Feber Andrew, Arya Manit, de Winter Patricia, Saqib Muhammad, Nigam Raj, Malone Peter R, Tan Wei Shen, Rodney Simon, Lechner Matthias, Freeman Alex, Jameson Charles, Muneer Asif, Beck Stephan, Kelly John D
UCL Cancer Institute, University College London, London, United Kingdom.
Division of Surgery and Interventional Science, UCL Medical School, University College London, London, United Kingdom. Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Clin Cancer Res. 2015 Mar 1;21(5):1196-206. doi: 10.1158/1078-0432.CCR-14-1656. Epub 2014 Dec 23.
Penile cancer is a rare malignancy in the developed world with just more than 1,600 new cases diagnosed in the United States per year; however, the incidence is much higher in developing countries. Although HPV is known to contribute to tumorigenesis, little is known about the genetic or epigenetic alterations defining penile cancer.
Using high-density genome-wide methylation arrays, we have identified epigenetic alterations associated with penile cancer. Q-MSP was used to validate lymph node metastasis markers in 50 cases. A total of 446 head and neck squamous cell carcinoma (HNSCC) and cervical squamous cell carcinoma (CESCC) samples were used to validate HPV-associated epigenetic alterations.
We defined 6,933 methylation variable positions (MVP) between normal and tumor tissue, which includes 997 hypermethylated differentially methylated regions associated with tumor supressor genes, including CDO1, AR1, and WT1. Analysis of penile cancer tumors identified a 4 gene epi-signature which accurately predicted lymph node metastasis in an independent cohort (AUC of 89%). Finally, we explored the epigenetic alterations associated with penile cancer HPV infection and defined a 30 loci lineage-independent HPV specific epi-signature which predicts HPV status and survival in independent HNSCC, CESC cohorts. Epi-signature-negative patients have a significantly worse overall survival [HNSCC P = 0.00073; 95% confidence interval (CI), 0.021-0.78; CESC P = 0.0094; HR = 3.91, 95% CI = 0.13-0.78], HPV epi-signature is a better predictor of survival than HPV status alone.
These data demonstrate for the first time genome-wide epigenetic events involved in an aggressive penile cancer phenotype and define the epigenetic alterations common across multiple HPV-driven malignancies.
阴茎癌在发达国家是一种罕见的恶性肿瘤，美国每年新诊断病例仅略多于1600例；然而，其发病率在发展中国家要高得多。尽管已知人乳头瘤病毒（HPV）会促进肿瘤发生，但对于定义阴茎癌的基因或表观遗传改变知之甚少。
我们使用高密度全基因组甲基化阵列，确定了与阴茎癌相关的表观遗传改变。采用定量甲基化特异性PCR（Q-MSP）在50例病例中验证淋巴结转移标志物。共使用446例头颈部鳞状细胞癌（HNSCC）和宫颈鳞状细胞癌（CESCC）样本验证HPV相关的表观遗传改变。
我们确定了正常组织和肿瘤组织之间的6933个甲基化可变位点（MVP），其中包括997个与肿瘤抑制基因相关的高甲基化差异甲基化区域，如CDO1、AR1和WT1。对阴茎癌肿瘤的分析确定了一个4基因表观遗传特征，该特征能准确预测独立队列中的淋巴结转移（曲线下面积为89%）。最后，我们探究了与阴茎癌HPV感染相关的表观遗传改变，并定义了一个30个位点的不依赖谱系的HPV特异性表观遗传特征，该特征可预测独立的HNSCC、CESC队列中的HPV状态和生存率。表观遗传特征阴性的患者总生存期明显更差[HNSCC P = 0.00073；95%置信区间（CI），0.021 - 0.78；CESC P = 0.0094；风险比（HR） = 3.91，95% CI = 0.13 - 0.78]，HPV表观遗传特征比单独的HPV状态更能预测生存率。
这些数据首次证明了全基因组表观遗传事件参与了侵袭性阴茎癌表型，并确定了多种HPV驱动恶性肿瘤共有的表观遗传改变。
