title: Germline mutations of the DNA repair pathways in uterine serous carcinoma.
abstract: OBJECTIVE
  Treatment options are limited for patients with uterine serous carcinoma (USC). Knowledge of USC's somatic mutation landscape is rapidly increasing, but its role in hereditary cancers remains unclear. We aim to evaluate the frequency and characteristics of germline mutations in genes commonly implicated in carcinogenesis, including those within homologous recombination (HR) and mismatch repair (MMR) pathways in patients with pure USC.
  
  
  METHODS
  By using targeted capture exome sequencing, 43 genes were analyzed in a cohort of 7 consecutive patients with paired tumor and non-tumor USC samples in our institutional tumor repository. Mutations predicted to have damaging effects on protein function are validated by Sanger Sequencing.
  
  
  RESULTS
  We found 21 germline mutations in 11 genes in our USC cohort. Five patients harbored 7 germline mutations (33.3%) within genes involved in the HR pathway, RAD51D being the most common. Four patients had 9 (42.8%) germline mutations in hereditary colon cancer genes, most commonly MLH. All patients (42.7%) who are platinum-sensitive had HR germline mutations (RAD50, NBN, ATM). Patients with HER2 overexpression (2/7, 28.6%) had germline HR mutations and were platinum-sensitive. Three patients in our cohort reported a personal history of breast cancer, one with HR germline mutation, and 2 in patients with germline mutations in HCC genes. In addition, 5 out of 7 patients had germline mutations in genes associated with growth factor signaling pathway.
  
  
  CONCLUSIONS
  A significant proportion of our cohort harbor germline mutations in DNA repair genes. This may be associated with the high rate of breast cancer in our patients and their family, and suggests a targeted cohort for genetic counseling. If validated in a larger cohort, our findings may allow clinicians to expand therapeutic options to include targeted therapies and inclusion of USC patient in preventative and genetic counseling.
authors.affiliation: Division of Gynecologic Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, United States.
authors.forename: Marina
authors.initials: M
authors.lastname: Frimer
authors.affiliation: Laboratory of Molecular Biology Peruvian National Institute of Health, Lima 9, Peru.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Levano
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, United States.
authors.forename: Alicia
authors.initials: A
authors.lastname: Rodriguez-Gabin
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, United States.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Gynecologic Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, United States.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Goldberg
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, United States.
authors.forename: Susan Band
authors.initials: SB
authors.lastname: Horwitz
authors.affiliation: Division of Gynecologic Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, United States. Electronic address: jh3558@cumc.columbia.edu.
authors.forename: June Y
authors.initials: JY
authors.lastname: Hou
mesh_terms: D000368:Aged; D018284:Cystadenocarcinoma, Serous / Q000235:genetics*; D004260:DNA Repair; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D059765:Homologous Recombination; D006801:Humans; D009154:Mutation; D014594:Uterine Neoplasms / Q000235:genetics*
keywords: DNA repair genes; Germline mutations; Hereditary gynecological cancer; Next generation sequencing; Uterine serous carcinoma