Patients with the DNA repair disorder Fanconi anemia (FA) have extremely high risks of cancer (>40-fold increase compared with normal), particularly head and neck squamous cell carcinoma (HNSCC, 800-fold) and gynecologic tumors (vulvar, 2000-fold). Data regarding the role of human papilloma virus (HPV) in these cancers are controversial. While HPV is associated with >25% of oropharyngeal HPV in the general population, the majority of HNSCC in FA are in the oral cavity, not the oropharynx. If HPV is causal in FA-related HNSCC, HPV vaccines might reduce the incidence of these tumors. However, there are no data available with regard to natural immunity to HPV in FA. There has also been concern about whether FA patients can mount a normal antibody response to the HPV vaccines. The inherited bone marrow failure syndromes study at the NCI is an IRB-approved, open cohort, enrolling family members both prospectively and retrospectively. The NCI FA cohort includes 35 patients who were age 9 or above as of July 2012 and who were alive as of 2006, when the HPV Gardasil vaccine became available. A telephone survey determined that 12 patients had been vaccinated, 16 had not, and 7 could not be reached. Sera were available for measurement of HPV antibody titers from 6 pre-vaccination and 25 unvaccinated (“natural history”) and from 10 patients after vaccination. Circulating HPV-16/18 L1 antibody titers were measured using ELISA. Among the unvaccinated, 4 female patients had titers of HPV16, 3 of whom also had titers of HPV18 titers above the detectable level. All 4 were married women over 30 years of age. The titers of both HPV16 and HPV18 in the 10 vaccinated patients were substantially elevated, and were within the range seen in normal vaccine recipients. Thus, FA patients follow the predicted pattern, with undetectable HPV serology prior to sexual exposure, and titers within the described normal range following vaccination. If HNSCC in FA patients are related to HPV infection, and if high serum antibody levels are protective with regard to HNSCC, as they are in reducing the risk of cervical cancer, then vaccination of male and female FA patients should reduce the future incidence of this devastating complication.
To directly test the hypothesis that HPV is causally-associated with cancer in FA, we examined tumor specimens from 5 HNSCC and 4 gynecologic tumors from FA patients. Samples were tested by a well-validated PCR method [SPF(10) PCR/DEIA/LiPA(25)] that detects a wide variety of HPV types. The one cervical cancer was positive for HPV16, while none of the 3 vulvar and none of the 5 HNSCC tumor tissues had detectable carcinogenic types of HPV DNA. These results suggest that HPV16/18 may not be the primary cause of vulvar cancer and HNSCC in FA patients, and that other causal pathways not predominant in the general population need to be considered in studies aimed at defining the etiology of these cancers.
Quint:DDL Diagnostic Laboratory: Employment. de Koning:DDL Diagnostic Laboratory: Employment.
Asterisk with author names denotes non-ASH members.