© 2004 by Oxford University Press
© 2004 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Human Papillomavirus DNA and p53 Polymorphisms in Squamous Cell Carcinomas From Fanconi Anemia Patients
Affiliation of authors: Laboratory of Epithelial Cancer Biology, Memorial Sloan-Kettering Cancer Center, New York, NY
Correspondence to: Bhuvanesh Singh, MD, Laboratory of Epithelial Cancer Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021 (e-mail: singhb{at}mskcc.org)
We reported a high prevalence of human papillomavirus (HPV) DNA and the absence of p53 mutations among 24 squamous cell carcinomas (SCCs) from 25 Fanconi anemia patients (1). By contrast, van Zeeburg et al. describe an unpublished series of five cases of head and neck squamous cell carcinoma (HNSCC) from Fanconi anemia patients in which they identified mutations in p53 in four cases and the absence of detectable HPV DNA in all cases.
Several factors may explain the different results obtained in these two studies, the least persuasive of which are the small sample size in the van Zeeberg et al. study and methodologic differences between the studies, including the source of DNA (we used laser capture microdissected specimens), the oligonucleotide primers used for HPV DNA detection (we used highly efficient CPI and CPIIG consensus primers and validated all findings with real-time polymerase chain reaction), and stringency of analyses performed (our experiments were repeated at least three times) (2,3).
One of the more important reasons for the differing results may be case selection. We included all cases of SCC reported in the International Fanconi Anemia Registry (IFAR) without restrictions. Conversely, the cases van Zeeburg et al. report on were presumably selected on the basis of the authors’ ability to establish long-term tumor cell cultures (at least for four of the five reported cases). This is an important distinction, because SCCs from Fanconi anemia patients are known to be difficult to put into culture, and therefore the cases reported by van Zeeburg et al. may not be representative of the HNSCCs found in Fanconi anemia patients.
A major clinical difference between SCCs in Fanconi anemia patients and those in the general population is the lower prevalence of tobacco and/or alcohol use among Fanconi anemia patients, which is known to have a substantial impact on the pattern of genomic aberrations in SCCs (4). Although van Zeeburg et al. agree that this is an important issue, they do not provide the carcinogen exposure histories for their case patients. Interestingly, one of the authors has previously published data on the absence of detectable HPV DNA in two of the five cases included in the current series (5). In that study, both cases of HNSCC occurred in patients who had a clinically significant history of tobacco or alcohol exposure, which sharply contrasts with the tobacco and/or alcohol exposures of most Fanconi anemia patients who develop SCC (5).
Our unpublished observations suggest that the incidence, pathogenesis, and genomic composition of Fanconi anemia-associated HNSCC that develop in patients who suffer graft-versus-host disease after having a bone marrow transplant may be different from those occurring in the absence of this disease (Kutler DI, Wreesmann VB, Goberdhan A, Ben-Porat L, Satagopan J, Ngai I, et al.: unpublished observations). In this respect, it is interesting to note that the rate of graft-versus-host disease is historically higher in Europe than in the United States due to differences in transplantation protocols. This clinical information should also be provided by van Zeeburg et al. to allow a meaningful assessment of their results.
Finally, on the basis of their unpublished findings, van Zeeburg et al. suggest that a unique pattern of loss-of-heterozygosity may help identify HPV DNA-positive HNSCCs. However, there are several problems with this approach. Fewer than 10% of patients with HNSCC in the general population report having no history of tobacco or alcohol use. Accordingly, the substantial amount of tobacco and/or alcohol consumption has complicated delineation of the contributions of HPV to the pathogenesis of HNSCC in the general population, not to mention the identification of reproducible differences in the genetic composition in HPV-related and HPV-unrelated cases of HNSCC. We performed a genomic screening study comparing all cases of HNSCC in Fanconi anemia patients (N = 18) with a group of randomly selected cases of HNSCC from the general population (n = 42; Kutler DI, Wreesmann VB, Goberdhan A, Ben-Porat L, Satagopan J, Ngai I, et al.: unpublished data). We found statistically significant differences in the pattern and frequency of chromosomal aberrations detected by comparative genomic hybridization between HNSCCs from the two populations. This result differs considerably from that in a previous report on two of the five cases in the authors’ series, in which no differences in chromosomal aberrations were found between the HNSCCs in two Fanconi anemia patients and those in the general population, reflecting the selection bias for the cases in their series (5).
Overall, the high prevalence of HNSCC in Fanconi anemia patients requires diligent surveillance of this patient population. On the basis of our findings, the role of HPV in the pathogenesis of HNSCC in Fanconi anemia patients merits further investigation, as does HPV vaccination as a mode of cancer prevention.
REFERENCES
1 Kutler DI, Wreesmann VB, Goberdhan A, Ben-Porat L, Satagopan J, Ngai I, et al. Human papillomavirus DBA and p53 polymorphisms in squamous cell carcinomas from Fanconi anemia patients. J Natl Cancer Inst 2003;95:1718–21.
2 van den Brule AJ, Pol R, Fransen-Daalmeijer N, Schouls LM, Meijer CJ, Snijders PJ. GP5+/6+ PCR followed by reverse line blot analysis enables rapid and high-throughput identification of human papillomavirus genotypes. J Clin Microbiol 2002;40:779–87.
3 Ha PK, Pai SI, Westra WH, Gillison ML, Tong BC, Sidransky D, et al. Real-time quantitative PCR demonstrates low prevalence of human papillomavirus type 16 in premalignant and malignant lesions of the oral cavity. Clin Cancer Res 2002;8:1203–9.
4 Brennan JA, Boyle JO, Koch WM, Goodman SN, Hruban RH, Eby YJ, et al. Association between cigarette smoking and mutation of the p53 gene in squamous-cell carcinoma of the head and neck. N Engl J Med 1995;332:712–7.
5 Hermsen MA, Xie Y, Rooimans MA, Meijer GA, Baak JP, Plukker JT, et al. Cytogenetic characteristics of oral squamous cell carcinomas in Fanconi anemia. Fam Cancer 2001;1:39–43.[CrossRef][Medline]
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J Natl Cancer Inst 2004 96: 968.
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