Please use this identifier to cite or link to this item:
https://repository.monashhealth.org/monashhealthjspui/handle/1/35576
Title: | Homologous recombination DNA repair defects in PALB2-associated breast cancers. | Authors: | Duijf P.;Kentwell M.;Kirk J.;Kollias J.;Lakhani S.;Lindeman G.;Lipton L.;Lobb L.;Lok S.;Macrea F.;Mann 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.;Walker L.;Wallis M.;Williams R.;Winship I.;Wu K.;Young M.A.;Rezoug Z.;Nguyen-Dumont T.;Peterlongo P.;Tondini C.;Terkelsen T.;Ronlund K.;Boonen S.E.;Mannerma A.;Winqvist R.;Janatova M.;Rajadurai P.;Xia B.;Norton L.;Robson M.E.;Ng P.-S.;Looi L.-M.;Southey M.C.;Weigelt B.;Soo-Hwang T.;Tischkowitz M.;Foulkes W.D.;Reis-Filho J.S.;Harris M. ;Tucker K.;Visvader J.;Li A.;Geyer F.C.;Blecua P.;Lee J.Y.;Selenica P.;Brown D.N.;Pareja F.;Lee S.S.K.;Kumar R.;Rivera B.;Bi R.;Piscuoglio S.;Wen H.Y.;Lozada J.R.;Gularte-Merida 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 S.-J.;De Fazio A.;Delatycki M.;Dobrovic A.;Dudding T.;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 D.G.;Gattas M.;Giles G.;Gill G.;Gleeson M.;Greening S.;Haan E.;Hayward N.;Hickie I.;Hopper J.;Hunt C.;James P.;Jenkins M.;Kefford R. | Institution: | (Li, Geyer, Lee, Selenica, Brown, Pareja, Lee, Kumar, Bi, Piscuoglio, Wen, Lozada, Gularte-Merida, Weigelt, Reis-Filho) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States (Li, Bi) Department of Pathology, Fudan University Shanghai Cancer Center and Shanghai Medical College, Fudan University, Shanghai, China (Blecua) Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States (Rivera, Cavallone) Departments of Oncology and Human Genetics, McGill University, Montreal, QC, Canada (Rivera, Cavallone, Foulkes) Cancer Axis, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada (Piscuoglio) Institute of Pathology, University Hospital Basel, Basel, Switzerland (Nguyen-Dumont, Southey) Genetic Epidemiology Laboratory, Department of Clinical Pathology, University of Melbourne, Parkville, VIC, Australia (Nguyen-Dumont) Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, VIC, Australia (Peterlongo) IFOM, The Italian Foundation for Cancer Research Institute of Molecular Oncology, Milan, Italy (Tondini) Ospedale Papa Giovanni XXIII, Bergamo, Italy (Terkelsen) Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark (Ronlund) Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark (Boonen) Clinical Genetics Unit, Department of Pediatrics, Zealand University Hospital, Roskilde, Denmark (Mannerma) Biocenter Kuopio and Cancer Center of Easter Finland, University of Eastern Finland, Kuopio, Finland (Winqvist) Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland (Janatova) Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czechia (Rajadurai) Department of Pathology, Subang Jaya Medical Centre, Subang Jaya, Selangor, Malaysia (Xia) Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States (Norton, Robson) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States (Ng, Soo-Hwang) Cancer Research Malaysia, Subang Jaya, Malaysia (Looi) Department of Pathology, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia (Soo-Hwang) University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia (Tischkowitz) Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom (Foulkes) Cancer Program, Research Institute McGill University Health Centre, Montreal, QC, Canada (Aghmesheh, Greening) Illawarra Cancer Care Centre, Wollongong Hospital, Wollongong, NSW 2500, Australia (Amor, Delatycki) Genetic Health Services Victoria, Royal Children's Hospital, Melbourne, VIC 3050, Australia (Andrews, Meiser, Tucker) Prince of Wales Hospital, Randwick, NSW 2031, Australia (Antill) The Family Cancer Clinic, Cabrini Hospital, Malvern, VIC 3144, Australia (Balleine, Kefford) Department of Medical Oncology, Westmead Hospital, Westmead, NSW 2145, Australia (Beesley, Edwards, Hayward, Spurdle, Trench) Queensland Institute of Medical Research, Herston, QLD 4002, Australia (Blackburn) Australian National University, Canberra ACT, Canberra 2601, Australia (Bogwitz, Kentwell, Macrea, Sexton, Taylor) Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia (Brown) University of Queensland, St. Lucia, QLD 4072, Australia (Burgess, Wallis) Clinical Genetics Service, Austin Health, VIC 3084, Australia (Burke, Patterson) Royal Hobart Hospital, Hobart, TAS 7001, Australia (Butow) Medical Psychology Unit, Royal Prince Alfred Hospital, Camperdown, NSW 2204, Australia (Caldon, Young) Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia (Campbell, Fellows, Fox, James, Thorne) Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia (Christian, Trainer) Genetics Department, Central Region Genetics Service, Wellington Hospital, Wellington 6021, New Zealand (Clarke, Mann) Westmead Institute for Cancer Research, University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia (Cohen) Gynaecological Cancer Research, St John of God Subiaco Hospital, Subiaco, WA 6008, Australia (Crook, Field) Department of Clinical Genetics, Royal North Shore Hospital, St Leonards, NSW 2065, Australia (Cui) Epidemiology and Preventive Medicine, Monash University, Prahan, Vic 3004, Australia (Cummings) Department of Pathology, University of Queensland Medical School, Herston, Qld 4006, Australia (Dawson, Dobrovic, Phillips) Sir Peter MacCallum Department of Oncology, Melbourne, VIC 3000, Australia (De Fazio) Department of Gynaecological Oncology, Westmead Institute for Cancer Research, Westmead Hospital, Westmead, NSW 2145, Australia (Dudding) Hunter Genetics, Hunter Area Health Service, Waratah 2298 NSW, Australia (Duijf) The University of Queensland Diamantina Institute, Brisbane, QLD 4102, Australia (Edkins) Clinical Chemistry, Princess Margaret Hospital for Children, Perth, WA 6001, Australia (Farshid) SA Tissue Pathology, IMVS, Adelaide, SA 5000, Australia (Flanagan) Epigenetics Unit, Department of Surgery and Oncology, Imperial College London, London W12 0NN, United Kingdom (Fong) Regional Cancer and Blood Services, Auckland City Hospital, Auckland 1023, New Zealand (Forbes) Surgical Oncology, University of Newcastle, Newcastle Mater Hospital, Waratah, NSW 2298, Australia (Forrest) Psychosocial Cancer Genetics Research Group, Parkville Familial Cancer Centre, Melbourne, Vic 3000, Australia (French) School of Molecular and Microbial Sciences, University of Queensland, St Lucia, Qld 4072, Australia (Friedlander) Department of Medical Oncology, Prince of Wales Hospital, Randwick, NSW 2031, Australia (Ortega) Tumour Development Group, Garvan Institute of Medical Research, The Kinghorn Cancer Centre, Darlinghurst, NSDW 2010, Australia (Gattas) Queensland Clinical Genetic Service, Royal Children's Hospital, Herston, QLD 4020, Australia (Giles, Milne) Anti-Cancer Council of Victoria, Melbourne, VIC 3004, Australia (Gill) Department of Surgery, Royal Adelaide Hospital, Adelaide 5000, Australia (Gleeson) Hunter Family Cancer Service, Waratah, NSW 2298, Australia (Haan) Department of Medical Genetics, Women's and Children's Hospital, North Adelaide, SA 5006, Australia (Harris, Hunt, O'Connell) Family Cancer Clinic, Monash Medical Centre, Clayton 3168, Australia (Hickie) Brain and Mind Centre, Camperdown, NSW 2050, Australia (Hopper, Jenkins) Centre for M.E.G.A. Epidemiology, University of Melbourne, Carlton, VIC 3010, Australia (Kirk) Familial Cancer Service, Department of Medicine, Westmead Hospital, Westmead, NSW 2145, Australia (Kollias) Breast Endocrine and Surgical Unit, Royal Adelaide Hospital, North Terrace, SA 5000, Australia (Lakhani, Simpson) University of Queensland, The Royal Brisbane & Women's Hospital, Herston, QLD 4029, Australia (Lindeman, Scott, Visvader) Walter and Eliza Hall Institute, PO Royal Melbourne, Hospital, Parkville, VIC 3050, Australia (Lipton) Medical Oncology and Clinical Haematology Unit, Western Hospital, Footscray, VIC 3011, Australia (Lobb) School of Medicine, University of Notre Dame, Kogarah, NSW 2217, Australia (Lok) Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Vic 3050, Australia (Marsh) Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW 2065, Australia (McLachlan) Department of Oncology, St Vincent's Hospital, Fitzroy, VIC 3065, Australia (Nightingale) Department of Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia (Pachter) Genetic Services of WA, King Edward Memorial Hospital, Subiaco, WA 6008, Australia (Saleh) Centre for Genetic Education, Prince of Wales Hospital, Randwick, NSW 2031, Australia (Salisbury) Anatomical Pathology, Prince of Wales Hospital, Randwick 2031 NSW, Australia (Saunders) School of Surgery and Pathology, QE11 Medical Centre, Nedlands, WA 6907, Australia (Saunus) Breast Pathology, University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Herston, Qld 4029, Australia (Scott) Hunter Area Pathology Service, John Hunter Hospital, NSW 2310, Australia (Shelling) Obstetrics and Gynaecology, University of Auckland, Auckland 1023, New Zealand (Spigelman, Williams, Wu) Family Cancer Clinic, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia (Stone) Centre for Genetic Origins of Health and Disease, University of Western Australia, Crawley, WA 6009, Australia (Walker) Department of Pathology, University of Otago, Christchurch 8011, New Zealand (Winship) Department of Medicine, Royal Melbourne Hospital, Parkville, VIC 3050, Australia | Issue Date: | 28-Aug-2019 | Copyright year: | 2019 | Publisher: | Nature Publishing Group | Place of publication: | United Kingdom | Publication information: | npj Breast Cancer. 5 (1) (no pagination), 2019. Article Number: 23. Date of Publication: 01 Dec 2019. | 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.Copyright © 2019, The Author(s). | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1038/s41523-019-0115-9 | ISSN: | 2374-4677 (electronic) | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/35576 | Type: | Article | Subjects: | very elderly adult aged article *breast cancer cancer patient clinical article female gene frequency gene inactivation germline mutation heterozygosity loss human middle aged *recombination repair somatic mutation tumor gene whole exome sequencing wild type *partner and localizer of BRCA2/ec [Endogenous Compound] whole exome sequencing wild type adult gene frequency germline mutation heterozygosity loss human middle aged *recombination repair somatic mutation tumor gene very elderly cancer patient clinical article female gene inactivation aged Article *breast cancer |
Appears in Collections: | Articles |
Show full item record
Items in Monash Health Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.