Cutaneous Viral Infections Across 2 Anatomic Sites Among a Cohort of Patients Undergoing Skin Cancer Screening.

BACKGROUND: Findings from previous studies of cutaneous human papillomavirus (cuHPV) infection and keratinocyte carcinomas have varied due to several factors, including use of different sample types for cuHPV DNA detection. Elucidating the relationship between cuHPV infection in eyebrow hairs (EBHs) and skin swabs (SSWs) is critical for advancing the design of future studies. METHODS: DNA corresponding to 46 ß-HPV and 52 γ-HPV types was measured in EBHs and SSWs obtained from 370 individuals undergoing routine skin cancer screening examinations. RESULTS: Prevalence of ß-HPV/γ-HPV was 92%/84% and 73%/43% in SSWs and EBHs, respectively, with 71%/39% of patients testing positive for ß-HPV/γ-HPV in both sample types. Number of cuHPV types detected and degree of infection were correlated across SSWs and EBHs. When the EBH was positive for a given ß-HPV/γ-HPV type, the SSW was positive for that same type 81%/72% of the time. CONCLUSIONS: Testing SSWs captures more cuHPV infection than EBHs, with EBH infections usually representing a subset of SSW infections. The importance of optimizing sensitivity of cuHPV infection detection using SSWs vs specificity using EBHs (or a combination of the 2) will be ascertained in an ongoing cohort study investigating cuHPV associations with subsequent keratinocyte carcinomas.

Prevalence of cutaneous viral infections in incident cutaneous squamous cell carcinoma detected among chronic lymphocytic leukemia and hematopoietic stem cell transplant patients.

The role of cutaneous viral infections in the development of non-melanoma skin cancer (NMSC), including cutaneous squamous cell carcinoma (SCC), among chronic lymphocytic leukemia (CLL) and blood and marrow transplant (BMT) patients is not established. CLL (n = 977) and BMT (n = 3587) patients treated at the Moffitt Cancer Center were included in a retrospective cohort study. Human papillomavirus (HPV) and human polyomavirus (HPyV) DNA were examined in a subset of incident SCC tumors. Five-year cumulative incidence of NMSC was 1.42% in both BMT (n = 31 NMSCs) and CLL (n = 18 NMSCs) cohorts. Of the nine SCC tumors examined from each cohort, 22.2% and 33.3% were positive for viral DNA in the transplant (HPV 65, MCV) and CLL (HPV 38, HPV 15, HPyV6) cohort, respectively. Enhanced skin cancer screening of BMT/CLL patients should be conducted to better capture incident NMSCs and examine the role of viral infections in these tumors.

Prevalence and Concordance of Cutaneous Beta Human Papillomavirus Infection at Mucosal and Cutaneous Sites.

Background: Cutaneous beta human papillomavirus (HPV) infection across cutaneous and mucosal tissues within individuals has not been examined. Methods: A subcohort of men (n = 87) participating in the HPV Infection in Men (HIM) study provided eyebrow hairs, forearm skin swabs, genital skin swabs, oral rinse samples, and anal swabs. Beta-HPV DNA in the 5 tissues was detected using a multiplex assay, and site-specific beta-HPV prevalence was examined. Results: Any beta-HPV was most prevalent in genital skin (81.6%), followed by forearm skin (64.4%), eyebrow hairs (60.9%), oral mucosa (35.6%), and anal mucosa (33.3%). Most prevalent beta-HPV types included HPV-38 (beta-2) in both genital skin (32.2%) and eyebrow hairs (16.1%), HPV-12 (beta-1) in forearm skin (23%) and oral mucosa (9.2%), and HPV-76 (beta-3) in anal mucosa (14.9%). Concordance of any beta-HPV infection was greater (31.0%) across the 3 keratinized tissue sites (genital skin, eyebrow hairs, forearm skin) than across the 2 mucosal sites (anal and oral mucosa, 6.9%). Conclusions: Prevalence of beta-HPV varied by anatomic site of infection. Biological properties of beta-HPV types detected at mucosal sites and their role in disease pathogenesis should be examined.

Cutaneous Human Papillomavirus Infection and Development of Subsequent Squamous Cell Carcinoma of the Skin.

The role of cutaneous human papillomavirus (HPV) infection in the development of subsequent cutaneous squamous cell carcinoma (SCC) is unknown. Pathologically confirmed cases of SCC (n = 150) enrolled in a previously conducted case-control study were included in a retrospective cohort study to examine the association of cutaneous HPV at the time of SCC diagnosis with the risk of subsequent SCC development. Data on HPV seropositivity, HPV DNA in eyebrow hairs (EB) and SCC tumors were available from the parent study. Incidence of subsequent SCC was estimated using person-years of follow up. Cox Proportional Hazards ratios were estimated to evaluate the associations of both, HPV seropositivity and HPV DNA positivity with subsequent SCC. The five year cumulative incidence of subsequent SCC was 72%. Seropositivity to cutaneous HPV was not associated with the risk of subsequent SCC (HR = 0.83, 95% CI = 0.41-1.67). Any beta HPV infection in EB was associated with reduced risk (HR = 0.30, 95% CI = 0.11-0.78) of subsequent SCC among cases who were positive for beta HPV DNA in tumor tissue. Infection with beta HPV type 2 (HR = 0.32, 95% CI = 0.12-0.86) in EB was associated with reduced risk of subsequent SCC among HPV DNA positive SCCs. In conclusion, beta HPV infection was inversely associated with the risk of subsequent SCC.

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer.

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Subsequent primary malignancies and acute myelogenous leukemia transformation among myelodysplastic syndrome patients treated with or without lenalidomide.

The few studies that have examined rates of acute myeloid leukemia (AML) transformation in lenalidomide-treated myelodysplastic syndrome (MDS) patients have been limited to deletion 5q MDS. The association between lenalidomide and subsequent primary malignancies (SPMs) in MDS patients has not been evaluated previously. We conducted a retrospective cohort study to evaluate the risk of both SPM and AML in association with lenalidomide. A cohort of MDS patients (n = 1248) treated between 2004 and 2012 at Moffitt Cancer Center were identified, and incident cases of SPM and AML transformation were ascertained. Using a nested case-control design, MDS controls were 1:1 matched to SPM (n = 41) and AML (n = 150) cases, on age and date of MDS diagnosis, gender, follow-up time, IPSS, and del (5q). Associations between lenalidomide and (1) SPM incidence and (2) AML transformation were estimated with hazards ratios (HR) and 95% confidence intervals (CIs) in the cohort and odds ratios (OR) in the case-control analysis. SPM incidence did not differ significantly between cohort MDS patients treated with (0.7 per 100 person-years) or without lenalidomide (1.4 per 100 person-years) (HR = 1.04, 95% CI = 0.40-2.74), whereas a significantly reduced SPM risk was observed in the case-control sample (OR = 0.03, 95% CI = <0.01-0.63). Lenalidomide was not associated with AML transformation in the cohort analysis (HR = 0.75, 95% CI = 0.44-1.27) or in the case-control analyses (OR = 1.16, 95% CI = 0.52-2.56), after adjustment for potential confounders. Lenalidomide was not associated with increased risk of SPM or AML transformation in a large cohort of MDS patients mostly including nondeletion 5q MDS.

Merkel cell polyomavirus (MCV) T-antigen seroreactivity, MCV DNA in eyebrow hairs, and squamous cell carcinoma.

BACKGROUND: The role of Merkel cell polyomavirus (MCV) infection in the etiology of non-melanoma skin cancers, other than Merkel cell carcinoma, is unclear. Previously, we reported a significant association between seropositivity to MCV capsid antigen and MCV DNA-positive cutaneous squamous cell carcinoma (SCC). Here we present associations between SCC and seroreactivity to MCV T-antigen (T-Ag) oncoprotein, as well as MCV DNA detected in eyebrow hairs. FINDINGS: A clinic-based case-control study, including 171 SCC cases and 300 controls without skin cancer, was conducted at Moffitt Cancer Center in Tampa, Florida. Multiplex assays were used to measure serum antibodies against MCV small and large T-Ag and MCV DNA in both eyebrow hairs and SCC tumors (n = 144). Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated using logistic regression to evaluate the associations between MCV and SCC. No significant association was observed between seroreactivity to MCV full-length large or small T-Ag and SCC, overall [ORlarge T-Ag = 0.99 (0.48-2.08), ORsmall T-Ag = 0.31 (0.06-1.62)] or when comparing tumor MCV DNA-positive cases to controls [ORlarge T-Ag = 1.06 (0.38-2.93)]. Only presence of MCV DNA in eyebrow hairs was significantly associated with MCV DNA-positive SCC [OR = 4.05 (2.01-8.18)]. CONCLUSION: MCV infection is unlikely to play a direct role in SCC.

Aspirin and Acetaminophen Use and the Risk of Cervical Cancer.

OBJECTIVE: In this study, we investigated whether regular use of aspirin or acetaminophen was associated with risk of cervical cancer in women treated at an American cancer hospital. METHODS: This case-control study included 328 patients with cervical cancer and 1,312 controls matched on age and decade enrolled. Controls were women suspected of having but not ultimately diagnosed with a neoplasm. Analgesic use was defined as regular (at least once per week for ≥6 months), frequent (≥7 tablets/week), very long term (≥11 years), or frequent, long term (≥7 tablets per week for ≥5 years). RESULTS: Compared to nonusers, frequent aspirin use was associated with decreased odds of cervical cancer (odds ratio, 0.53; 95% confidence interval, 0.29-0.97). A slightly larger association was observed with frequent, long-term use of aspirin (odds ratio, 0.46; 95% confidence interval, 0.22-0.95). Acetaminophen use was not associated with the risk of cervical cancer. CONCLUSIONS: Our findings suggest that frequent and frequent, long-term use of aspirin is associated with decreased odds of cervical cancer. To our knowledge, this is the first US-based study examining these associations. Given the widespread use of nonsteroidal anti-inflammatory drugs and acetaminophen worldwide, further investigations of the possible role of analgesics in cervical cancer, using a larger sample size with better-defined dosing regimens, are warranted.

Natural history of polyomaviruses in men: the HPV infection in men (HIM) study.

BACKGROUND: Several new polyomaviruses have been discovered in the last decade, including Merkel cell polyomavirus (MCPyV). Little is known about the natural history of the more recently discovered polyomaviruses. We estimated the incidence, prevalence, and persistence of 9 polyomaviruses (MCPyV, BK polyomavirus, KI polyomavirus, JC polyomavirus, WU polyomavirus, Human polyomavirus 6 [HPyV6], HPyV7, HPyV9, and Trichodysplasia spinulosa-associated polyomavirus) and examined factors associated with MCPyV infection in a prospective cohort of 209 men initially enrolled in the HPV Infection in Men (HIM) study. METHODS: Participants enrolled at the US site of the HIM study were recruited into a substudy of cutaneous viral infections and followed for a median of 12.6 months. Eyebrow hair and normal skin swab specimens were obtained at each study visit, and the viral DNA load was measured using multiplex polymerase chain reaction. RESULTS: MCPyV infection showed the highest prevalence (65.1% of normal skin swab specimens and 30.6% of eyebrow hair specimens), incidence (81.7 cases per 1000 person-months among normal skin swab specimens, and 24.1 cases per 1000 person-months among eyebrow hair specimens), and persistence (85.8% of normal skin swab specimens and 58.9% of eyebrow hair specimens) among all polyomaviruses examined. Age of >44 years (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.03-4.33) and Hispanic race (OR, 2.64; 95% CI, 1.01-6.88) were associated with an increased prevalence of MCPyV infection in eyebrow hair and normal skin swab specimens, respectively. CONCLUSION: MCPyV infection is highly prevalent in adults, with age and race being predisposing factors.

Natural history of cutaneous human papillomavirus (HPV) infection in men: the HIM study.

Accumulating evidence suggests that cutaneous human papillomavirus (HPV) infection is associated with non-melanoma skin cancer (NMSC). Little is known about the natural history of cutaneous HPV. A sub-cohort of 209 men with no NMSC history, initially enrolled in the HPV infection in men (HIM) study, were followed for a median of 12.6 months. Epidemiological data were collected through self-administered questionnaires. Cutaneous HPV DNA was measured in normal skin swabs (SS) and eyebrow hairs (EB) for 25 and 16 HPV types in genera ß and γ, respectively. Any ß HPV infection was more prevalent in SS (67.3%) compared to EB (56.5%, p = 0.04). Incidence in SS was higher than 20 per 1,000 person-months for HPV types 4, 5, 23, 38 and 76. Median duration of persistence of ß and γ HPV infection was 8.6 and 6.1 months in EB, respectively, and 11.3 months and 6.3 months, in SS, respectively. Older age (>44 years vs. 18-30 years) was significantly associated with prevalent (SS OR = 3.0, 95% CI = 1.2-7.0) and persistent ß HPV infection (EB OR = 6.1, 95% CI = 2.6-14.1). History of blistering sunburn was associated with prevalent (OR = 2.8, 95% CI = 1.3-5.8) and persistent (OR = 2.3, 95% CI = 1.2-4.6) ß HPV infection in SS. Cutaneous HPV is highly prevalent in men, with age and blistering sunburn being significant risk factors for cutaneous ß HPV infection.

Prospective study of seroreactivity to JC virus T-antigen and risk of colorectal cancers and adenomas.

John Cunningham virus (JCV) is a common polyomavirus classified as a possible carcinogen by the International Agency for Research on Cancer. JCV may play a role in colorectal carcinogenesis, although we previously reported no association between JCV capsid antibodies and colorectal cancer. No studies have examined the role of seroreactivity to JCV T-antigen (T-Ag) oncoprotein in colorectal cancer. A case-control study nested within a community-based prospective cohort (CLUE II) was conducted. In 1989, 25,080 residents of Washington County, Maryland, were enrolled in CLUE II, completing baseline questionnaires and providing blood samples. At follow-up, 257 incident colorectal cancer cases were identified by linkage to population-based cancer registries through 2006 and matched to controls on age, sex, race, and date of blood draw. One hundred and twenty-three colorectal adenoma cases were identified through self-report during follow-up and matched to controls on age, sex, race, date of blood draw, and colorectal cancer screening. Baseline serum samples were tested for seroreactivity to JCV T-Ag. Associations between JCV T-Ag seroreactivity and colorectal cancer/adenomas were evaluated using conditional logistic regression models. Overall, seroreactivity to JCV T-Ag was not statistically significantly associated with the risk of either colorectal cancer [OR, 1.34; 95% confidence interval (CI), 0.89-2.01] or adenoma (OR, 1.30; 95% CI, 0.70-2.42), while a borderline association with colorectal cancer was observed among women (OR, 1.82; 95% CI, 1.00-3.31). Our past evaluation of JCV capsid seropositivity, combined with current findings, does not support a notable etiologic role for JCV infection in colorectal cancer.

Socioeconomic factors and the risk for sarcoma.

Sarcomas are a heterogeneous group of rare malignancies arising from mesenchymal tissue. Although several occupational exposures have been evaluated in association with sarcoma, little is known about the role of socioeconomic indicators such as education. Socioeconomic status has been found to be associated with risk of development of several types of cancers, primarily lung, gastric, and cervical cancers. We conducted a hospital-based case-control study to evaluate the association of socioeconomic level with the risk for sarcoma. A total of 371 incident cases of sarcoma were matched in terms of age, sex, and year of enrollment in the study with 742 cancer-free controls. Education and income levels were evaluated as the indicators of socioeconomic status. Higher education (college level) was associated with a significantly lower risk for sarcoma [odds ratio (OR)=0.48, 95% confidence interval (CI)=0.29-0.80], even after adjusting for important confounders. After stratifying by sex, significantly lower risk for sarcoma was observed among men who had college level education compared with men with a level of education of eighth grade or lower (OR=0.38, 95% CI=0.19-0.74). A significant association between education and the risk for sarcoma remained after stratifying by income (OR=0.49, 95% CI=0.28-0.86, among the low income group). When analyzed as a composite exposure, individuals with high education and high income status had significantly lower risk for sarcoma compared with those with low income and low education status (OR=0.41, 95% CI=0.23-0.71). Thus, socioeconomic factors may play a significant role in determining the risk for sarcoma and should be explored further to elucidate the underlying factors that may explain these sociodemographic inequalities related to sarcoma.

Predictors of immunosuppressive regulatory T lymphocytes in healthy women.

Immunosuppressive regulatory T (Treg) cells play an important role in antitumor immunity, self-tolerance, transplantation tolerance, and attenuation of allergic response. Higher proportion of Treg cells has been observed in peripheral blood of cancer cases compared to controls. Little is known about potential epidemiological predictors of Treg cell levels in healthy individuals. We conducted a cross-sectional study including 75 healthy women, between 20 and 80 years of age, who participated in the Data Bank and BioRepository (DBBR) program at Roswell Park Cancer Institute (RPCI), Buffalo, NY, USA. Peripheral blood levels of CD4(+)CD25(+)FOXP3(+) Treg cells were measured using flow cytometric analysis. A range of risk factors was evaluated using Wilcoxon Rank-Sum test, Kruskal-Wallis test, and linear regression. Age, smoking, medications for treatment of osteoporosis, postmenopausal status, body mass index (BMI), and hormone replacement therapy (HRT) were found to be significant positive predictors of Treg cell levels in peripheral blood (P ≤ 0.05). Higher education, exercise, age at first birth, oral contraceptives, and use of Ibuprofen were found be significant (P < 0.05) negative predictors of Treg levels. Thus, various epidemiological risk factors might explain interindividual variation in immune response to pathological conditions, including cancer.

Genetic polymorphisms of ATP-binding cassette (ABC) proteins, overall survival and drug toxicity in patients with Acute Myeloid Leukemia.

The overall survival of patients with acute myeloid leukemia (AML) remains poor due to both intrinsic and acquired chemotherapy resistance. Over expression of ATP binding cassette (ABC) proteins in AML cells has been suggested as a putative mechanism of drug resistance. Genetic variation among individuals affecting the expression or function of these proteins may contribute to inter-individual variation in treatment outcomes. DNA from pre-treatment bone marrow or blood samples from 261 patients age 20-85 years, who received cytarabine and anthracycline-based therapy at Roswell Park Cancer Institute between 1994 and 2006, was genotyped for eight non-synonymous single nucleotide polymorphisms in the ABCB1, ABCC1 and ABCG2 drug transporter genes. Heterozygous (AG) or homozygous (AA) variant genotypes for rs2231137 (G34A) in the ABCG2 (BRCP) gene, compared to the wild type (GG) genotype were associated with both significantly improved survival (HR=0.44, 95%CI=0.25-0.79), and increased odds for toxicity (OR=8.41, 95%CI= 1.10-64.28). Thus genetic polymorphisms in the ABCG2 (BRCP) gene may contribute to differential survival outcomes and toxicities in AML patients via a mechanism of decreased drug efflux in both, AML cells and normal progenitors.