MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma

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.

The Evolution of Ovarian Carcinoma Subclassification

“…Separating prognostic information from predictive information requires controlled clinical trials and can often only be inferred from observational cohort studies. For example, the recently described favorable association of the proliferation marker MCM3 with survival is thought to be due to good response to standard platinum–taxane chemotherapy [ 66 ]. Another example is the prognostic association of BRCA1/2 mutations in patients, which could be at least partly due to a better response to platinum–taxane therapy [ 67 ].…”

Proteogenomic Characterization Reveals Therapeutic Opportunities Related to Mitochondrial Function in Melanoma

“…The six proteins form a heterohexameric complex with an 1:1:1:1:1:1 stoichiometry, which has DNA helicase activity (Das et al, 2014; Lee and Hurwitz, 2001; Miller et al, 2019; You et al, 1999). Independently, all these proteins have been reported to be upregulated in several cancers and associated with fast progression, proliferation, aggressiveness and short survival (Aporowicz et al, 2019; Cao et al, 2020; Das et al, 2014; Giaginis et al, 2009, 2011; Issac et al, 2019; Kang et al, 2022; Lee and Hurwitz, 2001; Stojkovic-Filipovic et al, 2016; Valverde et al, 2018; Wojnar et al, 2010; You et al, 1999). The relative abundances, extracted from MS data of the six elements of the MCM complex, were taken as a measurement of the proliferation rate of the cells in all samples included within the study.…”

CCNE1 and survival of patients with tubo‐ovarian high‐grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

“…Although the main function of CCNE1 is in cell‐cycle progression, the main oncogenic effect may be independent from proliferation. High proliferating HGSCs are associated with longer survival, likely because of better response to standard chemotherapy, 27,28 whereas CCNE1 alterations are associated with shorter survival and poor response to chemotherapy. CCNE1 protein expression is only weakly correlated with proliferation markers (Ki67, minichromosome maintenance complex component 3) 28 .…”

“…High proliferating HGSCs are associated with longer survival, likely because of better response to standard chemotherapy, 27,28 whereas CCNE1 alterations are associated with shorter survival and poor response to chemotherapy. CCNE1 protein expression is only weakly correlated with proliferation markers (Ki67, minichromosome maintenance complex component 3) 28 . Although uncontrolled cell‐cycle entry remains the main known function of CCNE1, overall, these data suggest that much of CCNE1's oncogenic function is related to a premature S‐phase entry resulting in chromosomal instability rather than increased proliferation 7,8 …”

“…Formalin‐fixed paraffin‐embedded tumor specimens ( n = 2419) with partial overlap to the previous specimens (1612/3029) were obtained from additional cores or sections 28 . RNA extraction methods, assay run parameters, data processing, and control/reference samples were as previously described 29 .…”