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Homologous recombination DNA repair defects in PALB2-associated breast cancers
A. Li, FC. Geyer, P. Blecua, JY. Lee, P. Selenica, DN. Brown, F. Pareja, SSK. Lee, R. Kumar, B. Rivera, R. Bi, S. Piscuoglio, HY. Wen, JR. Lozada, R. Gularte-Mérida, L. Cavallone, kConFab Investigators, Z. Rezoug, T. Nguyen-Dumont, P. Peterlongo,...
Language English Country United States
Document type Journal Article
Grant support
P30 CA008748
NCI NIH HHS - United States
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- Publication type
- Journal Article MeSH
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 Prevention Center Jewish General Hospital 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 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
IFOM The Italian Foundation for Cancer Research Institute of Molecular Oncology Milan Italy
Ospedale Papa Giovanni XXIII Bergamo Italy
Radiation Oncology Memorial Sloan Kettering Cancer Center New York NY USA
References provided by Crossref.org
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- $a Li, Anqi $u 1Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY USA. 2Department of Pathology, Fudan University Shanghai Cancer Center and Shanghai Medical College, Fudan University, Shanghai, P.R. China.
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