title: Analysis of Founder Mutations in Rare Tumors Associated With Hereditary Breast/Ovarian Cancer Reveals a Novel Association of BRCA2 Mutations with Ampulla of Vater Carcinomas.
abstract: BRCA1 and BRCA2 mutations are responsible for hereditary breast and ovarian cancer, but they also confer an increased risk for the development of rarer cancers associated with this syndrome, namely, cancer of the pancreas, male breast, peritoneum, and fallopian tube. The objective of this work was to quantify the contribution of the founder mutations BRCA2 c.156_157insAlu and BRCA1 c.3331_3334del for cancer etiology in unselected hospital-based cohorts of Portuguese patients diagnosed with these rarer cancers, by using a strategy that included testing of archival tumor tissue. A total of 102 male breast, 68 pancreatic and 33 peritoneal/fallopian tube carcinoma cases were included in the study. The BRCA2 c.156_157insAlu mutation was observed with a frequency of 7.8% in male breast cancers, 3.0% in peritoneal/fallopian tube cancers, and 1.6% in pancreatic cancers, with estimated total contributions of germline BRCA2 mutations of 14.3%, 5.5%, and 2.8%, respectively. No carriers of the BRCA1 c.3331_3334del mutation were identified. During our study, a patient with an ampulla of Vater carcinoma was incidentally found to carry the BRCA2 c.156_157insAlu mutation, so we decided to test a consecutive series of additional 15 ampullary carcinomas for BRCA1/BRCA2 mutations using a combination of direct founder mutation testing and full gene analysis with next generation sequencing. BRCA2 mutations were observed with a frequency of 14.3% in ampulla of Vater carcinomas. In conclusion, taking into account the implications for both the individuals and their family members, we recommend that patients with these neoplasias should be offered BRCA1/BRCA2 genetic testing and we here show that it is feasible to test for founder mutations in archival tumor tissue. Furthermore, we identified for the first time a high frequency of germline BRCA2 mutations in ampullary cancers.
authors.affiliation: Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Pinto
authors.affiliation: Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Peixoto
authors.affiliation: Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Santos
authors.affiliation: Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Rocha
authors.affiliation: Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Pinto
authors.affiliation: Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pinheiro
authors.affiliation: Department of Pathology, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Leça
authors.affiliation: Department of Pathology, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal.
authors.forename: Ana Teresa
authors.initials: AT
authors.lastname: Martins
authors.affiliation: Department of Pathology, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal.
authors.forename: Verónica
authors.initials: V
authors.lastname: Ferreira
authors.affiliation: Department of Pathology, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Bartosch
authors.affiliation: Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal.|Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
authors.forename: Manuel R
authors.identifier: http://orcid.org/0000-0002-3633-1659
authors.initials: MR
authors.lastname: Teixeira
mesh_terms: D014670:Ampulla of Vater / Q000473:pathology*; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D010051:Ovarian Neoplasms / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics*; D011174:Portugal; D011471:Prostatic Neoplasms / Q000235:genetics; D012189:Retrospective Studies
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human