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J Natl Cancer Inst. 2018 Dec 1;110(12):1400-1408. doi: 10.1093/jnci/djy063.

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

Author information

1
Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway.
2
Center for Cancer Biomedicine, University of Oslo, Oslo, Norway.
3
Department of Informatics.
4
Department of Gynecologic Oncology, Oslo University Hospital, Oslo, Norway.
5
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
6
Center for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.
7
Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, UK.

Abstract

Background:

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.

Methods:

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.

Results:

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).

Conclusions:

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.

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