High grade serous ovarian carcinomas originate in the fallopian tube

Sana Intidhar Labidi-Galy ,Siân Jones,Douglas I Lin,Noushin Niknafs,Michaël Noë ,Ronny Drapkin,Lauren Schwartz ,Rohit Bhattacharya,Eniko Papp,Robert B Scharpf,Laura D Wood,Dorothy Hallberg,Robert J Kurman ,Cécile L Maire ,Ayşe Ayhan ,Rachel Karchin,Jillian Phallen,Michaela Bowden,Vilmos Adleff,Marián Novak ,Michelle S Hirsch,Tian Li Wang ,Ie Ming Shih ,Carolyn Hruban ,Jean Christophe Tille ,Victor E Velculescu

doi:10.1038/s41467-017-00962-1

Abstract

High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian cancer and has a poor outcome. It has been proposed that fallopian tube cancers may be precursors of HGSOC but evolutionary evidence for this hypothesis has been limited. Here, we perform whole-exome sequence and copy number analyses of laser capture microdissected fallopian tube lesions (p53 signatures, serous tubal intraepithelial carcinomas (STICs), and fallopian tube carcinomas), ovarian cancers, and metastases from nine patients. The majority of tumor-specific alterations in ovarian cancers were present in STICs, including those affecting TP53, BRCA1, BRCA2 or PTEN. Evolutionary analyses reveal that p53 signatures and STICs are precursors of ovarian carcinoma and identify a window of 7 years between development of a STIC and initiation of ovarian carcinoma, with metastases following rapidly thereafter. Our results provide insights into the etiology of ovarian cancer and have implications for prevention, early detection and therapeutic intervention of this disease.

Highlights

High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian cancer and has a poor outcome
Laser capture microdissection (LCM) was used to isolate lesions after immunohistochemistry (IHC) staining of p53 in serous tubal intraepithelial carcinoma (STIC) and p53 signatures if these contained a TP53 missense mutation or after hematoxylin staining if the samples contained a TP53 nonsense mutation (Fig. 1)
We examined neoplastic samples from three individuals with germline BRCA alterations where STIC lesions were incidentally identified after prophylactic bilateral salpingo-oophorectomy, and one patient where two STICs were identified after resection of a pelvic mass (Supplementary Data 1)

Summary

Introduction

High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian cancer and has a poor outcome. Immunohistochemical as well as targeted sequencing analyses have shown that FT lesions harbor the same TP53 mutation as surrounding invasive carcinomas[17,18,19,20,21] These analyses suggest a clonal relationship among such tumors but given the limited number of genes analyzed do not conclusively identify the initiating lesions nor exclude the possibility of FT metastases from primary ovarian carcinomas[21, 22]. We examine whether the compendium of somatic alterations identified in different lesions may provide insights into the evolutionary relationship between primary FT lesions, including p53 signatures and STIC lesions, ovarian carcinomas, and intraperitoneal metastases

Methods

Results

Conclusion