Australia 
74  Department of Oncology, St Vincent’s Hospital, Fitzroy, VIC, Australia 
75  Department of Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia 
76  Genetic Services of WA, King Edward Memorial Hospital, Subiaco, WA, Australia 
77  Centre for Genetic Education, Prince of Wales Hospital, Randwick, NSW, Australia 
78  Anatomical Pathology, Prince of Wales Hospital, Randwick, Australia 
79  School of Surgery and Pathology, QE11 Medical Centre, Nedlands, WA, Australia 
80  Breast Pathology, University of Queensland Centre for Clinical Research, Royal Brisbane and Women’s Hospital, Herston, Qld, Australia 
81  Hunter Area Pathology Service, John Hunter Hospital, NSW, Australia 
82  Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand 
83  Family Cancer Clinic, St Vincent’s Hospital, Darlinghurst, NSW, Australia 
84  Centre for Genetic Origins of Health and Disease, University of Western Australia, Crawley, WA, Australia 
85  Department of Pathology, University of Otago, Christchurch, New Zealand 
86  Department of Medicine, Royal Melbourne Hospital, Parkville, VIC, Australia 
Pages
1-14
Publication year
2019
Publication date
Aug 2019
Publisher
Nature Publishing Group
e-ISSN
23744677
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41523-019-0115-9
ProQuest document ID
2269969563
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.