Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

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

doi:10.1158/1078-0432.CCR-22-1206

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Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

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

Citation: CLINICAL CANCER RESEARCH, Vol.28(24) : 5383-5395, 2022-12

Journal Title: CLINICAL CANCER RESEARCH

ISSN: 1078-0432

Issue Date: 2022-12

MeSH: Adenocarcinoma, Mucinous* / diagnosis ; Adenocarcinoma, Mucinous* / genetics ; Carcinoma, Ovarian Epithelial / pathology ; Female ; Gastrointestinal Neoplasms* / metabolism ; Humans ; Neoplasm Staging ; Ovarian Neoplasms* / metabolism ; Prognosis

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.