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Histone trimethylation at H3K4, H3K9 and H4K20 correlates with patient survival and tumor recurrence in early-stage colon cancer

Anne Benard1, Inès J Goossens-Beumer1, Anneke Q van Hoesel1, Wouter de Graaf1, Hamed Horati1, Hein Putter2, Eliane CM Zeestraten1, Cornelis JH van de Velde1 and Peter JK Kuppen1*

Author Affiliations

1 Department of Surgery, K6-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands

2 Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands

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BMC Cancer 2014, 14:531  doi:10.1186/1471-2407-14-531

Published: 22 July 2014



Post-translational modification of histone tails by methylation plays an important role in tumorigenesis. In this study, we investigated the nuclear expression of H3K4me3, H3K9me3 and H4K20me3 in early-stage colon cancer in relation to clinical outcome.


Tumor tissue cores of 254 TNM stage I-III colorectal cancer patients were immunohistochemically stained for H3K4me3, H3K9me3 and H4K20me3 and scored using the semi-automated Ariol system. Cox proportional hazard trend analyses were performed to assess the prognostic value of the combined markers with respect to patient survival and tumor recurrence.


The histone methylation markers only showed prognostic value in early-stage (TNM stage I and II) colon cancer. Therefore, only this patient set (n = 121) was used for further statistical analyses. Low nuclear expression of H3K4me3, and high expression of H3K9me3 and H4K20me3 were associated with good prognosis. In combined marker analyses, the patient group showing most favorable expression (low H3K4me3, high H3K9me3 and high H4K20me3) was associated with the best prognosis. Multivariate trend analyses showed significantly increased hazard ratios (HR) for each additional marker showing unfavorable expression, as compared to the “all favorable” reference group. The HR for disease-free survival was 3.81 (1.72-8.45; p = 0.001), for locoregional recurrence-free survival 2.86 (1.59-5.13; p < 0.001) and for distant recurrence-free survival 2.94 (1.66-5.22; p < 0.001).


Combined nuclear expression of histone modifications H3K4me3, H3K9me3 and H4K20me3 is prognostic in early-stage colon cancer. The combination of expression of the three histone modifications provides better stratification of patient groups as compared to the individual markers and provides a good risk assessment for each patient group.

Histone modifications; Trimethylation; Epigenetics; Colon cancer; Prognosis; Patient survival; Tumor recurrence