Kutler David I, Wreesmann Volkert B, Goberdhan Andy, Ben-Porat Leah, Satagopan Jaya, Ngai Ivan, Huvos Andrew G, Giampietro Philip, Levran Orna, Pujara Kanan, Diotti Rafaella, Carlson Diane, Huryn Laryssa A, Auerbach Arleen D, Singh Bhuvanesh
Laboratory of Epithelial Cancer Biology, Division of Head and Neck Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
J Natl Cancer Inst. 2003 Nov 19;95(22):1718-21. doi: 10.1093/jnci/djg091.
Fanconi anemia is an autosomal recessive disorder characterized by congenital malformations, bone marrow failure, and the development of squamous cell carcinomas (SCCs) and other cancers. Recent clinicopathologic evidence has raised the possibility that an environmental factor such as human papillomavirus (HPV) may be involved in the pathogenesis of SCCs in Fanconi anemia patients. Given the high prevalence of p53 mutations in SCCs among the general population and the lack of p53 mutations in HPV-related carcinogenesis, we evaluated the role of HPV and p53 mutations and polymorphisms in SCC from Fanconi anemia patients. We used polymerase chain reaction (PCR) screening and real-time PCR to detect and quantify HPV DNA in DNA extracted from microdissected SCCs obtained from 24 Fanconi anemia patients (n = 25 SCCs; case subjects) and 50 age-, sex-, and tumor site-matched SCC patients without Fanconi anemia (n = 50 SCCs; control subjects). We PCR-amplified and sequenced exons 4-9 of the p53 gene from SCC DNA. We detected HPV DNA in 84% of the SCC specimens from the case subjects and in 36% of the SCC specimens from the control subjects (P<.001). The prevalence of p53 mutations in SCCs from the case subjects (0%, 0/25) was statistically significantly lower than that of SCCs from the control subjects (36%, 12/33; P<.001). A greater proportion of patients with Fanconi anemia and SCC were homozygous for Arg72, a p53 polymorphism that may be associated with increased risk for HPV-associated human malignancies, than an ethnically-matched cohort of Fanconi anemia patients without SCC (75% versus 51%; P =.05). These data suggest that Fanconi anemia is associated with increased susceptibility to HPV-induced carcinogenesis.
范可尼贫血是一种常染色体隐性疾病，其特征为先天性畸形、骨髓衰竭以及鳞状细胞癌（SCC）和其他癌症的发生。最近的临床病理证据提示，诸如人乳头瘤病毒（HPV）等环境因素可能参与范可尼贫血患者SCC的发病机制。鉴于普通人群中SCC中p53突变的高发生率以及HPV相关致癌过程中缺乏p53突变，我们评估了HPV以及p53突变和多态性在范可尼贫血患者SCC中的作用。我们采用聚合酶链反应（PCR）筛查和实时PCR，以检测和定量从24例范可尼贫血患者（n = 25个SCC；病例组）和50例年龄、性别及肿瘤部位匹配的无范可尼贫血的SCC患者（n = 50个SCC；对照组）的显微切割SCC中提取的DNA中的HPV DNA。我们对SCC DNA中的p53基因第4至9外显子进行PCR扩增并测序。我们在84%的病例组SCC标本中检测到HPV DNA，而在36%的对照组SCC标本中检测到HPV DNA（P<0.001）。病例组SCC中p53突变的发生率（0%，0/25）在统计学上显著低于对照组SCC（36%，12/33；P<0.001）。与种族匹配的无SCC的范可尼贫血患者队列相比，范可尼贫血合并SCC患者中Arg72纯合子的比例更高，Arg72是一种p53多态性，可能与HPV相关人类恶性肿瘤风险增加有关（75%对51%；P = 0.05）。这些数据提示，范可尼贫血与HPV诱导的致癌作用易感性增加有关。
