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.

Biocenter Kuopio and Cancer Center of Easter Finland University of Eastern Finland Kuopio Finland

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

Cancer Research Malaysia Subang Jaya Malaysia

Clinical Genetics Unit Department of Pediatrics Zealand University Hospital Roskilde Denmark

Department of Clinical Genetics Aarhus University Hospital Aarhus Denmark

Department of Clinical Genetics Vejle Hospital Vejle Denmark

Department of Medical Genetics University of Cambridge Cambridge UK

Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA

Department of Pathology Faculty of Medicine University Malaya Kuala Lumpur Malaysia

Department of Pathology Fudan University Shanghai Cancer Center and Shanghai Medical College Fudan University Shanghai P R China

Department of Pathology Memorial Sloan Kettering Cancer Center New York NY USA

Department of Pathology Subang Jaya Medical Centre Subang Jaya Selangor Malaysia

Department of Radiation Oncology Rutgers Cancer Institute of New Jersey New Brunswick NJ USA

Departments of Oncology and Human Genetics McGill University Montreal Quebec Canada

Genetic Epidemiology Laboratory Department of Clinical Pathology University of Melbourne Parkville Victoria Australia

IFOM The Italian Foundation for Cancer Research Institute of Molecular Oncology Milan Italy

Institute of Biochemistry and Experimental Oncology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Pathology University Hospital Basel Basel Switzerland

Laboratory of Cancer Genetics and Tumor Biology Cancer and Translational Medicine Research Unit Biocenter Oulu University of Oulu Oulu Finland

Ospedale Papa Giovanni XXIII Bergamo Italy

Precision Medicine School of Clinical Sciences at Monash Health Monash University Victoria Australia

Radiation Oncology Memorial Sloan Kettering Cancer Center New York NY USA

University Malaya Cancer Research Institute Faculty of Medicine University Malaya Kuala Lumpur Malaysia

NPJ Breast Cancer. 2019 Nov 19;5:44. doi: 10.1038/s41523-019-0140-8. PubMed

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