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J Cancer Res Clin Oncol. 2018 Nov;144(11):2127-2137. doi: 10.1007/s00432-018-2733-2. Epub 2018 Aug 13.

Prognostic value of histone marks H3K27me3 and H3K9me3 and modifying enzymes EZH2, SETDB1 and LSD-1 in colorectal cancer.

Author information

1
Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
2
Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
3
Department of Epidemiology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
4
Department of Surgical Oncology and Clinics of Digestive Tract Cancer, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
5
Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal.
6
Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal. rmhenrique@icbas.up.pt.
7
Cancer Biology and Epigenetics Group, Research Center (CI-IPOP), Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal. rmhenrique@icbas.up.pt.
8
Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal. rmhenrique@icbas.up.pt.

Abstract

PURPOSE:

Studies on the performance of epigenetic-based biomarkers in colorectal cancer (CRC) are scarce and have shown contradictory results. Thus, we sought to examine the prognostic value of histone-modifying enzymes (EZH2, SETDB1 and LSD-1) and histone post-translational marks (H3K27me3 and H3K9me3) in CRC.

METHODS:

A retrospective series of 207 CRC patients primarily submitted to surgery in a cancer center was included in this study. Clinicopathological data were retrieved. One representative paraffin block per case was selected for immunohistochemistry, including normal and CRC tissues whenever possible. The percentage of positive nuclear staining (digital image analysis) was used to classify patients into "low" and "high" expression groups for each biomarker. Correlations between immunoexpression levels, clinicopathological features and clinical outcomes [disease-specific (DSS) and disease-free (DFS) survival] were examined. Statistical significance was set at p < 0.05.

RESULTS:

CRC tissues showed significantly lower expression of SETDB1 and higher expression of the remainder four biomarkers compared to normal mucosa. High EZH2 expression correlated with disease recurrence/progression, whereas low LSD1 expression and high H3K9me3 and H3K27me3 expression were associated with more advanced stage. In multivariable analysis, cases with high LSD1 expression displayed significantly better DSS and DFS (HR 0.477, 95% confidence interval: 0.247-0.923) adjusted for pathological TNM stage.

CONCLUSION:

EZH2, SETDB1, LSD1, H3K9me3 and H3K27me3 expression are altered in CRC and may play a role in colorectal carcinogenesis. LSD1 immunoexpression levels independently predicted patient outcome in this cohort. Further investigations, using larger series, are warranted to confirm its potential clinical value and unravel underlying molecular mechanisms.

KEYWORDS:

Biomarkers; Colorectal cancer; Epigenetics; Histone modifications; Prognosis

PMID:
30105513
DOI:
10.1007/s00432-018-2733-2
[Indexed for MEDLINE]

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