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Loss of Histone Variant Macroh2a2 Expression Associates With Downloaded from http://jcp.bmj.com/ on February 3, 2016 - Published by group.bmj.com JCP Online First, published on December 10, 2015 as 10.1136/jclinpath-2015-203367 Original article Loss of histone variant macroH2A2 expression associates with progression of anal neoplasm Wan-Hsiang Hu,1,2,3 Katsumi Miyai,4 Judith C Sporn,5 Linda Luo,1,2 Jean Y J Wang,2,6 Bard Cosman,1,7 Sonia Ramamoorthy1,2 1Department of Surgery, ABSTRACT found at promoters and in intergenic regions in ES University of California San Aims The macroH2A histone variants are epigenetic cells.13 The dynamic replacement of nucleosomes Diego Health System, San Diego, California, USA marks for inactivated chromatin. In this study, we with macroH2A2 in ES cells was dampened, 2Rebecca and John Moores examined the expression of macroH2A2 in anal whereas the stable association of macroH2A2 Cancer Center, University of neoplasm from anal intraepithelial neoplasia (AIN) to nucleosomes with intergenic regions was expanded California San Diego Health anal squamous cell carcinoma (SCC). upon differentiation.13 It was found that System, San Diego, California, Methods AIN and anal SCC samples were analysed for macroH2A2 is required for EPO-induced erythroid USA 14 3Department of Colorectal macroH2A2 expression, HIV and human papilloma virus maturation. Surgery, Kaohsiung Chang (HPV). The association of macroH2A2 expression with Previous studies have also suggested that Gung Memorial Hospital and clinical grade, disease recurrence, overall survival and macroH2A histones have tumour suppressor func- Chang Gung University College viral involvement was determined. tion.15 16 The Ladurner group was the first to of Medicine, Kaohsiung, Taiwan Results macroH2A2 was expressed in normal report that the expression of macroH2A1 and 4Department of Pathology, squamous tissue and lower grade AIN (I and II). macroH2A2 inversely correlated with proliferation School of Medicine, University Expression was lost in 38% of high-grade AIN (III) and in human breast and lung cancer. They also showed of California, San Diego, 71% of anal SCC (p=0.002). Patients with AIN with that the levels of macroH2A expression could be California, USA 5 macroH2A2-negative lesions showed earlier recurrence used as predictive biomarkers for lung cancer recur- Department of General 17 Surgery, Baystate Medical than those with macroH2A2-positive neoplasm rence. In a study of melanoma, the expression of Center, Springfield, (p=0.017). With anal SCC, macroH2A2 loss was more macroH2A2 was found in the benign naevi and Massachusetts, USA prevalent in the HPV-negative tumours. during radial growth, but lost in the vertical growth 6 – Division of Hematology Conclusions Loss of histone variant macroH2A2 phase and in metastatic melanoma.18 The expres- Oncology, Department of Medicine, School of Medicine, expression is associated with the progression of anal sion of macroH2A histones at the protein level in University of California, San neoplasm and can be used as a prognostic biomarker for other cancer types has not been investigated. Diego, California, USA high-grade AIN and SCC. Examination of The Cancer Genome Atlas (TCGA) 7 Department of Surgery, database for H2AFY and H2AFY2 sequence, copy ’ Veteran s Administration number and RNA levels showed alterations in only Medical Center, University of California, San Diego INTRODUCTION a small fraction of cases (<10%) across TCGA Healthcare System, San Diego, Among the core histones, the H2A family has the cancer types. Analyses of the RNA levels found California, USA highest number of variants, including H2AX, that significant reduction in H2AFY2, but not H2AZ and macroH2A.1 The macroH2A histone H2AFY, RNA expression (outliners) occurred in a Correspondence to Dr Sonia Ramamoorthy, variants are conserved in vertebrates and are small fraction of cases among several cancer types. Department of Surgery, encoded by two genes: H2AFY for macroH2A1 Therefore, it appears that macroH2A2 was more Rebecca and John Moores and H2AFY2 for macroH2A2. Each of these likely to be reduced than macroH2A1 in human Cancer Center, University of macrohistone variants contain an N-terminal tumour samples. However, the TCGA network has California San Diego Health H2A-histone domain and a C-terminal Macro not examined the expression of macroH2A histone System, 3855 Health Sciences 23 Drive, La Jolla CA 92093, USA; domain that is found in other non-histone pro- proteins. [email protected] teins, for example, poly-ADP ribose polymerases In this study, we investigated the expression of (PARP-9, -14 and -15) and poly-ADP ribose glyco- macroH2A2 protein in anal dysplasia and anal Received 27 August 2015 hydrolase.4 The Macro domain of mH2A1.1 binds squamous cell carcinoma (SCC). In the USA, neo- Revised 16 November 2015 Accepted 20 November 2015 to ADP ribose that is generated from NAD by plasm of the anal squamous tissue has been increas- enzymes such as the NAD-dependent histone dea- ing steadily in recent years, with estimated new – cetylase SIRT1.4 6 The ligand for the Macro cases and deaths of 7210 and 950, respectively, in domain of macroH2A2 is presently unknown. The 2014.19 SCC is likely to progress from a continuum macroH2A histones are enriched on the inactivated of precancerous lesions known as anal intraepithe- X-chromosome but not required for the establish- lial neoplasia (AIN). These precancerous AIN – ment of X-inactivation.7 9 The macroH2A histones lesions are divided into three categories according are also epigenetic and repressive markers of many to degrees of histological atypia.20 In another classi- developmental regulator genes in the male pluripo- fication, AIN I is known as low-grade anal squa- tent cells.10 MacroH2A variants have been shown mous intraepithelial lesion, and AIN II and III are to act cooperatively as a barrier to the reprogram- combined into the group of high-grade anal squa- ming of somatic cells with macroH2A2 being the mous intraepithelial lesion (HSIL).20 21 Infections To cite: Hu W-H, Miyai K, predominant inhibitor.11 In mice, the combined with human papilloma virus (HPV) and HIV are Sporn JC, et al. J Clin Pathol 22 Published Online First: knockout of macroH2A1 and macroH2A2 did not important risk factors for anal SCC. Their indi- [please include Day Month affect early development but affected the growth vidual effect on the development of anal SCC is Year] doi:10.1136/jclinpath- and the fertility of adult mice.12 In embryonic stem difficult to assess due to the prevalence of HPV and 2015-203367 (ES) cells, macroH2A-containing nucleosomes are a higher risk of contracting HPV in patients who Hu W-H, et al. J Clin Pathol 2015;0:1–5. doi:10.1136/jclinpath-2015-203367 1 Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence. Downloaded from http://jcp.bmj.com/ on February 3, 2016 - Published by group.bmj.com Original article are HIV positive.23 In this study, we examined the expression of expression of positive (P) and negative (N) samples is shown in macroH2A2 by immunohistochemistry staining of AIN and anal figure 1A. We separated the samples into four groups, AIN I, SCC samples in association with the status of HIV and HPV AIN II, AIN III and anal SCC, and determined the fraction of infections. samples that were negative (N) for macroH2A2 staining. As shown in figure 1B, macroH2A2 expression was found in 100% MATERIALS AND METHODS of AIN I and AIN II samples. However, macroH2A2 expression Patients and specimens was lost in 38% of the AIN III and 71% of the anal SCC Tissue samples including AIN and anal SCC were collected samples. These results show a statistically significant correlation from the patients in UC San Diego Medical Center, California, between the loss of macroH2A2 expression and the progression between 2000 and 2008. Patients’ clinical characteristics were of anal neoplasm from AIN I/II to AIN III and anal SCC also summarised. In patients with AIN, treatment included exci- (p=0.002). The clinical–pathological characteristics of the sion and ablation. Time to recurrence was calculated between patients with AIN and anal SCC and the status of macroH2A2 onset and first recurrence after treatment. According to their expression in this study are also summarised in table 1. clinical stage, patients with anal SCC received the treatments including local excision, concurrent chemoradiotherapy or macroH2A2 expression and recurrence of AIN and anal SCC abdominoperineal resection. The dose of radiotherapy typically In this study, we determined the recurrence of lesions in patients ranged from 5040 to 5940 cGy in 28 fractions. The regimens of with AIN over a 5-year follow-up period and we performed a chemotherapy were 5-fluorouracil with mitomycin or cisplatin. Kaplan–Meier analysis of the time to first recurrence as a func- Patients with anal SCC who were progressive after the day of tion of macroH2A2 expression. As shown in figure 2A, the time tissue biopsy were excluded from recurrence evaluation. We to recurrence was significantly shorter in the evaluated the 5-year recurrence-free survival of AIN and 5-year macroH2A2-negative group than the macroH2A2-positive disease-free survival of patients with anal SCC according to the group (p=0.017). The relationship between disease-free survival interval of survival without AIN and anal SCC recurrence. of anal SCC patients and macroH2A2 expression is illustrated in figure 2B. Immunohistochemistry The sections cut from the formalin-fixed and paraffin-embedded tissues were deparaffinised in xylene and dehydrated in ethanol. Relationship of macroH2A2 loss with HPV and HIV infections They were then incubated in the Decloaking chamber With the anal SCC samples, we also determined the presence of (DC2002; Biocare Medical, Concord, California, USA) contain- HPV and HIV sequences in the genomic DNA and assessed the ing 200 ml 1× Nuclear Decloaker solution (CB911M; Biocare Medical).
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