The molecular origin and taxonomy of mucinous ovarian carcinoma

Dane Cheasley ,Georgina L Ryland ,David G Hunstman ,Anne Marie Mes-Masson ,Orla Mcnally ,Nadia Traficante ,Jan Pyman ,Kathryn Alsop ,Alison Hadley ,Hugo Saunders ,Kurosh Rahimi ,Michael S Anglesio ,Simone M Rowley ,David D Bowtell ,George Au-Yeung ,Carolina Salazar ,Zhongyue Xing ,Cécile Le Page ,Prue E Allan ,Charlie Gourley ,Georgia Chenevix-Trench ,Renee Demeo ,Niko Thio ,Simon Hughes ,Diane Provencher ,Michael Churchman ,Clare L Scott ,Goli Samimi ,Matthew J Wakefield ,Sumitra Ananda ,Jessica N Mcalpine ,Kimberly R Kalli ,Ian G Campbell ,Alison Brand ,Clare G Fedele ,Andrew N Stephens ,Sián Fereday ,Stephen B Fox ,Anna Defazio ,Rhiannon Dudley ,Catherine J Kennedy ,Yoke Eng Chiew ,Gwo Yaw Ho ,Joy Hendley ,Alice J Sharpe ,Magnus Zethoven ,Yoland Antill ,Sally M Hunter ,Michelle C Torres ,Michael Christie ,Jason Li ,Scott H Kaufmann ,Nicole Fairweather ,Maret Böhm ,Richard Lupat ,Martin Köbel ,Tom Jobling ,Neville F Hacker ,Linda Mileshkin ,Kaushalya Amarasinghe ,C Blake Gilks ,Timothy Semple ,R Sharma ,Kylie L Gorringe

doi:10.1038/s41467-019-11862-x

Abstract

Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases.

Highlights

Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs
We amassed over 500 potential mucinous ovarian tumors, including putative precursors, and undertook extensive pathological and clinical review to define a cohort of 255 primary MOC (Supplementary Data 1)
Cases were ascertained from participating tissue banks and hospital databases as ovarian tumors with mucinous histology, and were reviewed with current diagnostic criteria to exclude mixed mucinous and non-mucinous ovarian tumors, and ovarian metastases from non-ovarian primaries

Summary

Introduction

Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. We show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. The cell of origin for MOC remains unknown, mucinous benign cystadenomas and mucinous borderline ovarian tumors (MBT), the latter characterized by proliferative and atypical epithelial cells lacking stromal invasion, have been suggested as putative precursor lesions to MOC. The contamination of earlier molecular data with metastatic tumors masquerading as MOC and the low sample size of more contemporary studies mean that the genetic events that drive invasive progression and metastasis of primary MOC remain largely unknown.

Methods

Results

Conclusion