Pérot Philippe, Mullins Christina Susanne, Naville Magali, Bressan Cédric, Hühns Maja, Gock Michael, Kühn Florian, Volff Jean-Nicolas, Trillet-Lenoir Véronique, Linnebacher Michael, Mallet François
Cancer Biomarkers Research Group, Joint Unit Hospices Civils de Lyon, bioMérieux, Centre Hospitalier Lyon Sud, Pierre Bénite, France.
Current address: Institut Pasteur, Laboratory for Pathogen Discovery, Paris, France.
Oncotarget. 2015 Nov 24;6(37):40095-111. doi: 10.18632/oncotarget.5539.
Expression of the human endogenous retrovirus (HERV)-H family has been associated with colorectal carcinomas (CRC), yet no individual HERV-H locus expression has been thoroughly correlated with clinical data.Here, we characterized HERV-H reactivations in clinical CRC samples by integrating expression profiles, molecular patterns and clinical data. Expression of relevant HERV-H sequences was analyzed by qRT-PCR on two well-defined clinical cohorts (n = 139 pairs of tumor and adjacent normal colon tissue) including samples from adenomas (n = 21) and liver metastases (n = 16). Correlations with clinical and molecular data were assessed.
CRC specific HERV-H sequences were validated and found expressed throughout CRC disease progression. Correlations between HERV-H expression and lymph node invasion of tumor cells (p = 0.0006) as well as microsatellite instable tumors (p < 0.0001) were established. No association with regard to age, tumor localization, grading or common mutations became apparent. Interestingly, CRC expressed elements belonged to specific young HERV-H subfamilies and their 5' LTR often presented active histone marks.
These results suggest a functional role of HERV-H sequences in colorectal carcinogenesis. The pronounced connection with microsatellite instability warrants a more detailed investigation. Thus, HERV-H sequences in addition to tumor specific mutations may represent clinically relevant, truly CRC specific markers for diagnostic, prognostic and therapeutic purposes.
人类内源性逆转录病毒（HERV）-H家族的表达与结直肠癌（CRC）相关，但尚未有单个HERV-H基因座的表达与临床数据进行全面关联。在此，我们通过整合表达谱、分子模式和临床数据，对临床CRC样本中的HERV-H激活进行了表征。通过qRT-PCR分析了两个明确的临床队列（n = 139对肿瘤和相邻正常结肠组织）中相关HERV-H序列的表达，这些队列包括腺瘤样本（n = 21）和肝转移样本（n = 16）。评估了与临床和分子数据的相关性。
验证了CRC特异性HERV-H序列，并发现其在CRC疾病进展过程中均有表达。建立了HERV-H表达与肿瘤细胞淋巴结侵袭（p = 0.0006）以及微卫星不稳定肿瘤（p < 0.0001）之间的相关性。未发现与年龄、肿瘤定位、分级或常见突变有明显关联。有趣的是，CRC表达的元件属于特定的年轻HERV-H亚家族，其5' LTR通常呈现活跃的组蛋白标记。
这些结果表明HERV-H序列在结直肠癌发生中具有功能性作用。与微卫星不稳定性的显著关联值得更详细的研究。因此，除肿瘤特异性突变外，HERV-H序列可能代表用于诊断、预后和治疗目的的临床相关、真正的CRC特异性标志物。
