Pancreatic Cancer with Mutation in BRCA1/2, MLH1, and APC Genes: Phenotype Correlation and Detection of a Novel Germline BRCA2 Mutation

Genes (Basel). 2022 Feb 9;13(2):321. doi: 10.3390/genes13020321.


Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer death worldwide; most of cases are sporadic, however about 5% to 10% report a hereditary predisposition. Several hereditary syndromes have been associated with familial pancreatic cancer (FPC) onset, including hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), Familial atypical multiple mole melanoma (FAMMM), Familial adenomatous polyposis (FAP), Li-Fraumeni syndrome (LFS), Peutz-Jeghers syndrome (PJS), and Hereditary pancreatitis (HP).The aim of this study was to determine the mutational status of a cohort of 56 HBOC families, 7 LS families, 3 FAP and FAMMM families, and 1 LFS family with at least one case of PDAC. Mutation analysis of BRCA1/2, ATM, CHEK2, PALB2, RAD51C, RAD51D, NBN, CDH1, TP53, MLH1, MSH2, MSH6, and PMS2 genes, showedmutation in BRCA1/2, MLH1, and APC genes. We founda high mutation rate in patients belong HBOC and LS families, with a percentage of 28.6% in both syndromes and prevalence in HBOC of BRCA2 mutations with one case of double mutation in BRCA2 gene. In FAP family, we found a pathogenic mutation in APC gene in 1/3 families. We observed an early onset of PDAC and a lower survival in PDAC patients belonging to mutated families, while no evidence of possible pancreatic cancer cluster regions was found. Moreover, we identified a novel BRCA2 germline mutation, c.5511delT (p.Phe1837LeufsX3), not reported in any database, that segregated with disease in HBOC patients. Mutational analysis was extended to family membersof mutated patients, both healthy and cancer affected, which revealed 23 unaffected family members that inherited the proband's mutation. Although correlative by its nature, the presence of a BRCA mutation in PDAC patients may have benefits in terms of optimized treatment and longer outcome.

Keywords: BRCA genes; MMR genes; familial adenomatous polyposis; hereditary breast and ovarian cancer syndrome; hereditary nonpolyposis colon cancer syndrome; pancreatic ductal adenocarcinoma.

MeSH terms

  • Adenomatous Polyposis Coli Protein
  • Adenomatous Polyposis Coli* / genetics
  • BRCA1 Protein / genetics
  • BRCA2 Protein
  • Carcinoma, Pancreatic Ductal* / genetics
  • Colorectal Neoplasms, Hereditary Nonpolyposis* / genetics
  • Female
  • Genes, APC
  • Germ Cells
  • Hereditary Breast and Ovarian Cancer Syndrome* / genetics
  • Humans
  • MutL Protein Homolog 1 / genetics
  • Mutation
  • Pancreatic Neoplasms* / genetics
  • Phenotype


  • APC protein, human
  • Adenomatous Polyposis Coli Protein
  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • MLH1 protein, human
  • MutL Protein Homolog 1

Supplementary concepts

  • Pancreatic Carcinoma