High Frequency of Activating PIK3CA Mutations in Human Papillomavirus-Positive Oropharyngeal Cancer
High Frequency of Activating PIK3CA Mutations in Human Papillomavirus-Positive Oropharyngeal Cancer
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DOI：
10.1001/jamaoto.2013.3210
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发表时间：
2013-06-01
影响因子：
7.8
通讯作者：
Barrett, John W.
中科院分区：
文献类型：
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作者：
Nichols, Anthony C.;Palma, David A.;Barrett, John W.
重要性：头颈部鳞状细胞癌（HNSCC）的大规模全外显子组测序研究已经确定，这种疾病是由肿瘤抑制基因的频繁突变和癌基因的罕见激活突变所主导的，这些突变很容易被分子药物靶向。然而，这些报告中有证据表明，磷酸肌醇3-激酶催化亚基p110 α（PIK 3CA）的激活突变在人乳头瘤病毒（HPV）阳性肿瘤患者中很常见。我们着手测试口咽部患者样本从我们institution.Objective：为了确认是否激活突变PIK 3CA是HPV阳性HNSCC频繁，因为这种突变的癌基因代表了一个潜在的治疗target.Design，设置，和参与者：回顾性搜索的伦敦健康科学中心病理数据库进行识别口咽癌样本。采用实时荧光定量聚合酶链反应（PCR）检测87例患者治疗前原发部位活检标本中高危型HPV 16和18型。主要结果和指标：检测标本中3个突变热点的激活突变（密码子542、545和1047），然后使用正向和反向引物进行桑格测序。41例HPV阴性肿瘤中仅4例（10%）显示PIK 3CA热点突变，包括3例密码子1047和1例密码子542。在46例HPV阳性肿瘤中，13例（28%）显示激活PIK 3CA突变，包括7例密码子542，5例密码子545和1例密码子1047。HPV阳性和HPV阴性癌症之间PIK 3CA突变频率的差异显著不同（P= 0.03）结论和相关性：尽管有人建议激活PIK 3CA突变在HPV阳性HNSCC中很常见，但据我们所知，这是第一项明确识别这种现象的研究。在HPV阳性患者中使用分子药物靶向PIK 3CA可能是提高治愈率并降低这一快速增长的患者队列中治疗毒性作用的机制。
Importance: Large-scale whole-exome sequencing studies of head and neck squamous cell carcinoma (HNSCC) have established that the disease is dominated by frequent mutations in tumor suppressor genes with rare activating mutations in oncogenes that would be easily targetable with molecular agents. There was evidence in these reports, however, that activating mutations in phosphoinositide 3-kinase catalytic subunit p110 alpha (PIK3CA) were common in patients with human papillomavirus (HPV)-positive tumors. We set out to test this prediction in oropharyngeal patient samples from our institution.Objective: To confirm whether activating mutations in PIK3CA are frequent in HPV-positive HNSCC because this mutated oncogene represents a potential therapeutic target.Design, Setting, and Participants: A retrospective search of the London Health Sciences Centre pathology database was performed to identify oropharyngeal cancer samples. DNA from pretreatment primary site biopsy samples from 87 patients were tested for high-risk HPV types 16 and 18 by real-time polymerase chain reaction.Main Outcomes and Measures: Samples were tested for activating mutations at the 3 mutational hot spots (codons 542, 545, and 1047) by polymerase chain reaction followed by Sanger sequencing using forward and reverse primers.Results: Only 4 of 41 HPV-negative tumors (10%) demonstrated PIK3CA hot spot mutations, including 3 at codon 1047 and 1 at codon 542. Of 46 HPV-positive tumors, 13 (28%) demonstrated activating PIK3CA mutations, including 7 at codon 542, 5 at codon 545, and 1 at codon 1047. The difference in PIK3CA mutation frequency was significantly different between HPV-positive and HPV-negative cancers (P=.03).Conclusions and Relevance: Although there has been a suggestion that activating PIK3CA mutations are common in HPV-positive HNSCC, to our knowledge, this is the first study to clearly identify this phenomenon. Targeting PIK3CA with molecular agents in HPV-positive patients may be a mechanism to improve cure rates and decrease treatment toxic effects in this rapidly growing cohort of patients.