Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2

Rick A. C. M. Boonen, Amélie Rodrigue, Chantal Stoepker, Wouter W. Wiegant, Bas Vroling, Milan Sharma, Magdalena B. Rother, Nandi Celosse, Maaike P. G. Vreeswijk, Fergus Couch, Jacques Simard, Peter Devilee, Jean-Yves Masson and Haico Attikum ()
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Rick A. C. M. Boonen: Leiden University Medical Center
Amélie Rodrigue: Oncology Division
Chantal Stoepker: Leiden University Medical Center
Wouter W. Wiegant: Leiden University Medical Center
Bas Vroling: Bio-Prodict
Milan Sharma: Leiden University Medical Center
Magdalena B. Rother: Leiden University Medical Center
Nandi Celosse: Leiden University Medical Center
Maaike P. G. Vreeswijk: Leiden University Medical Center
Fergus Couch: Mayo Clinic
Jacques Simard: Oncology Division
Peter Devilee: Leiden University Medical Center
Jean-Yves Masson: Oncology Division
Haico Attikum: Leiden University Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Heterozygous carriers of germ-line loss-of-function variants in the DNA repair gene PALB2 are at a highly increased lifetime risk for developing breast cancer. While truncating variants in PALB2 are known to increase cancer risk, the interpretation of missense variants of uncertain significance (VUS) is in its infancy. Here we describe the development of a relatively fast and easy cDNA-based system for the semi high-throughput functional analysis of 48 VUS in human PALB2. By assessing the ability of PALB2 VUS to rescue the DNA repair and checkpoint defects in Palb2 knockout mouse embryonic stem (mES) cells, we identify various VUS in PALB2 that impair its function. Three VUS in the coiled-coil domain of PALB2 abrogate the interaction with BRCA1, whereas several VUS in the WD40 domain dramatically reduce protein stability. Thus, our functional assays identify damaging VUS in PALB2 that may increase cancer risk.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13194-2

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DOI: 10.1038/s41467-019-13194-2

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