Rare germline variants in PALB2 and BRCA2 in familial and sporadic chordoma

Author:

Xia, Bing

Biswas,Kajal

Foo, Tzeh Keong

Torres, Thiago

Riedel-Topper, Maximilian

Southon,Eileen

Kang, Zhihua

Huo, Yanying

Reid,Susan

Stauffer,Stacey

Zhou,Weiyin

Zhu, Bin

Koka, Hela

Yepes, Sally

Brodie, Seth A

Jones,Kristine

Vogt,Aurelie

Zhu,Bin

Cater, Brian

Freedman, Neal D

Hicks,Belynda

Yeager, Meredith

Chanock, Stephen J

Couch, Fergus

Parry, Dilys M

Monteiro, Alvaro N

Goldstein, Alisa M

Carvalho, Marcelo A

Sharan,Shyam [ORCID]

Yang, Xiaohong R [ORCID]
Author Address

Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, NJ, USA., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, NIH, DHHS, Frederick, MD, USA., Instituto Nacional de C 226;ncer, Divis 227;o de Pesquisa Cl 237;nica, Rio de Janeiro, 20230-130, Brazil., Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA., American Cancer Society, Inc, Atlanta, GA, 30303, USA., Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA., Cancer Epidemiology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA., Instituto Federal do Rio de Janeiro - IFRJ, Rio de Janeiro, 20270-021, Brazil.,

Abstract:

Chordoma is a rare bone tumor with genetic risk factors largely unknown. We conducted a whole-exome sequencing (WES) analysis of germline DNA from 19 familial chordoma cases in five pedigrees and 137 sporadic chordoma patients and identified 17 rare germline variants in PALB2 and BRCA2, whose products play essential roles in homologous recombination (HR) and tumor suppression. One PALB2 variant showed disease co-segregation in a family with four affected people or obligate gene carrier. Chordoma cases had a significantly increased burden of rare variants in both genes when compared to population-based controls. Four of the six PALB2 variants identified from chordoma patients modestly affected HR function and three of the 11 BRCA2 variants caused loss of function in experimental assays. These results, together with previous reports of abnormal morphology and Brachyury expression of the notochord in Palb2 knockout mouse embryos and genomic signatures associated with HR defect and HR gene mutations in advanced chordomas, suggest that germline mutations in PALB2 and BRCA2 may increase chordoma susceptibility. Our data shed light on the etiology of chordoma and support the previous finding that PARP-1 inhibitors may be a potential therapy for some chordoma patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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