Variations in HPV function are associated with survival in squamous cell carcinoma
Variations in HPV function are associated with survival in squamous cell carcinoma
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DOI：
10.1172/jci.insight.124762
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发表时间：
2019-01-10
期刊：
影响因子：
8
通讯作者：
Pickering, Curtis R.
中科院分区：
文献类型：
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作者：
Gleber-Netto, Frederico O.;Rao, Xiayu;Pickering, Curtis R.
HPV+口咽鳞状细胞癌（OPSCC）的发病率一直在急剧增加。虽然这些患者的长期生存率很高，但他们经常遭受与放射治疗相关的永久性疾病。这促使制定降级临床方案以降低发病率。然而，一部分患者甚至对标准治疗没有反应，结果很差。目前尚不清楚如何正确识别和治疗高危和低危HPV+ OPSCC患者。由于HPV阳性驱动放疗敏感性，我们假设HPV生物学的变化可能导致治疗反应和结果的差异。通过分析基因表达数据，我们确定了HPV+ OPSCC中HPV相关分子的变异。一部分肿瘤的分子特征与典型的HPV+肿瘤不同，并且表现出较差的治疗反应，这表明与HPV肿瘤的分子和临床相似性。这些分子变化也在体外观察到，并与辐射敏感性。最后，我们开发了一种用于鉴定HPV+ OPSCC亚组的预后生物标志物特征，并在口咽癌和宫颈癌的独立队列中对其进行了验证。这些发现可以转化为改善患者分层，以减少治疗强度，并为治疗耐药HPV相关癌症提供新的治疗方法。
Incidence of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has been increasing dramatically. Although long-term survival rates for these patients are high, they often suffer from permanent radiotherapy-related morbidity. This has prompted the development of de-escalation clinical protocols to reduce morbidity. However, a subset of patients do not respond even to standard therapy and have poor outcomes. It is unclear how to properly identify and treat the high-and low-risk HPV+ OPSCC patients. Since HPV positivity drives radiotherapy sensitivity, we hypothesized that variations in HPV biology may cause differences in treatment response and outcome. By analyzing gene expression data, we identified variations in HPV-related molecules among HPV+ OPSCC. A subset of tumors presented a molecular profile distinct from that of typical HPV+ tumors and exhibited poor treatment response, indicating molecular and clinical similarities with HPV-tumors. These molecular changes were also observed in vitro and correlated with radiation sensitivity. Finally, we developed a prognostic biomarker signature for identification of this subgroup of HPV+ OPSCC and validated it in independent cohorts of oropharyngeal and cervical carcinomas. These findings could translate to improved patient stratification for treatment deintensification and new therapeutic approaches for treatment-resistant HPV-related cancer.