Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes
Authors: Meagher Nicola S. , Gorringe Kylie L. , Wakefield Matthew , Bolithon Adelyn , Pang Chi Nam Ignatius , Chiu Derek S. , Anglesio Michael S. , Mallitt Kylie-Ann , Doherty Jennifer A. , Harris Holly R. , Schildkraut Joellen M. , Berchuck Andrew , Cushing-Haugen Kara L. , Chezar Ksenia , Chou Angela , Tan Adeline , Alsop Jennifer , Barlow Ellen , Beckmann Matthias W. , Boros Jessica , Bowtell David D.L. ,   for the AOCS Group, Brand Alison H. , Brenton James D. , Campbell Ian , Cheasley Dane , Cohen Joshua , Cybulski Cezary , Elishaev Esther , Erber Ramona , Farrell Rhonda , Fischer Anna , Fu Zhuxuan , Gilks Blake , Gill Anthony J. ,   for the Australian Pancreatic Genome Initiative, Gourley Charlie , Grube Marcel , Harnett Paul R. , Hartmann Arndt , Hettiaratchi Anusha , Høgdall Claus K. , Huzarski Tomasz , Jakubowska Anna , Jimenez-Linan Mercedes , Kennedy Catherine J. , Kim Byoung-Gie , Kim Jae-Weon , Kim Jae-Hoon , Klett Kayla , Koziak Jennifer M. , Lai Tiffany , Laslavic Angela , Lester Jenny , Leung Yee , Li Na , Liauw Winston , Lim Belle W.X. , Linder Anna , Lubiński Jan , Mahale Sakshi , Mateoiu Constantina , McInerny Simone , Menkiszak Janusz , Minoo Parham , Mittelstadt Suzana , Morris David , Orsulic Sandra , Park Sang-Yoon , Pearce Celeste Leigh , Pearson John V. , Pike Malcolm C. , Quinn Carmel M. , Mohan Ganendra Raj , Rao Jianyu , Riggan Marjorie J. , Ruebner Matthias , Salfinger Stuart , Scott Clare L. , Shah Mitul , Steed Helen , Stewart Colin J.R. , Subramanian Deepak , Sung Soseul , Tang Katrina , Timpson Paul , Ward Robyn L. , Wiedenhoefer Rebekka , Thorne Heather ,   for the kConFab Investigators, Cohen Paul A. , Crowe Philip , Fasching Peter A. , Gronwald Jacek , Hawkins Nicholas J. , Høgdall Estrid , Huntsman David G. , James Paul A. , Karlan Beth Y. , Kelemen Linda E. , Kommoss Stefan , Konecny Gottfried E. , Modugno Francesmary , Park Sue K. , Staebler Annette , Sundfeldt Karin , Wu Anna H. , Talhouk Aline , Pharoah Paul D.P. , Anderson Lyndal , DeFazio Anna , Köbel Martin , Friedlander Michael L. , Ramus Susan J. 
Published: October 2022

Abstract

Purpose:
Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features.

Experimental Design:
Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55).

Results:
Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04–7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04–1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01–1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%).

Conclusions:
An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.