MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma.
Eun Young Kang,
Joshua Millstein,
Gordana Popovic,
Nicola S Meagher,
Adelyn Bolithon,
Aline Talhouk,
Derek S Chiu,
Michael S Anglesio,
Betty Leung,
Katrina Tang,
Neil Lambie,
Marina Pavanello,
Annalyn Da-Anoy,
Diether Lambrechts,
Liselore Loverix,
Siel Olbrecht,
Christiani Bisinotto,
Jesus Garcia-Donas,
Sergio Ruiz-Llorente,
Monica Yagüe-Fernandez,
Robert P Edwards,
Esther Elishaev,
Alexander Olawaiye,
Sarah Taylor,
Beyhan Ataseven,
Andreas du Bois,
Philipp Harter,
Jenny Lester,
Claus K Høgdall,
Sebastian M Armasu,
Yajue Huang,
Robert A Vierkant,
Chen Wang,
Stacey J Winham,
Sabine Heublein,
Felix K F Kommoss,
Daniel W Cramer,
Naoko Sasamoto,
Lilian van-Wagensveld,
Maria Lycke,
Constantina Mateoiu,
Janine Joseph,
Malcolm C Pike,
Kunle Odunsi,
Chiu-Chen Tseng,
Celeste L Pearce,
Sanela Bilic,
Thomas P Conrads,
Arndt Hartmann,
Alexander Hein,
Michael E Jones,
Yee Leung,
Matthias W Beckmann,
Matthias Ruebner,
Minouk J Schoemaker,
Kathryn L Terry,
Mona A El-Bahrawy,
Penny Coulson,
John L Etter,
Katherine LaVigne-Mager,
Juergen Andress,
Marcel Grube,
Anna Fischer,
Nina Neudeck,
Greg Robertson,
Rhonda Farrell,
Ellen Barlow,
Carmel Quinn,
Anusha Hettiaratchi,
Yovanni Casablanca,
Ramona Erber,
Colin J R Stewart,
Adeline Tan,
Yu Yu,
Jessica Boros,
Alison H Brand,
Paul R Harnett,
Catherine J Kennedy,
Nikilyn Nevins,
Terry Morgan,
Peter A Fasching,
Ignace Vergote,
Anthony J Swerdlow,
Francisco J Candido Dos Reis,
G Larry Maxwell,
Susan L Neuhausen,
Arantzazu Barquin-Garcia,
Francesmary Modugno,
Kirsten B Moysich,
Philip J Crowe,
Akira Hirasawa,
Florian Heitz,
Beth Y Karlan,
Ellen L Goode,
Peter Sinn,
Hugo M Horlings,
Estrid Høgdall,
Karin Sundfeldt,
Stefan Kommoss,
Annette Staebler,
Anna H Wu,
Paul A Cohen,
Anna DeFazio,
Cheng-Han Lee,
Helen Steed,
Nhu D Le,
Simon A Gayther,
Kate Lawrenson,
Paul D P Pharoah,
Gottfried Konecny,
Linda S Cook,
Susan J Ramus,
Linda E Kelemen,
Martin Köbel
Abstract
Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.
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Virchows Archiv : an international journal of pathology