High risk HPV-positive lung carcinomas: molecular evidence for a pattern of pulmonary metastasis. Homo sapiens

BACKGROUND: Infection with high-risk types of human papillomavirus (hrHPV) is associated with cervical, anogenital and oropharyngeal cancers. A role for hrHPV in lung cancer has been proposed, although previous reports on the contribution of hrHPV infection to lung cancer have provided contradictory results. The current study evaluated hrHPV prevalence in lung tumor specimens of different histological subtypes in a Western study population using a validated test algorithm for hrHPV detection in formalin-fixed paraffin-embedded (FFPE) tumor specimen (i.e., GP5+6+-PCR and p16INK4A immunohistochemistry). MATERIALS AND METHODS: Tumor tissue specimens from 228 lung cancer patients were subjected to GP5+6+-PCR and p16INK4A immunohistochemistry. hrHPV-positive tumors were further characterized using genotyping of GP5+/6+-PCR products, HPV E7 transcript analysis, loss of heterozygosity (LOH) analysis and array comparative genomic hybridization (arrayCGH), and the clinical history of patients was retrieved. RESULTS: Three patients (3/228, 1.3%) with hrHPV-positive lung tumors were identified, revealing hrHPV types 16, 18 and 33, respectively. All three patients (1 male, 2 females) had a history of hrHPV-associated disease; two cervical carcinoma, and one oropharyngeal carcinoma. Further characterization revealed identical hrHPV genotype, pattern of p16INK4A expression, HPV E7 mRNA expression, and genomic aberrations in the individual pairings of lung tumor and foregoing hrHPV-associated cancer. CONCLUSION: The present study found molecular evidence that supports association of hrHPV in lung cancer with the presence of pulmonary metastasis of a hrHPV-positive cancer that originated elsewhere, and not with primary lung cancer in a Western population. Overall design: 2 lung cancer samples (FFPE), 1 cervical cancer sample (FFPE), 1 head and neck cancer sample (FFPE)

研究背景：高危型人乳头瘤病毒（human papillomavirus, hrHPV）感染与宫颈癌、肛门生殖器癌及口咽癌密切相关。尽管已有研究提出hrHPV在肺癌中存在致病作用，但既往关于hrHPV感染对肺癌发病贡献的相关报道结论并不一致。本研究针对西方研究队列中不同组织学亚型的肺肿瘤标本，采用经验证的福尔马林固定石蜡包埋（formalin-fixed paraffin-embedded, FFPE）肿瘤标本hrHPV检测算法（即GP5+6+-聚合酶链反应[GP5+6+-PCR]与p16INK4A免疫组化），对hrHPV的检出率进行了评估。材料与方法：本研究纳入228例肺癌患者的肿瘤组织标本，对其开展GP5+6+-PCR与p16INK4A免疫组化检测。对于hrHPV阳性的肿瘤标本，进一步通过GP5+/6+-PCR产物基因分型、HPV E7转录本分析、杂合性缺失（loss of heterozygosity, LOH）分析以及阵列比较基因组杂交（array comparative genomic hybridization, arrayCGH）进行特征鉴定，并调取患者的临床病史资料。研究结果：本研究共检出3例hrHPV阳性的肺肿瘤患者（3/228，1.3%），对应的hrHPV型别分别为16型、18型及33型。3例患者中1例为男性、2例为女性，均有hrHPV相关疾病病史：其中2例为宫颈癌，1例为口咽癌。进一步特征分析显示，每例患者的肺肿瘤与既往hrHPV相关癌组织的hrHPV基因型、p16INK4A表达模式、HPV E7 mRNA表达情况以及基因组畸变特征均完全一致。研究结论：本研究获得的分子证据表明，在西方人群中，肺癌检出的hrHPV与原发于其他部位的hrHPV阳性肿瘤发生肺转移相关，而非与原发性肺癌相关。实验整体设计：2例肺癌福尔马林固定石蜡包埋（FFPE）标本、1例宫颈癌FFPE标本、1例头颈部癌FFPE标本