title: Next-Generation Sequencing of Tubal Intraepithelial Carcinomas.
abstract: OBJECTIVE
  High-grade serous carcinoma (HGSC) is the most prevalent and lethal form of ovarian cancer. HGSCs frequently arise in the distal fallopian tubes rather than the ovary, developing from small precursor lesions called serous tubal intraepithelial carcinomas (TICs, or more specifically, STICs). While STICs have been reported to harbor TP53 mutations, detailed molecular characterizations of these lesions are lacking.
  
  
  METHODS
  We performed targeted next-generation sequencing (NGS) on formalin-fixed, paraffin-embedded tissue from 4 women, 2 with HGSC and 2 with uterine endometrioid carcinoma (UEC) who were diagnosed as having synchronous STICs. We detected concordant mutations in both HGSCs with synchronous STICs, including TP53 mutations as well as assumed germline BRCA1/2 alterations, confirming a clonal association between these lesions. Next-generation sequencing confirmed the presence of a STIC clonally unrelated to 1 case of UEC, and NGS of the other tubal lesion diagnosed as a STIC unexpectedly supported the lesion as a micrometastasis from the associated UEC.
  
  
  CONCLUSIONS
  We demonstrate that targeted NGS can identify genetic alterations in minute lesions, such as TICs, and confirm TP53 mutations as early driving events for HGSC. Next-generation sequencing also demonstrated unexpected associations between presumed STICs and synchronous carcinomas, providing evidence that some TICs are actually metastases rather than HGSC precursors.
authors.affiliation: Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: McDaniel
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Stall
authors.affiliation: Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Hovelson
authors.affiliation: Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor.
authors.forename: Andi K
authors.initials: AK
authors.lastname: Cani
authors.affiliation: Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor.
authors.forename: Chia-Jen
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor4Department of Urology, University of Michigan, Ann Arbor5Comprehensive Cancer Center, University of Michigan, Ann Arbor.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.affiliation: Michigan Center for Translational Pathology, Department of Pathology, University of Michigan, Ann Arbor5Comprehensive Cancer Center, University of Michigan, Ann Arbor6Department of Internal Medicine, University of Michigan, Ann Arbor.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Cho
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D002278:Carcinoma in Situ / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005185:Fallopian Tube Neoplasms / Q000235:genetics* / Q000556:secondary; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D061206:Neoplasm Micrometastasis; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000235:genetics* / Q000556:secondary; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011237:Predictive Value of Tests; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53