The ARF-p16 gene locus in carcinogenesis and therapy of head and neck squamous cell carcinoma.
The ARF-p16 gene locus in carcinogenesis and therapy of head and neck squamous cell carcinoma.
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ARF-p16 基因位点在头颈鳞状细胞癌的发生和治疗中的作用。
DOI：
10.1097/00005537-200212000-00002
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发表时间：
2002
期刊：
影响因子：
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通讯作者：
Yarbrough,WendellG
中科院分区：
文献类型：
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作者：
Yarbrough,WendellG
目的/假设我们已经确定了肿瘤包括头颈部鳞状细胞癌（HNSCC）的高发家族。这些激酶中黑色素瘤的发生表明ARF‐p16基因可能参与了致癌作用。我们希望确定与家族性易感性HNSCC相关的基因缺陷，并确定基因的恢复是否可能具有治疗benefit.Study DesignTranslational molecular research.MethodsMolecular techniques被用于识别受影响家族的ARF‐p16基因突变，并测试p16和ARF突变体的活性。此外，还分析了HNSCC肿瘤组织，以确定野生型p16等位基因是否丢失或维持。ARF-表达腺病毒的创建，其对HNSCC细胞系和正常的头颈部上皮细胞的效果determined. ResultsARF-p16基因的突变被发现在两个家庭与易感性发展HNSCC。在两个家族的生殖系DNA中检测到的独立突变使p16失活，但不使ARF失活，并且失活的突变p16等位基因与两个家族内的疾病分离。野生型p16等位基因在来自两个家族的HNSCC肿瘤组织中丢失。发现ARF治疗HNSCC的功效取决于HNSCC肿瘤细胞内p53活性的保留。值得注意的是，ARF表达被发现杀死细胞，这取决于视网膜母细胞瘤活性的丧失。由于视网膜母细胞瘤的活性损失几乎是普遍的肿瘤，ARF杀死肿瘤细胞保留p53，但ARF幸免于正常cells.ConclusionsOur结果支持一个新的家族性头颈癌的临床实体的认识。我们已经表明，这种综合征是与失活突变的p16基因，这些突变分离与疾病在两个描述的家庭。来自两个家族的HNSCC组织中野生型p16等位基因的缺失强烈支持突变型p16在致癌作用中的作用。我们还研究了p16基因的交替阅读框产物ARF的治疗效用。ARF杀死细胞取决于视网膜母细胞瘤活性的丧失和p53的保留，这一发现表明ARF可能有效治疗大约50%的头颈癌，同时保留正常细胞。p16基因突变作为家族性HNSCC的致病因素的认识，为HNSCC的诊断提供了一个方便的工具。家族性头颈癌的临床接受将确保患者得到适当的诊断和管理。
Objectives/HypothesisWe have identified families with a high incidence of tumors including head and neck squamous cell carcinoma (HNSCC). The occurrence of melanoma in these kindreds suggested that the ARF‐p16 gene may be involved in carcinogenesis. We wished to determine the gene defect associated with the familial predisposition to HNSCC and to determine whether restoration of the gene may have therapeutic benefit.Study DesignTranslational molecular research.MethodsMolecular techniques were used to identify mutations of the ARF‐p16 gene from the affected families and to test the activity of p16 and ARF mutants. In additional, HNSCC tumor tissue was analyzed to determine whether the wild‐type p16 allele was lost or maintained. ARF‐expressing adenoviruses were created, and their effect on HNSCC cell lines and normal head and neck epithelial cells was determined.ResultsMutation of the ARF‐p16 gene was found in two families with predisposition to develop HNSCC. Independent mutations detected in the germline DNA of both families inactivated p16, but not ARF, and the inactive mutant p16 allele segregated with disease within both families. The wild‐type p16 allele was lost in HNSCC tumor tissue from both families. The efficacy of ARF in treatment of HNSCC was found to depend on retention of p53 activity within HNSCC tumor cells. Remarkably, ARF expression was found to kill cells, depending on loss of retinoblastoma activity. Because loss of retinoblastoma activity is nearly universal in tumors, ARF killed tumor cells that retained p53, but ARF spared normal cells.ConclusionsOur results support the recognition of a new clinical entity of familial head and neck cancer. We have shown that this syndrome is associated with inactivating mutations of the p16 gene that these mutations segregate with disease in two described families. Loss of the wild‐type p16 allele in HNSCC tissue from both families strongly supports the role of the mutant p16 in carcinogenesis. We have also investigated the therapeutic utility of the alternate reading frame product of the p16 gene, ARF. The finding that ARF kills cells depending on loss of retinoblastoma activity and retention of p53 suggests that ARF may be effective in treatment of roughly 50% of head and neck cancers while sparing normal cells. Recognition of p16 mutations as an etiological factor in familial HNSCC provides an accessible tool for diagnosis of this syndrome. Clinical acceptance of familial head and neck cancer will ensure that patients are appropriately diagnosed and managed.