MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma.
Eun Young KangJoshua MillsteinGordana PopovicNicola S MeagherAdelyn BolithonAline TalhoukDerek S ChiuMichael S AnglesioBetty LeungKatrina TangNeil LambieMarina PavanelloAnnalyn Da-AnoyDiether LambrechtsLiselore LoverixSiel OlbrechtChristiani BisinottoJesus Garcia-DonasSergio Ruiz-LlorenteMonica Yagüe-FernandezRobert P EdwardsEsther ElishaevAlexander OlawaiyeSarah TaylorBeyhan AtasevenAndreas du BoisPhilipp HarterJenny LesterClaus K HøgdallSebastian M ArmasuYajue HuangRobert A VierkantChen WangStacey J WinhamSabine HeubleinFelix K F KommossDaniel W CramerNaoko SasamotoLilian van-WagensveldMaria LyckeConstantina MateoiuJanine JosephMalcolm C PikeKunle OdunsiChiu-Chen TsengCeleste L PearceSanela BilicThomas P ConradsArndt HartmannAlexander HeinMichael E JonesYee LeungMatthias W BeckmannMatthias RuebnerMinouk J SchoemakerKathryn L TerryMona A El-BahrawyPenny CoulsonJohn L EtterKatherine LaVigne-MagerJuergen AndressMarcel GrubeAnna FischerNina NeudeckGreg RobertsonRhonda FarrellEllen BarlowCarmel QuinnAnusha HettiaratchiYovanni CasablancaRamona ErberColin J R StewartAdeline TanYu YuJessica BorosAlison H BrandPaul R HarnettCatherine J KennedyNikilyn NevinsTerry MorganPeter A FaschingIgnace VergoteAnthony J SwerdlowFrancisco J Candido Dos ReisG Larry MaxwellSusan L NeuhausenArantzazu Barquin-GarciaFrancesmary ModugnoKirsten B MoysichPhilip J CroweAkira HirasawaFlorian HeitzBeth Y KarlanEllen L GoodePeter SinnHugo M HorlingsEstrid HøgdallKarin SundfeldtStefan KommossAnnette StaeblerAnna H WuPaul A CohenAnna DeFazioCheng-Han LeeHelen SteedNhu D LeSimon A GaytherKate LawrensonPaul D P PharoahGottfried KonecnyLinda S CookSusan J RamusLinda E KelemenMartin KoebelPublished in: Virchows Archiv : an international journal of pathology (2021)
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.