Homologous recombination DNA repair defects in PALB2-associated breast cancers
|Author:||Li, Anqi1,2,3; Geyer, Felipe C.1; Blecua, Pedro4;|
1Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA.
2Fudan Univ, Shanghai Canc Ctr, Dept Pathol, Shanghai, Peoples R China.
3Fudan Univ, Shanghai Med Coll, Dept Pathol, Shanghai, Peoples R China.
4Mem Sloan Kettering Canc Ctr, Radiat Oncol, 1275 York Ave, New York, NY 10021 USA.
5McGill Univ, Dept Oncol, Montreal, PQ, Canada.
6McGill Univ, Dept Human Genet, Montreal, PQ, Canada.
7Jewish Gen Hosp, Lady Davis Inst, Canc Axis, Montreal, PQ, Canada.
8Univ Hosp Basel, Inst Pathol, Basel, Switzerland.
9Jewish Gen Hosp, Canc Prevent Ctr, Montreal, PQ, Canada.
10Univ Melbourne, Dept Clin Pathol, Genet Epidemiol Lab, Parkville, Vic, Australia.
11Monash Univ, Sch Clin Sci Monash Hlth, Precis Med, Melbourne, Vic, Australia.
12Italian Fdn Canc Res Inst Mol Oncol, IFOM, Milan, Italy.
13Osped Papa Giovanni XXIII, Bergamo, Italy.
14Aarhus Univ Hosp, Dept Clin Genet, Aarhus, Denmark.
15Vejle Hosp, Dept Clin Genet, Vejle, Denmark.
16Zealand Univ Hosp, Dept Pediat, Clin Genet Unit, Roskilde, Denmark.
17Univ Eastern Finland, Bioctr Kuopio, Kuopio, Finland.
18Univ Eastern Finland, Canc Ctr Easter Finland, Kuopio, Finland.
19Univ Oulu, Bioctr Oulu, Canc & Translat Med Res Unit, Lab Canc Genet & Tumor Biol, Oulu, Finland.
20Charles Univ Prague, Fac Med 1, Inst Biochem & Expt Oncol, Prague, Czech Republic.
21Subang Jaya Med Ctr, Dept Pathol, Subang Jaya, Selangor, Malaysia.
22Rutgers Canc Inst New Jersey, Dept Radiat Oncol, New Brunswick, NJ USA.
23Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA.
24Canc Res Malaysia, Subang Jaya, Malaysia.
25Univ Malaya, Fac Med, Dept Pathol, Kuala Lumpur, Malaysia.
26Univ Malaya, Canc Res Inst, Fac Med, Kuala Lumpur, Malaysia.
27Univ Cambridge, Dept Med Genet, Cambridge, England.
28McGill Univ, Canc Program, Res Inst, Hlth Ctr, Montreal, PQ, Canada.
29Wollongong Hosp, Illawarra Canc Care Ctr, Wollongong, NSW 2500, Australia.
30Royal Childrens Hosp, Genet Hlth Serv Victoria, Melbourne, Vic 3050, Australia.
31Prince Wales Hosp, Randwick, NSW 2031, Australia.
32Cabrini Hosp, Family Canc Clin, Malvern, Vic 3144, Australia.
33Westmead Hosp, Dept Med Oncol, Westmead, NSW 2145, Australia.
34Queensland Inst Med Res, Herston, Qld 4002, Australia.
35Australian Natl Univ, Canberra, ACT 2601, Australia.
36Royal Melbourne Hosp, Familial Canc Ctr, Parkville, Vic 3050, Australia.
37Univ Queensland, St Lucia, Qld 4072, Australia.
38Austin Hlth, Clin Genet Serv, Heidelberg, Vic 3084, Australia.
39Royal Hobart Hosp, Hobart, Tas 7001, Australia.
40Royal Prince Alfred Hosp, Med Psychol Unit, Camperdown, NSW 2204, Australia.
41Garvan Inst Med Res, Darlinghurst, NSW 2010, Australia.
42Peter MacCallum Canc Ctr, Canc Genet Lab, Melbourne, Vic 3000, Australia.
43Wellington Hosp, Genet Dept, Cent Reg Genet Serv, Wellington 6021, New Zealand.
44Univ Sydney, Westmead Hosp, Westmead Inst Canc Res, Westmead, NSW 2145, Australia.
45St John God Subiaco Hosp, Gynaecol Canc Res, Subiaco, WA 6008, Australia.
46Royal North Shore Hosp, Dept Clin Genet, St Leonards, NSW 2065, Australia.
47Monash Univ, Epidemiol & Prevent Med, Prahran, Vic 3004, Australia.
48Univ Queensland, Dept Pathol, Med Sch, Herston, Qld 4006, Australia.
49Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3000, Australia.
50Westmead Hosp, Westmead Inst Canc Res, Dept Gynaecol Oncol, Westmead, NSW 2145, Australia.
51Hunter Area Hlth Serv, Hunter Genet, Waratah, NSW 2298, Australia.
52Univ Queensland, Diamantina Inst, Brisbane, Qld 4102, Australia.
53Princess Margaret Hosp Children, Clin Chem, Perth, WA 6001, Australia.
54IMVS, SA Tissue Pathol, Adelaide, SA 5000, Australia.
55Imperial Coll London, Dept Surg & Oncol, Epigenct Unit, London W12 0NN, England.
56Auckland City Hosp, Reg Canc & Blood Serv, Auckland 1023, New Zealand.
57Univ Newcastle, Newcastle Mater Hosp, Surg Oncol, Waratah, NSW 2298, Australia.
58Parkville Familial Canc Ctr, Psychosocial Canc Genet Res Grp, Melbourne, Vic 3000, Australia.
59Univ Queensland, Sch Mol & Microbial Sci, St Lucia, Qld 4072, Australia.
60Prince Wales Hosp, Dept Med Oncol, Randwick, NSW 2031, Australia.
61Kinghorn Canc Ctr, Garvan Inst Med Res, Tumour Dev Grp, Darlinghurst, NSW 2010, Australia.
62Royal Childrens Hosp, Queensland Clin Genet Serv, Herston, Qld 4020, Australia.
63Anticanc Council Victoria, Melbourne, Vic 3004, Australia.
64Royal Adelaide Hosp, Dept Surg, Adelaide, SA 5000, Australia.
65Hunter Family Canc Serv, Waratah, NSW 2298, Australia.
66Womens & Childrens Hosp, Dept Med Genet, Adelaide, SA 5006, Australia.
67Monash Med Ctr, Family Canc Clin, Clayton, Vic 3168, Australia.
68Brain & Mind Ctr, Camperdown, NSW 2050, Australia.
69Univ Melbourne, Ctr MEGA Epidemiol, Carlton, Vic 3010, Australia.
70Westmead Hosp, Dept Med, Familial Canc Serv, Westmead, NSW 2145, Australia.
71Royal Adelaide Hosp, Breast Endocrine & Surg Unit, North Terrace, SA 5000, Australia.
72Univ Queensland, Royal Brisbane & Womens Hosp, Herston, Qld 4029, Australia.
73Royal Melbourne Hosp, Walter & Eliza Hall Inst, Parkville, Vic 3050, Australia.
74Western Hosp, Med Oncol & Clin Haematol Unit, Footscray, Vic 3011, Australia.
75Univ Notre Dame, Sch Med, Kogarah, NSW 2217, Australia.
76Royal Melbourne Hosp, Dept Med Oncol, Parkville, Vic 3050, Australia.
77Royal North Shore Hosp, Kolling Inst Med Res, St Leonards, NSW 2065, Australia.
78St Vincents Hosp, Dept Oncol, Fitzroy, Vic 3065, Australia.
79Peter MacCallum Canc Ctr, Dept Surg, Melbourne, Vic 3000, Australia.
80King Edward Mem Hosp, Genet Serv WA, Subiaco, WA 6008, Australia.
81Prince Wales Hosp, Ctr Genet Educ, Randwick, NSW 2031, Australia.
82Prince Wales Hosp, Anat Pathol, Randwick, NSW 2031, Australia.
83QE11 Med Ctr, Sch Surg & Pathol, Nedlands, WA 6907, Australia.
84Univ Queensland, Royal Brisbane & Womens Hosp, Breast Pathol, Ctr Clin Res, Herston, Qld 4029, Australia.
85John Hunter Hosp, Hunter Area Pathol Serv, New Lambton Hts, NSW 2310, Australia.
86Univ Auckland, Obstet & Gynaecol, Auckland 1023, New Zealand.
87St Vincents Hosp, Family Canc Clin, Darlinghurst, NSW 2010, Australia.
88Univ Western Australia, Ctr Genet Origins Hlth & Dis, Crawley, WA 6009, Australia.
89Univ Otago, Dept Pathol, Christchurch 8011, New Zealand.
90Royal Melbourne Hosp, Dept Med, Parkville, Vic 3050, Australia.
|Online Access:||PDF Full Text (PDF, 2 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2020042822779
|Publish Date:|| 2020-04-28
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.
npj breast cancer
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
Research reported in this paper was supported in part by the Breast Cancer Research Foundation and the Sarah Jenkins Fund, a Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute (grant No. P30CA008748; MSK), a grant of the Ministry of Health of the Czech Republic (NV15-29959A), Charles University projects PROGRES Q28/LF1 and SVV2019/260367, an HIR Grant UM.C/HlR/MOHE/06 from the Ministry of Higher Education, Malaysia, and the National Health and Medical Research Council, Australia (NHMRC, Project Grant APP1029974). kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the NHMRC, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. W.D.F. was funded in part by Susan G Komen. A.L. was supported by the China Scholarship Council. T.N.-D. is an Early Career Fellow of the National Breast Cancer Foundation and M.S. is a NHMRC Senior Research Fellow of the National Health and Medical Research Council. M.T. was funded by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Addenbrooke’s Hospital and European Union Seventh Framework Program (2007–2013)/European Research Council (310018). S.P. was supported by the Swiss National Science Foundation (Ambizione grant number: PZ00P3_168165). J.S.R-F. is partly funded by the Breast Cancer Research Foundation and Britta Weigelt by Cycle for Survival.
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