Human Papillomavirus DNA and p53 Polymorphisms in Squamous Cell Carcinomas From Fanconi Anemia Patients

Abstract

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.

The Fanconi Anemia/BRCA pathway: new faces in the crowd

“…This work has demonstrated an association with human papilloma virus (HPV) infection and the tumor development. HPV E6 protein is known to reduce p53 protein levels as part of the infective process, thereby preventing the activation of apoptotic pathways (Kutler et al 2003c).…”

Skin cancer after nonmyeloablative hematopoietic cell transplantation

“…44 HPV-associated cancers express oncoproteins that inactivate certain tumor suppressor genes, including p53. [45][46][47] Kutler et al 48 utilized PCR techniques to detect HPV DNA in SCCs obtained from 24 patients with Fanconi anemia (FA); HPV DNA was detected in 84% of the SCCs obtained from patients with FA and in 36% of SCCs from control patients. Mutations of p53 are strongly associated with the development of BCC and SCC with approximately 56% of BCC and 490% of SCCs harbor p53 mutations.…”

Current topics in the epidemiology of oral cavity and oropharyngeal cancers

“…145,146 Approximately 14% of individuals with FA develop HNSCC by the age of 40, and the majority occur in the absence of alcohol and tobacco exposure. 145 Recently, high-risk HPV was detected in the majority (84%) of oral cancers from patients with FA, 147 suggesting the FA gene defects may increase sensitivity to HPV-mediated tumorigenesis. 148,149 Although oral cancers have been reported among individuals affected by other inherited cancer syndromes (eg, xeroderma pigmentosum and dyskeratosis congenital, Blooms Syndrome), these associations are less well studied.…”