title: The potential utility of geminin as a predictive biomarker in breast cancer.
abstract: Compared with other markers of cell proliferation, geminin is unique being expressed selectively during the proliferative phase of the cell cycle, specifically S, G2 and early mitosis, disappearing completely at the metaphase-anaphase transition. We aimed to compare the prognostic significance of geminin to that of Ki67, a proliferation marker which has been investigated in many breast cancer studies. Breast cancer tissue microarrays containing 368 tumours were stained using anti-geminin and Ki67 antibodies. Labelling index (LI) was calculated for geminin, and the percentage of positive cancer nuclei was determined for Ki67. A receiver operation characteristics analysis was used to determine the optimum cut-off value for geminin (LI ≥ 2), and for Ki67, a score of ≥14 % was considered as positive for survival analysis. Geminin expression correlated positively with Ki67 expression (r = 0.686, p = 0.001). Survival analysis showed only geminin, and not Ki67-positive patients to have poor (breast cancer-specific survival) BCSS [HR 2.85 (1.53-5.32)] and (disease-free survival) DFS [HR 2.63 (1.47-4.71)]. On univariate analysis, along with known clinicopathological variables, both Ki67 and geminin LI were found to be significant predictors of BCSS and DFS. On multivariate analysis, only tumour size, nodal status and adjuvant hormonal therapy were found to be independent predictors for both BCSS and DFS, while geminin positivity (LI ≥ 2 %) was found to be an independent predictor for BCSS [HR 2.27 (1.01-5.06); p = 0.04]. In comparison with Ki67, a more established proliferation marker, geminin expression was a better predictor of adverse outcome in this cohort of breast cancers. Selective expression of geminin during the proliferative phase of the cell cycle and its nuclear specificity increase its potential to be used as an alternative marker of proliferation in breast cancer patients.
authors.affiliation: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Leeds, LS9 7TF, UK.
authors.forename: Sreekumar
authors.initials: S
authors.lastname: Sundara Rajan
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Hanby
authors.forename: Kieran
authors.initials: K
authors.lastname: Horgan
authors.forename: Helene H
authors.initials: HH
authors.lastname: Thygesen
authors.forename: Valerie
authors.initials: V
authors.lastname: Speirs
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D064248:Geminin / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D011379:Prognosis; D012372:ROC Curve; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D064248:Geminin; D019394:Ki-67 Antigen