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.
| Original language | English |
|---|---|
| Journal | Virchows Archiv |
| Volume | 480 |
| Pages (from-to) | 855–871 |
| ISSN | 0945-6317 |
| DOIs | |
| Publication status | Published - 2022 |
Bibliographical note
Publisher Copyright:© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Keywords
- High-grade serous carcinoma
- MCM3
- Proliferation
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MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma. / Kang, Eun Young; Millstein, Joshua; Popovic, Gordana; Meagher, Nicola S.; Bolithon, Adelyn; Talhouk, Aline; Chiu, Derek S.; Anglesio, Michael S.; Leung, Betty; Tang, Katrina; Lambie, Neil; Pavanello, Marina; Da-anoy, Annalyn; Lambrechts, Diether; Loverix, Liselore; Olbrecht, Siel; Bisinotto, Christiani; Garcia-Donas, Jesus; Ruiz-Llorente, Sergio; Yagüe-Fernandez, Monica; Edwards, Robert P.; Elishaev, Esther; Olawaiye, Alexander; Taylor, Sarah; Ataseven, Beyhan; du Bois, Andreas; Harter, Philipp; Lester, Jenny; Høgdall, Claus K.; Armasu, Sebastian M.; Huang, Yajue; Vierkant, Robert A.; Wang, Chen; Winham, Stacey J.; Heublein, Sabine; Kommoss, Felix K.F.; Cramer, Daniel W.; Sasamoto, Naoko; van-Wagensveld, Lilian; Lycke, Maria; Mateoiu, Constantina; Joseph, Janine; Pike, Malcolm C.; Odunsi, Kunle; Tseng, Chiu Chen; Pearce, Celeste L.; Bilic, Sanela; Conrads, Thomas P.; Hartmann, Arndt; Hein, Alexander; Jones, Michael E.; Leung, Yee; Beckmann, Matthias W.; Ruebner, Matthias; Schoemaker, Minouk J.; Terry, Kathryn L.; El-Bahrawy, Mona A.; Coulson, Penny; Etter, John L.; LaVigne-Mager, Katherine; Andress, Juergen; Grube, Marcel; Fischer, Anna; Neudeck, Nina; Robertson, Greg; Farrell, Rhonda; Barlow, Ellen; Quinn, Carmel; Hettiaratchi, Anusha; Casablanca, Yovanni; Erber, Ramona; Stewart, Colin J.R.; Tan, Adeline; Yu, Yu; Boros, Jessica; Brand, Alison H.; Harnett, Paul R.; Kennedy, Catherine J.; Nevins, Nikilyn; Morgan, Terry; Fasching, Peter A.; Vergote, Ignace; Swerdlow, Anthony J.; Candido dos Reis, Francisco J.; Maxwell, G. Larry; Neuhausen, Susan L.; Barquin-Garcia, Arantzazu; Modugno, Francesmary; Moysich, Kirsten B.; Crowe, Philip J.; Hirasawa, Akira; Heitz, Florian; Karlan, Beth Y.; Goode, Ellen L.; Sinn, Peter; Horlings, Hugo M.; Høgdall, Estrid; Sundfeldt, Karin; Kommoss, Stefan; Staebler, Annette; Wu, Anna H.; Cohen, Paul A.; DeFazio, Anna; Lee, Cheng Han; Steed, Helen; Le, Nhu D.; Gayther, Simon A.; Lawrenson, Kate; Pharoah, Paul D.P.; Konecny, Gottfried; Cook, Linda S.; Ramus, Susan J.; Kelemen, Linda E.; Köbel, Martin.
In: Virchows Archiv, Vol. 480, 2022, p. 855–871.Research output: Contribution to journal › Journal article › Research › peer-review
}
TY - JOUR
T1 - MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma
AU - Kang, Eun Young
AU - Millstein, Joshua
AU - Popovic, Gordana
AU - Meagher, Nicola S.
AU - Bolithon, Adelyn
AU - Talhouk, Aline
AU - Chiu, Derek S.
AU - Anglesio, Michael S.
AU - Leung, Betty
AU - Tang, Katrina
AU - Lambie, Neil
AU - Pavanello, Marina
AU - Da-anoy, Annalyn
AU - Lambrechts, Diether
AU - Loverix, Liselore
AU - Olbrecht, Siel
AU - Bisinotto, Christiani
AU - Garcia-Donas, Jesus
AU - Ruiz-Llorente, Sergio
AU - Yagüe-Fernandez, Monica
AU - Edwards, Robert P.
AU - Elishaev, Esther
AU - Olawaiye, Alexander
AU - Taylor, Sarah
AU - Ataseven, Beyhan
AU - du Bois, Andreas
AU - Harter, Philipp
AU - Lester, Jenny
AU - Høgdall, Claus K.
AU - Armasu, Sebastian M.
AU - Huang, Yajue
AU - Vierkant, Robert A.
AU - Wang, Chen
AU - Winham, Stacey J.
AU - Heublein, Sabine
AU - Kommoss, Felix K.F.
AU - Cramer, Daniel W.
AU - Sasamoto, Naoko
AU - van-Wagensveld, Lilian
AU - Lycke, Maria
AU - Mateoiu, Constantina
AU - Joseph, Janine
AU - Pike, Malcolm C.
AU - Odunsi, Kunle
AU - Tseng, Chiu Chen
AU - Pearce, Celeste L.
AU - Bilic, Sanela
AU - Conrads, Thomas P.
AU - Hartmann, Arndt
AU - Hein, Alexander
AU - Jones, Michael E.
AU - Leung, Yee
AU - Beckmann, Matthias W.
AU - Ruebner, Matthias
AU - Schoemaker, Minouk J.
AU - Terry, Kathryn L.
AU - El-Bahrawy, Mona A.
AU - Coulson, Penny
AU - Etter, John L.
AU - LaVigne-Mager, Katherine
AU - Andress, Juergen
AU - Grube, Marcel
AU - Fischer, Anna
AU - Neudeck, Nina
AU - Robertson, Greg
AU - Farrell, Rhonda
AU - Barlow, Ellen
AU - Quinn, Carmel
AU - Hettiaratchi, Anusha
AU - Casablanca, Yovanni
AU - Erber, Ramona
AU - Stewart, Colin J.R.
AU - Tan, Adeline
AU - Yu, Yu
AU - Boros, Jessica
AU - Brand, Alison H.
AU - Harnett, Paul R.
AU - Kennedy, Catherine J.
AU - Nevins, Nikilyn
AU - Morgan, Terry
AU - Fasching, Peter A.
AU - Vergote, Ignace
AU - Swerdlow, Anthony J.
AU - Candido dos Reis, Francisco J.
AU - Maxwell, G. Larry
AU - Neuhausen, Susan L.
AU - Barquin-Garcia, Arantzazu
AU - Modugno, Francesmary
AU - Moysich, Kirsten B.
AU - Crowe, Philip J.
AU - Hirasawa, Akira
AU - Heitz, Florian
AU - Karlan, Beth Y.
AU - Goode, Ellen L.
AU - Sinn, Peter
AU - Horlings, Hugo M.
AU - Høgdall, Estrid
AU - Sundfeldt, Karin
AU - Kommoss, Stefan
AU - Staebler, Annette
AU - Wu, Anna H.
AU - Cohen, Paul A.
AU - DeFazio, Anna
AU - Lee, Cheng Han
AU - Steed, Helen
AU - Le, Nhu D.
AU - Gayther, Simon A.
AU - Lawrenson, Kate
AU - Pharoah, Paul D.P.
AU - Konecny, Gottfried
AU - Cook, Linda S.
AU - Ramus, Susan J.
AU - Kelemen, Linda E.
AU - Köbel, Martin
N1 - Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - High-grade serous carcinoma
KW - MCM3
KW - Proliferation
U2 - 10.1007/s00428-021-03232-0
DO - 10.1007/s00428-021-03232-0
M3 - Journal article
C2 - 34782936
AN - SCOPUS:85119070861
VL - 480
SP - 855
EP - 871
JO - Virchows Archiv
JF - Virchows Archiv
SN - 0945-6317
ER -