Homologous recombination DNA repair defects in PALB2-associated breast cancers

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  • Anqi Li, Department of Pathology, Fudan University Shanghai Cancer Center and Shanghai Medical College, Fudan University, Shanghai, P.R. China.
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  • Felipe C Geyer, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA.
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  • Pedro Blecua, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, USA.
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  • Ju Youn Lee, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA.
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  • Pier Selenica, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA.
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  • David N Brown, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA.
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  • Fresia Pareja, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA.
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  • Simon S K Lee, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA.
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  • Rahul Kumar, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA.
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  • Barbara Rivera, Cancer Axis, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec Canada.
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  • Rui Bi, Department of Pathology, Fudan University Shanghai Cancer Center and Shanghai Medical College, Fudan University, Shanghai, P.R. China.
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  • Salvatore Piscuoglio, Institute of Pathology, University Hospital Basel, Basel, Switzerland.
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  • Hannah Y Wen, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA.
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  • John R Lozada, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA.
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  • Rodrigo Gularte-Mérida, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA.
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  • Luca Cavallone, Cancer Axis, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec Canada.
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  • Zoulikha Rezoug, Cancer Prevention Center, Jewish General Hospital, Montreal, Quebec Canada.
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  • Tu Nguyen-Dumont, Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Victoria, Australia.
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  • Paolo Peterlongo, IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, c/o IFOM-IEO campus, via Adamello 16, 20139 Milan, Italy.
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  • Carlo Tondini, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
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  • Thorkild Terkelsen
  • Karina Rønlund, Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.
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  • Susanne E Boonen, Clinical Genetics Unit, Department of Pediatrics, Zealand University Hospital, Roskilde, Denmark.
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  • Arto Mannerma, Biocenter Kuopio and Cancer Center of Easter Finland, University of Eastern Finland, Kuopio, Finland.
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  • Robert Winqvist, Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
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  • Marketa Janatova, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
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  • Pathmanathan Rajadurai, Department of Pathology, Subang Jaya Medical Centre, Subang Jaya, Selangor Malaysia.
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  • Bing Xia, Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ USA.
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  • Larry Norton, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY USA.
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  • Mark E Robson, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY USA.
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  • Pei-Sze Ng, Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, Subang Jaya, 47500 Malaysia.
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  • Lai-Meng Looi, Department of Pathology, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia.
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  • Melissa C Southey, Genetic Epidemiology Laboratory, Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia.
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  • Britta Weigelt, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA.
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  • Teo Soo-Hwang, University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia.
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  • Marc Tischkowitz, Department of Medical Genetics, University of Cambridge, Cambridge, UK.
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  • William D Foulkes, Cancer Program, Research Institute McGill University Health Centre, Montreal, Quebec Canada.
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  • Jorge S Reis-Filho, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA.
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  • KConFab Investigators

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.

OriginalsprogEngelsk
Artikelnummer23
TidsskriftNPJ Breast Cancer
Vol/bind5
ISSN2374-4677
DOI
StatusUdgivet - 8 aug. 2019

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