@article{2e03ad3b1b73401bb221dd796c584279,
title = "Rare germline variants in PALB2 and BRCA2 in familial and sporadic chordoma",
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 cosegregation 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.",
keywords = "BRCA2, PALB2, chordoma, genetic susceptibility, rare germline variants",
author = "Bing Xia and Kajal Biswas and Foo, {Tzeh K.} and Gomes, {Thiago T.} and Maximilian Riedel-Topper and Eileen Southon and Zhihua Kang and Yanying Huo and Susan Reid and Stacey Stauffer and Weiyin Zhou and Bin Zhu and Hela Koka and Sally Yepes and Brodie, {Seth A.} and Kristine Jones and Aurelie Vogt and Bin Zhu and Brian Carter and Freedman, {Neal D.} and Belynda Hicks and Meredith Yeager and Chanock, {Stephen J.} and Fergus Couch and Parry, {Dilys M.} and Monteiro, {Alvaro N.} and Goldstein, {Alisa M.} and Carvalho, {Marcelo A.} and Sharan, {Shyam K.} and Yang, {Xiaohong R.}",
note = "Funding Information: We are indebted to the participating families, whose generosity and cooperation have made this study possible. We thank the Cancer Sequencing Working Group and Cancer Genomics Research Laboratory of the Division of Cancer Epidemiology & Genetics (DCEG) at the National Cancer Institute (NCI). This study was funded by Intramural Research Program of DCEG and Center for Cancer Research at NCI, National Institutes of Health, USA; and by NCI grants R01CA138804 and R01CA262227 to BX. This workstudy was also supported by Funda{\c c}{\~a}o Carlos Chagas Filho de Amparo {\`a} Pesquisa do Estado do Rio de Janeiro, Conselho Nacional de Desenvolvimento Cient{\'i}fico e Tecnol{\'o}gico, Funda{\c c}{\~a}o do C{\^a}ncer (Programa de Oncobiologia) (MAC), and Moffitt foundation (AM). TKF and ZK were recipients of New Jersey Commission on Cancer Research (NJCCR) Postdoctoral Fellowships. Funding Information: We are indebted to the participating families, whose generosity and cooperation have made this study possible. We thank the Cancer Sequencing Working Group and Cancer Genomics Research Laboratory of the Division of Cancer Epidemiology & Genetics (DCEG) at the National Cancer Institute (NCI). This study was funded by Intramural Research Program of DCEG and Center for Cancer Research at NCI, National Institutes of Health, USA; and by NCI grants R01CA138804 and R01CA262227 to BX. This workstudy was also supported by Funda{\c c}{\~a}o Carlos Chagas Filho de Amparo {\`a} Pesquisa do Estado do Rio de Janeiro, Conselho Nacional de Desenvolvimento Cient{\'i}fico e Tecnol{\'o}gico, Funda{\c c}{\~a}o do C{\^a}ncer (Programa de Oncobiologia) (MAC), and Moffitt foundation (AM). TKF and ZK were recipients of New Jersey Commission on Cancer Research (NJCCR) Postdoctoral Fellowships. Publisher Copyright: {\textcopyright} 2022 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.",
year = "2022",
month = oct,
doi = "https://doi.org/10.1002/humu.24427",
language = "American English",
volume = "43",
pages = "1396--1407",
journal = "Human mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "10",
}