title: Genomics of Ovarian Cancer Progression Reveals Diverse Metastatic Trajectories Including Intraepithelial Metastasis to the Fallopian Tube.
abstract: Accumulating evidence has supported the fallopian tube rather than the ovary as the origin for high-grade serous ovarian cancer (HGSOC). To understand the relationship between putative precursor lesions and metastatic tumors, we performed whole-exome sequencing on specimens from eight HGSOC patient progression series consisting of serous tubal intraepithelial carcinomas (STIC), invasive fallopian tube lesions, invasive ovarian lesions, and omental metastases. Integration of copy number and somatic mutations revealed patient-specific patterns with similar mutational signatures and copy-number variation profiles across all anatomic sites, suggesting that genomic instability is an early event in HGSOC. Phylogenetic analyses supported STIC as precursor lesions in half of our patient cohort, but also identified STIC as metastases in 2 patients. Ex vivo assays revealed that HGSOC spheroids can implant in the fallopian tube epithelium and mimic STIC lesions. That STIC may represent metastases calls into question the assumption that STIC are always indicative of primary fallopian tube cancers.
  
  
  
  We find that the putative precursor lesions for HGSOC, STIC, possess most of the genomic aberrations present in advanced cancers. In addition, a proportion of STIC represent intraepithelial metastases to the fallopian tube rather than the origin of HGSOC. Cancer Discov; 6(12); 1342-51. ©2016 AACR.See related commentary by Swisher et al., p. 1309This article is highlighted in the In This Issue feature, p. 1293.
authors.affiliation: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Eckert
authors.affiliation: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Shawn
authors.initials: S
authors.lastname: Pan
authors.affiliation: Center for Research Informatics, The University of Chicago, Chicago, Illinois.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Hernandez
authors.affiliation: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Loth
authors.affiliation: Center for Research Informatics, The University of Chicago, Chicago, Illinois.
authors.forename: Jorge
authors.initials: J
authors.lastname: Andrade
authors.affiliation: Center for Research Informatics, The University of Chicago, Chicago, Illinois.|Department of Pediatrics, The University of Chicago, Chicago, Illinois.
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Volchenboum
authors.affiliation: University of Chicago Genomics Facility, The University of Chicago, Chicago, Illinois.
authors.forename: Pieter
authors.initials: P
authors.lastname: Faber
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois.
authors.forename: Anthony
authors.initials: A
authors.lastname: Montag
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lastra
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Peter
authors.affiliation: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: S Diane
authors.initials: SD
authors.lastname: Yamada
authors.affiliation: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, Illinois. elengyel@uchicago.edu.
authors.forename: Ernst
authors.initials: E
authors.lastname: Lengyel
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000601:surgery; D018450:Disease Progression; D005185:Fallopian Tube Neoplasms / Q000235:genetics* / Q000601:surgery; D005260:Female; D042822:Genomic Instability; D023281:Genomics / Q000379:methods; D006801:Humans; D009362:Neoplasm Metastasis; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000601:surgery; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000601:surgery; D010534:Peritoneal Neoplasms / Q000235:genetics* / Q000601:surgery; D010802:Phylogeny; D017422:Sequence Analysis, DNA / Q000379:methods*; D014407:Tumor Cells, Cultured