No human virus sequences detected by next-generation sequencing in benign verrucous skin tumors occurring in BRAF-inhibitor-treated patients
No human virus sequences detected by next-generation sequencing in benign verrucous skin tumors occurring in BRAF-inhibitor-treated patients
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DOI：
10.1111/exd.12249
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发表时间：
2013-11-01
影响因子：
3.6
通讯作者：
Gutzmer, Ralf
中科院分区：
文献类型：
--
作者：
Ganzenmueller, Tina;Hage, Elias;Gutzmer, Ralf
用BRAF抑制剂（例如维罗非尼）（一种用于携带某些BRAF突变的晚期黑素瘤的新型靶向疗法）治疗的患者产生许多不良皮肤副作用，包括皮肤肿瘤，例如鳞状细胞癌或非恶性疣状角质形成细胞增殖，称为BRAF抑制剂相关疣状角化病（BAVK）病变。这些角质形成细胞增殖被认为是由MAPK通路在具有野生型BRAF但具有突变RAS的细胞中的反常超活化引起的。然而，由于这些病变的临床和组织学疣样外观，可能怀疑有其他病因辅助因子，如感染因子（即致癌病毒）。因此，我们在转录水平上对维罗非尼治疗患者的454个BAVK病变进行了高通量测序，以鉴定已知[例如人乳头瘤病毒（HPV）]或甚至未知病毒的活跃转录病毒序列。下一代测序没有识别出从4名患者的BAVK病变获得的1595161个读数中的任何人类病毒的转录本。尽管如此，所有对照都被正确识别，并且对源自皮肤微生物组（例如皮肤微生物群和细菌微生物群）的序列的检测证实了测序数据的有效性和灵敏度。我们的结果与其他人最近报道的初步组织学和免疫组化结果一致，他们也未能检测到HPV蛋白在BAVK中的表达。虽然患者数量有限，我们不能排除遗漏非常低丰度的病毒转录物的可能性，但我们的研究反对维罗非尼治疗下发生的BRAF抑制剂相关疣状角化病的病毒病因。
Patients treated with BRAF inhibitors (e.g. vemurafenib), a novel targeted therapy for advanced melanoma harbouring certain BRAF mutations, develop numerous adverse cutaneous side effects, including skin tumors such as squamous cell carcinoma or non-malignant verruciform keratinocyte proliferations, termed BRAF-inhibitor-associated verrucous keratosis (BAVK) lesions'. These keratinocyte proliferations are believed to be caused by paradoxical hyperactivation of the MAPK pathway in cells with wild-type BRAF, but mutated RAS. However, due to the clinical and histological verruca-like appearance of these lesions, additional aetiologic cofactors, such as infectious agents (i.e. oncogenic viruses), might be suspected. Therefore, we performed 454 high-throughput sequencing of BAVK lesions from vemurafenib-treated patients on the transcript level to identify actively transcribed viral sequences of known [e.g. human papilloma viruses (HPV)] or even yet-unknown viruses. Next-generation sequencing did not identify transcripts of any human viruses out of 1595161 reads obtained from BAVK lesions of four patients. Nevertheless, all controls were recognized correctly, and the detection of sequences derived from the cutaneous microbiome (e.g. skin commensals and bacterial phages) confirmed the validity and sensitivity of the sequencing data. Our results are consistent with preliminary histological and immunohistochemical findings recently reported by others, who also failed to detect the expression of HPV proteins in BAVK. Although the patient number is limited and we cannot exclude the possibility of having missed a viral transcript of very low abundance, our study argues against a viral aetiology of BRAF-inhibitor-associated verruciform keratoses occurring under vemurafenib.