Association Between Proportion of Nuclei With High Chromatin Entropy and Prognosis in Gynecological Cancers

• Published in: JNCI : Journal of the National Cancer Institute Vol. 110; no. 12; pp. 1400 - 1408
• Main Authors: Nielsen, Birgitte, Kleppe, Andreas, Hveem, Tarjei Sveinsgjerd, Pradhan, Manohar, Syvertsen, Rolf Anders, Nesheim, John Arne, Kristensen, Gunnar Balle, Trovik, Jone, Kerr, David James, Albregtsen, Fritz, Danielsen, Håvard Emil
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.12.2018
• Subjects: Aged; Aged, 80 and over; Biomarkers, Tumor; Cell Nucleus - pathology; Chromatin; Cohort Studies; Entropy; Female; Genital Neoplasms, Female - epidemiology; Genital Neoplasms, Female - etiology; Genital Neoplasms, Female - mortality; Genital Neoplasms, Female - pathology; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Grading; Neoplasm Staging; Norway - epidemiology; Prognosis; Registries; Norway
• DOI: 10.1093/jnci/djy063
• ISSN: 0027-8874

Nuclear texture analysis measuring differences in chromatin structure has provided prognostic biomarkers in several cancers. There is a need for improved cell-by-cell chromatin analysis to detect nuclei with highly disorganized chromatin. The purpose of this study was to develop a method for detecting nuclei with high chromatin entropy and to evaluate the association between the presence of such deviating nuclei and prognosis. A new texture-based biomarker that characterizes each cancer based on the proportion of high-chromatin entropy nuclei (<25% vs ≥25%) was developed on a discovery set of 175 uterine sarcomas. The prognostic impact of this biomarker was evaluated on a validation set of 179 uterine sarcomas, as well as on independent validation sets of 246 early-stage ovarian carcinomas and 791 endometrial carcinomas. More than 1 million images of nuclei stained for DNA were included in the study. All statistical tests were two-sided. An increased proportion of high-chromatin entropy nuclei was associated with poor clinical outcome. The biomarker predicted five-year overall survival for uterine sarcoma patients with a hazard ratio (HR) of 2.02 (95% confidence interval [CI] = 1.43 to 2.84), time to recurrence for ovarian cancer patients (HR = 2.91, 95% CI = 1.74 to 4.88), and cancer-specific survival for endometrial cancer patients (HR = 3.74, 95% CI = 2.24 to 6.24). Chromatin entropy was an independent prognostic marker in multivariable analyses with clinicopathological parameters (HR = 1.81, 95% CI = 1.21 to 2.70, for sarcoma; HR = 1.71, 95% CI = 1.01 to 2.90, for ovarian cancer; and HR = 2.03, 95% CI = 1.19 to 3.45, for endometrial cancer). A novel method detected high-chromatin entropy nuclei, and an increased proportion of such nuclei was associated with poor prognosis. Chromatin entropy supplemented existing prognostic markers in multivariable analyses of three gynecological cancer cohorts.