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

Endocr Pathol. 2019 Sep;30(3):237-245. doi: 10.1007/s12022-019-9569-4.


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.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Female
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • Homologous Recombination / genetics*
  • Humans
  • Male
  • Mediastinal Neoplasms / diagnosis
  • Mediastinal Neoplasms / genetics
  • Mediastinal Neoplasms / pathology
  • Middle Aged
  • Neoplasm Metastasis
  • Neuroendocrine Tumors / diagnosis
  • Neuroendocrine Tumors / genetics*
  • Neuroendocrine Tumors / pathology
  • Pancreatic Neoplasms / diagnosis
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Pedigree
  • Signal Transduction / genetics