Chromatin Organization Marker and Cancer-Specific Survival

Key Points

  • Chromatin heterogeneity was associated with poorer cancer-specific survival in several cancer types.
  • Chromatin heterogeneity was associated with poorer survival in both microsatellite-stable and microsatellite-unstable stage II colorectal cancer.

In a study reported in The Lancet Oncology, Kleppe et al found that a novel marker for chromatin organization in tumor cell nuclei was associated with outcome in a variety of cancer types.

Study Details

In the study, machine learning algorithms analyzed chromatin organization in 461,000 images of tumor cell nuclei stained for DNA from 390 patients (discovery cohort) treated for stage I or II colorectal cancer at Aker University Hospital in Oslo. The identified marker of chromatin heterogeneity, termed “nucleotyping,” was independently validated in six patient cohorts: 442 patients with stage I or II colorectal cancer in the Gloucester Colorectal Cancer Study; 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.

Associations With Outcome

On univariate analysis, patients in all cohorts with chromatin heterogeneous tumors had worse cancer-specific survival vs those with chromatin homogeneous tumors. In multivariate analysis, chromatin heterogeneity vs homogeneity was associated with poorer cancer-specific survival in the discovery cohort (hazard ratio [HR] = 1.7, 95% confidence interval [CI] = 1.1–2.5), the Gloucester colorectal cancer cohort (HR =1.9, 95% CI = 1.1–3.2), QUASAR 2 colorectal cancer cohort (HR = 2.6, 95% CI = 1.2–5.6), ovarian carcinoma cohort (HR = 1.8, 95% CI = 1.1–3.0), uterine sarcoma cohort (HR = 1.6, 95% CI = 1.0–2.4), and endometrial carcinoma cohort (HR = 1.9, 95% CI = 1.1–3.1), but not in the prostate carcinoma cohort (HR = 1.43, 95% CI = 0.68–2.99).

Chromatin heterogeneity was associated with poorer cancer-specific survival in microsatellite-unstable (HR = 2.9, 95% CI = 1.0–8.4) and microsatellite-stable (HR = 1.8, 95% CI = 1.2–2.7) stage II colorectal cancer, whereas microsatellite instability was not significantly associated with outcome in chromatin homogeneous (HR = 1.3, 95% CI = 0.7–2.4) or chromatin heterogeneous (HR = 0.8, 95% CI = 0.3–2.0) stage II colorectal cancer.

The investigators concluded, “The 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 patients with stage II colorectal cancer who might have greater absolute benefit from adjuvant chemotherapy. Clinical trials are warranted to evaluate the survival benefit and cost-effectiveness of using Nucleotyping to guide treatment decisions in multiple clinical settings.”

The study was funded by The Research Council of Norway, the South-Eastern Norway Regional Health Authority, the National Institute for Health Research, and the Wellcome Trust.

Håvard E. Danielsen, PhD, of the Institute for Cancer Genetics and Informatics, Oslo University Hospital, is the corresponding author for The Lancet Oncology article. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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