P1-05-05: Prognostic Utility of Histone Modifier Gene Expression Profiles in Human Breast Cancer.
Authors: Patani N , Jiang WG , Newbold RF , Mokbel K 
Published: June 2012

Background: Gene expression is stringently controlled under physiological conditions by epigenetic mechanisms, including the specific methylation of cytosine residues within CpG dinucleotides and orchestrated adjustments in the histone dependent organisation of chromatin. The organisation of DNA within the chromatin template depends upon highly conserved histone proteins, the properties of which continue to exceed the simplistic packaging role originally assigned to them. Histone modifier enzymes impart a dynamic histone code and specific permutations have significant implications for chromatin topology and the functional configuration of promoters. This study follows our initial report describing potential tumour suppressor function associated with the histone methyltransferase SETD2 in human breast cancer. The objective was to evaluate the expression profiles of sixteen additional histone modifier genes in women with primary operable breast cancer within a well annotated cohort with extended follow-up.

Methods: Primary breast cancer tissues (n= 127) and adjacent benign/normal tissues (n=33) underwent RNA extraction and reverse transcription. The transcript levels of histone modifier genes were evaluated using real-time quantitative PCR, these included: histone acetyltransferases (CREBBP), Class 1 (HDAC1 and HDAC2), II (HDAC5) and III (SIRT1) histone deacetylases and histone methyltransferases (SUV39H1 and SUV39H2) amongst others. Transcript levels were analysed against a range of clinico-pathological variables, including: tumour size, grade, nodal involvement, histological subtype, receptor status, TNM stage, Nottingham Prognostic Index, disease free and overall survival over a 10 year follow-up period.

Results: Transcript levels of the histone modifier genes in breast cancer tissues differed significantly from non-malignant samples (HDAC5, HDAC1, KDM4A and KDM6A). Amongst breast cancers, significant differences in transcript levels were associated with established pathological parameters and prognostic indices: tumour grade (KAT5, HDAC1, KDM4A, SUV39H1 and KDM6A), receptor status (KAT5, SMYD3 and KDM1A), histological type (KAT5, KDM5C, MYST1, KDM4A and MLL), TNM stage (SUV39H1, KAT2B, KDM1A, KDM4A, KDM5C, MYST1, HDAC5 and KAT5), Nottingham Prognostic Index (KDM5C, MLL, MYST1 and SMYD3), disease free survival (SUV39H1, SMYD3, HDAC5, KDM6A, HDAC1, KDM1A, KDM4A, MYST1, KDM5C, KAT5 and MLL) and overall survival (MYST1). Interestingly, significant correlations were also identified between the differential expression profiles of particular histone modifying genes.

Conclusion: The expression profiles of histone modifier genes differ significantly between breast cancer tissues and normal/benign samples. Particular expression profiles in breast cancer are significantly associated with established pathological parameters, prognostic indices, disease free and overall survival. The biological significance and clinical relevance of altered expression of specific histone modifier genes and particular permutations of misexpression remain to be fully elucidated and further study is warranted. Epigenetic signatures derived from histone modifier genes may offer utility as biomarkers and histone modifier enzymes have potential for targeted therapeutic strategies.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-05-05.