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Neuroendocrine Neoplasms Associated with Germline Pathogenic Variants in the Homologous Recombination Pathway

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Abstract

Neuroendocrine neoplasms (NENs) have been primarily associated with germline pathogenic variants in genes involved in chromatin remodeling (MEN1), cell cycle control (CDKN1B), PI3K/mTOR signaling (TSC1/2, PTEN) as well as pseudohypoxia (VHL, SDHx). Recent work has implicated various genes involved in DNA repair pathways in the pathophysiology of a subset of pancreatic neuroendocrine neoplasms, including BRCA2, via the homologous recombination pathway (HRD). To date, germline variants in other HRD pathway genes have not been described to contribute to NEN. PALB2, RAD51C, and BARD1 are additional tumor suppressor genes which also mediate repair of double stranded DNA breaks through the HRD pathway and are implicated in hereditary breast (PALB2; BARD1) and ovarian (RAD51C) cancer. Here we report three cases of NEN associated with germline pathogenic variants in PALB2 (pancreatic NEN), RAD51C (thymic NEN), and BARD1 (pancreaticoduodenal NEN) respectively, further linking the DNA repair pathway to NENs.

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Acknowledgements

We would like to thank our patients for consenting to the writing of this report and also to Dr. William Foulkes for reviewing this manuscript.

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Authors and Affiliations

  1. Fred A. Litwin Family Center in Genetic Medicine, University Health Network, Toronto, ON, Canada

    Marta Szybowska, Josh Silver & Raymond H. Kim

  2. Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, Canada

    Ozgur Mete

  3. Medical Genetics, McGill University Health Centre, Montreal, QC, Canada

    Evan Weber

  4. Department of Molecular Genetics, University of Toronto, Toronto, Canada

    Josh Silver

  5. Division of Medical Oncology, Department of Medicine, University of Toronto, Toronto, Canada

    Raymond H. Kim

  6. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Fred. A. Litwin Centre in Genetic Medicine, University Health Network, University of Toronto, 60 Murray St. 3L-400, Toronto, Ontario, M5T 3L9, Canada

    Raymond H. Kim

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Szybowska, M., Mete, O., Weber, E. et al. Neuroendocrine Neoplasms Associated with Germline Pathogenic Variants in the Homologous Recombination Pathway. Endocr Pathol 30, 237–245 (2019). https://doi.org/10.1007/s12022-019-9569-4

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