Changes in Chromatin Structure in Curettage Specimens Identifies High-Risk Patients in Endometrial Cancer

Hveem, Tarjei S.; Njølstad, Tormund S.; Nielsen, Birgitte; Syvertsen, Rolf Anders; Nesheim, John Arne; Kjæreng, Marna L.; Kildal, Wanja; Pradhan, Manohar; Marcickiewicz, Janusz; Tingulstad, Solveig; Staff, Anne Cathrine; Haugland, Hans Kristian; Eraker, Runar; Oddenes, Klaus; Rokne, J A; Tjugum, Jostein; Lode, Margaret S.; Amant, Frédéric; Werner, Henrica M.J.; Bjørge, Line; Albregtsen, Fritz; Liestøl, Knut; Salvesen, Helga B.; Trovik, Jone; Danielsen, Håvard E.

doi:10.1158/1055-9965.epi-16-0215

Cited by 11 publications

(24 citation statements)

References 28 publications

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“…The analysed tissue samples were usually prepared and imaged using the same methods and equipment, and attempts to make the assessments of chromatin aberrations robust to moderate technical deviations have rarely been made, which severely limits their applicability, not only in the clinic, but also in research facilities. Despite obvious limitations, findings from previous studies of this type (eg, our own studies on ovarian carcinoma, 7 uterine sarcoma, 8 prostate carcinoma, 9 and endometrial carcinoma 10 ) suggest that such alterations in chromatin organisation could be a consistent finding in carcinogenesis. We hypothesised that generic texture patterns of aberrant chromatin could be detectable in most cancer types and wanted to reliably detect these patterns independently of moderate deviations in preparation methods and imaging equipment.…”

Section: Introductionmentioning

confidence: 67%

“…Earlier methods for assessing aberrant chromatin organisation have been reported for the ovarian carcinoma, 7 uterine sarcoma, 8 prostate carcinoma, 9 and endometrial carcinoma cohorts. 10 The major difference from the present study is that in those studies, a different marker was developed in each cohort, which allowed adaption to the particular cancer type, sample preparation methods, and imaging equipment. None of the earlier developed markers are suitable for validation on external cohorts of different cancer types, and they were only validated internally in the same patient series used to develop the marker.…”

Section: Discussionmentioning

confidence: 94%

“…791 tumour samples from consenting patients with endometrial carcinoma who were treated between 2001 and 2011 in the Molecular Markers in Treatment of Endometrial Cancer (MoMaTEC) trial ( NCT00598845 ) were included in the endometrial carcinoma validation cohort ( figure 1G ; appendix p 9 ). 10 767 patients had hysterectomy, three patients had tumour reduction, and 21 patients had curettage. The number of patients who received adjuvant treatment and the types of adjuvant treatments are described in the appendix (p 27) .…”

Section: Methodsmentioning

confidence: 99%

“…Each analysis included only patients with complete data for the variables in question, but imputation for missing data was subsequently done using multiple imputation by chained equations to assess all patients. The clinical and pathological markers included in multivariable analyses were the same as those that had been used in the previous studies of the individual patient cohorts 7 , 8 , 9 , 10 , 12 or, in case of the colorectal cancer validation cohorts, were the same prognostic markers as those applied to the discovery cohort. Subsequently, number of investigated lymph nodes (<12 vs ≥12) and tumour sidedness (left vs right) were separately added to the multivariable model.…”

Section: Methodsmentioning

confidence: 99%

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Chromatin organisation and cancer prognosis: a pan-cancer study

Kleppe

Albregtsen

Vlatkovic

et al. 2018

The Lancet Oncology

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SummaryBackgroundChromatin organisation affects gene expression and regional mutation frequencies and contributes to carcinogenesis. Aberrant organisation of DNA has been correlated with cancer prognosis in analyses of the chromatin component of tumour cell nuclei using image texture analysis. As yet, the methodology has not been sufficiently validated to permit its clinical application. We aimed to define and validate a novel prognostic biomarker for the automatic detection of heterogeneous chromatin organisation.MethodsMachine learning algorithms analysed the chromatin organisation in 461 000 images of tumour cell nuclei stained for DNA from 390 patients (discovery cohort) treated for stage I or II colorectal cancer at the Aker University Hospital (Oslo, Norway). The resulting marker of chromatin heterogeneity, termed Nucleotyping, was subsequently independently validated in six patient cohorts: 442 patients with stage I or II colorectal cancer in the Gloucester Colorectal Cancer Study (UK); 391 patients with stage II colorectal cancer in the QUASAR 2 trial; 246 patients with stage I ovarian carcinoma; 354 patients with uterine sarcoma; 307 patients with prostate carcinoma; and 791 patients with endometrial carcinoma. The primary outcome was cancer-specific survival.FindingsIn all patient cohorts, patients with chromatin heterogeneous tumours had worse cancer-specific survival than patients with chromatin homogeneous tumours (univariable analysis hazard ratio [HR] 1·7, 95% CI 1·2–2·5, in the discovery cohort; 1·8, 1·0–3·0, in the Gloucester validation cohort; 2·2, 1·1–4·5, in the QUASAR 2 validation cohort; 3·1, 1·9–5·0, in the ovarian carcinoma cohort; 2·5, 1·8–3·4, in the uterine sarcoma cohort; 2·3, 1·2–4·6, in the prostate carcinoma cohort; and 4·3, 2·8–6·8, in the endometrial carcinoma cohort). After adjusting for established prognostic patient characteristics in multivariable analyses, Nucleotyping was prognostic in all cohorts except for the prostate carcinoma cohort (HR 1·7, 95% CI 1·1–2·5, in the discovery cohort; 1·9, 1·1–3·2, in the Gloucester validation cohort; 2·6, 1·2–5·6, in the QUASAR 2 cohort; 1·8, 1·1–3·0, for ovarian carcinoma; 1·6, 1·0–2·4, for uterine sarcoma; 1·43, 0·68–2·99, for prostate carcinoma; and 1·9, 1·1–3·1, for endometrial carcinoma). Chromatin heterogeneity was a significant predictor of cancer-specific survival in microsatellite unstable (HR 2·9, 95% CI 1·0–8·4) and microsatellite stable (1·8, 1·2–2·7) stage II colorectal cancer, but microsatellite instability was not a significant predictor of outcome in chromatin homogeneous (1·3, 0·7–2·4) or chromatin heterogeneous (0·8, 0·3–2·0) stage II colorectal cancer.InterpretationThe consistent prognostic prediction of Nucleotyping in different biological and technical circumstances suggests that the marker of chromatin heterogeneity can be reliably assessed in routine clinical practice and could be used to objectively assist decision making in a range of clinical settings. An immediate application would be to identify high-risk patie...

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Section: Introductionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Chromatin organisation and cancer prognosis: a pan-cancer study

Kleppe

Albregtsen

Vlatkovic

et al. 2018

The Lancet Oncology

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“…Although the respective role of chromosomal content and chromatin structure in EC has been associated with histopathology and molecular pathology (22)(23)(24)(25), the overall impact of the numerical and structural aberrations of chromosomes, which is the signi cance of CIN, is unclear. Since there is no CIN-speci c biomarker for EC, we selected the CIN25 and CIN70 signatures from a pan-cancer genomic instability study to measure the CIN status (26).…”

Section: Introductionmentioning

confidence: 99%

Integrating Pathology, Chromosomal Instability and Mutations for Risk Stratification in Early-stage Endometrioid Endometrial Carcinoma

Guo

et al. 2020

Preprint

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Background: Risk stratifications for endometrial carcinoma (EC) depend on histopathology and molecular pathology. Histopathological risk stratification lacks reproducibility, neglects heterogeneity and contributes little to surgical procedures. Existing molecular stratification is useless in patient with specific pathological or molecular characteristics, and cannot guide postoperative adjuvant radiotherapies. Chromosomal instability (CIN), the numerical and structural alterations of chromosome resulting from ongoing errors of chromosome segregation, is an intrinsic biological mechanism for the evolution of different prognostic factors of histopathology and molecular pathology, which may be applicable to the risk stratification of EC.Results: By analysis of CIN25 and CIN70, two reliable gene expression signatures for CIN, we found that EC with unfavorable prognostic factors of histopathology or molecular pathology had serious CIN. However, POLE-mutant, as a favorable prognostic factor, had elevated CIN signatures, and CTNNB1-mutant, as an unfavorable prognostic factor, had decreased CIN signatures. Only if these two mutations were excluded were CIN signatures strongly prognostic for outcomes in different adjuvant radiotherapy subgroups. Integrating pathology, CIN signatures and POLE / CTNNB1 mutation stratified stageⅠendometrioid EC into four groups with improved risk prognostication and treatment recommendations.Conclusions:We revealed the possibility of integrating histopathology and molecular pathology by CIN for risk stratification in early-stage EC. Our integrated risk model deserves for further improvement and validation.

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Can aggressive cancers be identified by the “aggressiveness” of their chromatin?

Gurova

2022

BioEssays

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Phenotypic plasticity is a crucial feature of aggressive cancer, providing the means for cancer progression. Stochastic changes in tumor cell transcriptional programs increase the chances of survival under any condition. I hypothesize that unstable chromatin permits stochastic transitions between transcriptional programs in aggressive cancers and supports non‐genetic heterogeneity of tumor cells as a basis for their adaptability. I present a mechanistic model for unstable chromatin which includes destabilized nucleosomes, mobile chromatin fibers and random enhancer‐promoter contacts, resulting in stochastic transcription. I suggest potential markers for “unsettled” chromatin in tumors associated with poor prognosis. Although many of the characteristics of unstable chromatin have been described, they were mostly used to explain changes in the transcription of individual genes. I discuss approaches to evaluate the role of unstable chromatin in non‐genetic tumor cell heterogeneity and suggest using the degree of chromatin instability and transcriptional noise in tumor cells to predict cancer aggressiveness.

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Changes in Chromatin Structure in Curettage Specimens Identifies High-Risk Patients in Endometrial Cancer

Cited by 11 publications

References 28 publications

Chromatin organisation and cancer prognosis: a pan-cancer study

Chromatin organisation and cancer prognosis: a pan-cancer study

Integrating Pathology, Chromosomal Instability and Mutations for Risk Stratification in Early-stage Endometrioid Endometrial Carcinoma

Can aggressive cancers be identified by the “aggressiveness” of their chromatin?

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