Nicolas F Schlecht

Albert Einstein College of Medicine, New York, New York, United States

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Publications (93)

  • [Show abstract] [Hide abstract] ABSTRACT: Betel quid chewing is a major oral cancer risk factor and the human papillomaviruses (HPV) may play an aetiological role in these cancers. However, little is known about the shape of the dose-response relationship between the betel quid chewing habit and oral cancer risk in populations without HPV. We estimate the shape of this dose-response relationship, and discuss implications for prevention.
    Article · Sep 2016 · Oral Oncology
  • Shilpi S. Mehta-Lee · Anton Palma · Peter S. Bernstein · [...] · Nicolas F. Schlecht
    [Show abstract] [Hide abstract] ABSTRACT: Objective Preterm birth is a leading cause of perinatal morbidity and mortality. Prevention strategies rarely focus on preconception care. We sought to create a preconception nomogram that identifies nonpregnant women at highest risk for preterm birth using the Pregnancy Risk Assessment Monitoring System (PRAMS) surveillance data. Methods We used PRAMS data from 2004 to 2009. The odds ratios (ORs) of preterm birth for each preconception variable was estimated and adjusted analyses were conducted. We created a validated nomogram predicting the probability of preterm birth using multivariate logistic regression coefficients. Results 192,208 cases met inclusion criteria. Demographic/maternal health characteristics and associations with preterm birth and ORs are reported. After validation, we identified the following significant predictors of preterm birth: prior history of preterm birth or low birth weight baby, prior spontaneous or elective abortion, maternal diabetes prior to conception, maternal race (e.g., non-Hispanic black), intention to get pregnant prior to conception (i.e., did not want or wanted it sooner), and smoking prior to conception (p < 0.05). Overall, our preconception preterm risk model correctly classified 76.1 % of preterm cases with a negative predictive value (NPV) of 76.7 %. A nomogram using a 0-100 scale illustrates our final preconception model for predicting preterm birth. Conclusion This preconception nomogram can be used by clinicians in multiple settings as a tool to help predict a woman's individual preterm birth risk and to triage high-risk non-pregnant women to preconception care. Future studies are needed to validate the nomogram in a clinical setting.
    Article · Jul 2016 · Maternal and Child Health Journal
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    [Show abstract] [Hide abstract] ABSTRACT: Background: The epidermal growth factor receptor (EGFR) signaling network is involved in lung carcinogenesis. This study examined whether ligands that activate or suppress the EGFR signaling network were associated with lung cancer risk in ever smokers. Methods: A nested case-control study within the Women’s Health Initiative assessed baseline plasma levels of insulin, insulin-like growth factor (IGF)-1, insulin-like growth factor binding protein (IGFBP)-3, interleukin (IL)-6, hepatocyte growth factor (HGF), and nerve growth factor (NGF) in 1143 ever-smoking lung cancer cases and 1143 controls. Leptin was measured as an adiposity biomarker. Conditional logistic regression was used in data analyses. Results: Leptin was inversely associated with lung cancer risk (odds ratio [ORcontinuous] per Ln [pg/mL] = 0.85, 95% confidence interval [CI] = 0.74 to 0.98). After adjusting for adiposity and other risk factors, null associations were found for IL-6, HGF, and NGF. In current smokers, but not former smokers, high insulin levels were associated with increased lung cancer risk (OR for 4th quartile vs others [ORq4] = 2.06, 95% CI = 1.30 to 3.26) whereas IGFBP-3 had a linear inverse association (ORcontinuous per μg/mL = 0.64, 95% CI = 0.41 to 0.98). The insulin association was consistent across subgroups defined by body mass index and histological type, but the IGFBP-3 association was specific to small cell lung cancer. There was a modest positive association between IGF-1 and lung cancer risk in current smokers (ORq4 = 1.44, 95% CI = 0.90 to 2.29). Conclusions: Independent of obesity, high insulin levels but reduced levels of IGFBP-3 were associated with increased lung cancer risk in current smokers.
    Full-text Article · Jul 2016 · JNCI Journal of the National Cancer Institute
  • N. Ari Wijetunga · Thomas J. Belbin · Robert D. Burk · [...] · Nicolas F. Schlecht
    [Show abstract] [Hide abstract] ABSTRACT: Objective: To conduct a comprehensive mapping of the genomic DNA methylation in CDKN2A, which codes for the p16(INK4A) and p14(ARF) proteins, and 14 of the most promising DNA methylation marker candidates previously reported to be associated with progression of low-grade cervical intraepithelial neoplasia (CIN1) to cervical cancer. Methods: We analyzed DNA methylation in 68 HIV-seropositive and negative women with incident CIN1, CIN2, CIN3 and invasive cervical cancer, assaying 120 CpG dinucleotide sites spanning APC, CDH1, CDH13, CDKN2A, CDKN2B, DAPK1, FHIT, GSTP1, HIC1, MGMT, MLH1, RARB, RASSF1, TERT and TIMP3 using the Illumina Infinium array. Validation was performed using high resolution mapping of the target genes with HELP-tagging for 286 CpGs, followed by fine mapping of candidate genes with targeted bisulfite sequencing. We assessed for statistical differences in DNA methylation levels for each CpG loci assayed using univariate and multivariate methods correcting for multiple comparisons. Results: In our discovery sample set, we identified dose dependent differences in DNA methylation with grade of disease in CDKN2A, APC, MGMT, MLH1 and HIC1, whereas single CpG locus differences between CIN2/3 and cancer groups were seen for CDH13, DAPK1 and TERT. Only those CpGs in the gene body of CDKN2A showed a monotonic increase in methylation between persistent CIN1, CIN2, CIN3 and cancers. Conclusion: Our data suggests a novel link between early cervical disease progression and DNA methylation in a region downstream of the CDKN2A transcription start site that may lead to increased p16(INK4A)/p14(ARF) expression prior to development of malignant disease.
    Article · Jul 2016 · Gynecologic Oncology
  • [Show abstract] [Hide abstract] ABSTRACT: Some studies suggest that periodontal diseases may increase the risk of oral cancer, but contradictory results also exist. Inadequate control of confounders, including life course exposures, may have influenced prior findings. We estimate the extent to which high levels of periodontal disease, measured by gingival inflammation and recession, are associated with oral cancer risk using a comprehensive subset of potential confounders and applying a stringent adjustment approach. In a hospital-based case-control study, incident oral cancer cases (N=350) were recruited from two major referral hospitals in Kerala, South India, from 2008 to 2012. Controls (N=371), frequency-matched by age and sex, were recruited from clinics at the same hospitals. Structured interviews collected information on several domains of exposure via detailed life course questionnaires. Periodontal diseases, as measured by gingival inflammation and gingival recession, were evaluated visually by qualified dentists following a detailed protocol. The relationship between periodontal diseases and oral cancer risk was assessed by unconditional logistic regression using a stringent empirical selection of potential confounders corresponding to a 1% change-in-estimates. Generalized gingival recession was significantly associated with oral cancer risk (Odds Ratio=1.83, 95% Confidence Interval: 1.10-3.04). No significant association was observed for gingival inflammation and oral cancer. Our findings support the hypothesis that high levels of periodontal diseases increase the risk of oral cancer. This article is protected by copyright. All rights reserved.
    Article · May 2016 · International Journal of Cancer
  • Andrew M. Tilston-Lünel · Kathryn E. Haley · Nicolas F. Schlecht · [...] · Paul A. Reynolds
    [Show abstract] [Hide abstract] ABSTRACT: Crumbs 3 (CRB3) is a component of epithelial junctions that has been implicated in apical-basal polarity, apical identity, apical stability, cell adhesion, and cell growth. CRB3 undergoes alternative splicing to yield two variants: CRB3a and CRB3b. Here, we describe novel data demonstrating that as with previous studies on CRB3a, CRB3b also promotes the formation of tight junctions (TJs). However, significantly we demonstrate that the 4.1-ezrin-radixin-moesin (FERM)-binding motif (FBM) of CRB3b is required for CRB3b functionality and that ezrin binds to the FBM of CRB3b. Furthermore, we show that ezrin contributes to CRB3b functionality and the correct distribution of TJ proteins. We demonstrate that both CRB3 isoforms are required for the production of functionally mature TJs and also the localization of ezrin to the plasma membrane. Finally, we demonstrate that reduced CRB3b expression in head and neck squamous cell carcinoma (HNSCC) correlates with cytoplasmic ezrin, a biomarker for aggressive disease, and show evidence that whilst CRB3a expression has no effect, low CRB3b and high cytoplasmic ezrin expression combined may be prognostic for HNSCC.
    Article · Apr 2016 · Journal of Molecular Cell Biology
  • [Show abstract] [Hide abstract] ABSTRACT: Purpose: To determine whether HMG-CoA reductase inhibitors (statins) are associated with a lower risk of pancreatic cancer. Methods: The population included 160,578 postmenopausal women enrolled in the Women's Health Initiative (WHI) in which 385 incident cases of pancreatic cancer were identified over an average of 8.69 (SD ±4.59) years. All diagnoses were confirmed by medical record and pathology review. Information on statin use and other risk factors was collected at baseline and during follow-up. Multivariable-adjusted hazards ratios (HRs) and 95 % confidence intervals (CIs) evaluating the relationship between prior statin use (at baseline only as well as in a time-dependent manner) and risk of pancreatic cancer were computed from Cox proportional hazards regression analyses after adjusting for appropriate confounders. We also evaluated the effect of statin type, potency, lipophilic status, and duration of use. All statistical tests were two-sided. Results: Statins were used at baseline by 12,243 (7.5 %) women. The annualized rate of pancreatic cancer in statin users and nonusers, respectively, was 0.0298 versus 0.0271 %. The multivariable-adjusted HR for statin users versus nonusers at baseline was 0.92 and 95 % CI 0.57-1.48. In a time-dependent model, the HR for low-potency statins was 0.46, 95 % CI 0.20-1.04. There was no significant effect seen by statin lipophilicity or duration of use. Conclusions: There was no significant relationship between statins and pancreatic cancer risk in the WHI; however, there was a marginal inverse association noted for low-potency statins. Analyses of larger numbers of cases are needed to further explore this relationship.
    Article · Feb 2016 · Cancer Causes and Control
  • [Show abstract] [Hide abstract] ABSTRACT: Objective: To examine the association of knowledge about human papillomavirus (HPV) on the time to completion of the 3-dose quadrivalent vaccine series in an inner-city population of adolescent female subjects at high risk for infection. Study design: We prospectively followed 139 female subjects aged 14-20 years enrolled in a vaccine surveillance study in New York City during a period of at least 24 months. Participants were given a 30-item true or false survey on HPV at enrollment and ranked according to the number of correct responses. Multivariate Cox regression was used to examine the association between level of knowledge about HPV and time to completion (in days) of vaccine dose 1-3, dose 1-2, and dose 2-3. Results: Overall time to completion of the 3-dose vaccine ranged from 158 days to 1114 days. Participants in the high knowledge group (top quartile) were significantly more likely to complete the 3-dose series earlier (hazard ratio 1.69, 95% CI 1.03-2.77; P = .04), in particular doses 2-3 (hazard ratio 1.71, 95% CI 1.02-2.89; P = .04), than those with low-to-moderate knowledge (bottom 3 quartiles). Conclusions: These findings suggest that knowledge of HPV is associated with shorter time to complete the 3-dose HPV vaccine series. Educational campaigns at time of vaccination may be important to improve vaccine adherence.
    Article · Feb 2016 · The Journal of pediatrics
  • Anton Palma · David W. Lounsbury · Nicolas F. Schlecht · Ilir Agalliu
    [Show abstract] [Hide abstract] ABSTRACT: Since 2012, US guidelines have recommended against prostate-specific antigen (PSA) screening for prostate cancer. However, evidence of screening benefit from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening trial and the European Randomized Study of Screening for Prostate Cancer has been inconsistent, due partly to differences in noncompliance and contamination. Using system dynamics modeling, we replicated the PLCO trial and extrapolated follow-up to 20 years. We then simulated 3 scenarios correcting for contamination in the PLCO control arm using Surveillance, Epidemiology, and End Results (SEER) incidence and survival data collected prior to the PSA screening era (scenario 1), SEER data collected during the PLCO trial period (1993-2001) (scenario 2), and data from the European trial's control arm (1991-2005) (scenario 3). In all scenarios, noncompliance was corrected using incidence and survival rates for men with screen-detected cancer in the PLCO screening arm. Scenarios 1 and 3 showed a benefit of PSA screening, with relative risks of 0.62 (95% confidence interval: 0.53, 0.72) and 0.70 (95% confidence interval: 0.59, 0.83) for cancer-specific mortality after 20 years, respectively. In scenario 2, however, there was no benefit of screening. This simulation showed that after correcting for noncompliance and contamination, there is potential benefit of PSA screening in reducing prostate cancer mortality. It also demonstrates the utility of system dynamics modeling for synthesizing epidemiologic evidence to inform public policy.
    Article · Dec 2015 · American Journal of Epidemiology
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    N.F. SCHLECHT · A. OSADA · K.S. KURTZ · J. KAZIMIROFF
    Full-text Dataset · Sep 2015
  • [Show abstract] [Hide abstract] ABSTRACT: Oral cancer is a major public health issue in India with approximately 77,000 new cases and 52,000 deaths yearly. Paan chewing, tobacco and alcohol use are strong risk factors for this cancer in India. Human papillomaviruses (HPV) are also related to a subset of head and neck cancers. We examined the association between oral HPV and oral cancer in a sample of Indian subjects participating in a hospital-based case-control study. We recruited incident oral cancer cases (N=350) and controls frequency-matched by age and sex (N=371) from two main referral hospitals in Kerala, South India. Socio-demographic and behavioral data were collected by interviews. Epithelial cells were sampled using Oral CDx® brushes from the oral cancer site and the normal mucosa. Detection and genotyping of 36 HPV genotypes were done using a polymerase chain reaction protocol. Data collection procedures were performed by qualified dentists via a detailed protocol with strict quality control, including independent HPV testing in India and Canada. HPV DNA was detected in none of the cases or controls. Associations between oral cancer and risk factors usually associated with HPV infection, such as oral sex and number of lifetime sexual partners, were examined by logistic regression and were not associated with oral cancer. Lack of a role for HPV infection in this study may reflect cultural or religious characteristics specific to this region in India that are not conducive to oral HPV transmission. A nationwide representative prevalence study is needed to investigate HPV prevalence variability among Indian regions. This article is protected by copyright. All rights reserved. © 2014 Wiley Periodicals, Inc. © 2015 UICC.
    Article · Aug 2015 · International Journal of Cancer
  • Miriam M Ben-Dayan · Thomas MacCarthy · Nicolas F Schlecht · [...] · Aviv Bergman
    [Show abstract] [Hide abstract] ABSTRACT: Context .- Oropharyngeal squamous cell carcinoma is associated both with tobacco use and with human papillomavirus (HPV) infection. It is argued that carcinogen-driven tumorigenesis is a distinct disease from its virally driven counterpart. We hypothesized that tumorigenesis is the result of a loss of genotypic robustness resulting in an increase in phenotypic variation in tumors compared with adjacent histologically normal tissues, and that carcinogen-driven tumorigenesis results in greater variation than its virally driven counterpart. Objectives .- To examine the loss of robustness in carcinogen-driven and virally driven oropharyngeal squamous cell carcinoma samples, and to identify potential pathways involved. Design .- We used coefficients of variation for messenger RNA and microRNA expression to measure the loss of robustness in oropharyngeal squamous cell carcinoma samples. Tumors were compared with matched normal tissues, and were further categorized by HPV and patient smoking status. Weighted gene coexpression networks were constructed for genes with highly variable expression among the HPV(-) tumors from smokers. Results .- We observed more genes with variable messenger RNA expression in tumors compared with normal tissues, regardless of HPV and smoking status, and more microRNAs with variable expression in HPV(-) and HPV(+) tumors from smoking patients than from nonsmokers. For both the messenger RNA and microRNA data, we observed more variance among HPV(-) tumors from smokers compared with HPV(+) tumors from nonsmokers. The gene coexpression network construction highlighted pathways that have lost robustness in carcinogen-induced tumors but appear stable in virally induced tumors. Conclusion .- Using coefficients of variation and coexpression networks, we identified multiple altered pathways that may play a role in carcinogen-driven tumorigenesis.
    Article · Jul 2015 · Archives of pathology & laboratory medicine
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    [Show abstract] [Hide abstract] ABSTRACT: Study objective: The increasing prevalence of adolescent obesity has led to consideration of the potential effect of obesity on risky sexual behaviors. In the current study we examined whether body mass index (BMI) was related to age at sexual debut, type of sexual behavior, partner number, and condom use in a population of adolescent women at high risk for obesity and risky sexual behaviors. Design, setting, and participants: Cross-sectional examination of 860 sexually active, predominantly minority, adolescent women who received medical care at an urban health center from 2007 through 2013. Intervention and main outcome measures: Self-reported age at sexual debut, types of sexual intercourse, number of partners and condom use was compared with clinically assessed BMI. Results: BMI was positively associated with number of sexual partners (P = .001) and history of attempted anal intercourse (P = .002). An inverse association was observed with age at first anal intercourse (P = .040). Conclusion: In this sample of adolescent women, increased BMI was associated with riskier sexual practices at a younger age. Results of this study suggest that overweight and obese adolescents are a vulnerable population who might need targeted sexual health counseling.
    Full-text Article · Jun 2015 · Journal of Pediatric and Adolescent Gynecology
  • Lourdes Oriana Linares · Viswanathan Shankar · Angela Diaz · [...] · Nicolas F Schlecht
    [Show abstract] [Hide abstract] ABSTRACT: This study investigated the association of cervical human papillomavirus (HPV) infection with cumulative psychosocial risk reflecting family disadvantage, psychological distress, and unhealthy lifestyle. The sample (N = 745) comprised sexually active female adolescent patients (12-19 yr), primarily ethnic minorities, enrolled in a free HPV vaccination program. Subjects completed questionnaires and provided cervical swabs for HPV DNA testing. Unweighted and weighted principal component analyses for categorical data were used to derive multisystemic psychosocial risk indices using 9 indicators: low socioeconomic status, lack of adult involvement, not attending high school/college, history of treatment for depression/anxiety, antisocial/delinquent behavior, number of recent sexual partners, use of alcohol, use of drugs, and dependency risk for alcohol/drugs. The association between cervical HPV (any type, high-risk types, vaccine types) assayed by polymerase chain reaction and self-reported number of psychosocial risk indicators was estimated using multivariable logistic regression. Subjects had a median of 3 psychosocial risk indicators. Multiple logistic regression analyses showed associations with unweighted and weighted number of psychosocial indicators for HPV any type (adjusted odds ratio [aOR] = 1.1; 95% confidence interval [CI], 1.0-1.2), with the strongest associations between weighted drug/alcohol use, drug/alcohol dependency risk, and antisocial/delinquent behavior and detection of HPV vaccine types (aOR = 1.5; 95% CI, 1.1-2.0) independent of number of recent sexual partners and vaccine dose (0-3). Increased HPV infections including HPV vaccine types were associated with greater number of psychosocial risk indicators even after controlling for demographics, sexual behavior, history of chlamydia, and vaccine dose.
    Article · May 2015 · Journal of developmental and behavioral pediatrics: JDBP
  • Nicole V J Anayannis · Nicolas F Schlecht · Thomas J Belbin
    [Show abstract] [Hide abstract] ABSTRACT: Context .- Growing evidence suggests that as many as half of all oropharyngeal squamous cell carcinomas (OPSCCs) harbor human papillomavirus (HPV) infections. Despite being more advanced at diagnosis, HPV-positive OPSCCs are associated with a better response to therapy and longer patient survival than HPV-negative OPSCCs. Human papillomavirus-positive OPSCC has also been shown to have distinct host gene expression profiles compared with HPV-negative OPSCC. Recently, this distinction has been shown to include the epigenome. It is well supported that cancers are epigenetically deregulated. This review highlights epigenetic differences between HPV-positive and HPV-negative OPSCCs. The epigenetic mechanisms highlighted include methylation changes to host and viral DNA, and host chromatin modification. We also review the current evidence regarding host DNA methylation changes associated with smoking, and deregulation of microRNA expression in HPV-positive OPSCC. Objective .- To provide an overview of epigenetic mechanisms reported in HPV-positive OPSCC, with analogies to cervical cancer, and discussion of the challenges involved in studying epigenetic changes in HPV-associated OPSCC in combination with changes associated with smoking. Data Sources .- Sources were a literature review of peer-reviewed articles in PubMed on HPV and either OPSCC or head and neck squamous cell carcinoma, and related epigenetic mechanisms. Conclusions .- Epigenetic changes are reported to be a contributing factor to maintaining a malignant phenotype in HPV-positive OPSCC. The epigenetic mechanisms highlighted in this review can be studied for potential as biomarkers or as drug targets. Furthermore, continued research on the deregulation of epigenetic mechanisms in HPV-positive OPSCC (compared with HPV-negative OPSCC) may contribute to our understanding of the clinical and biologic differences between HPV-positive and HPV-negative OPSCC.
    Article · May 2015 · Archives of pathology & laboratory medicine
  • Article · Apr 2015
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    Katia Muller · Julie Kazimiroff · Mahnaz Fatahzadeh · [...] · Nicolas F Schlecht
    [Show abstract] [Hide abstract] ABSTRACT: We evaluated the risk factors associated with oral human papillomavirus (HPV) infection and oral lesions in 161 HIV-positive and 128 HIV-negative patients presenting for oral examination at two urban health-care centers. Patients were interviewed on risk factors and provided oral-rinse samples for HPV-DNA typing by PCR. Statistical associations were assessed by logistic regression. Oral HPV was prevalent in 32% and 16% of HIV-positive and negative patients, including high-risk type 16 (8% and 2%, respectively, p=0.049) and uncommon types 32/42 (6% and 5%, p=0.715). Among HIV-negative patients, significant risk factors for oral HPV included multiple sexual partners (≥21 vs. ≤5; odds ratio [OR]=9.1, 95% confidence interval [CI]:1.7-49.3), heavy tobacco smoking (>20 pack-years vs. none; OR=9.2, 95%CI:1.4-59.4), and marijuana use (OR=4.0, 95%CI:1.3-12.4). Among HIV-positive patients, lower CD4 count only was associated with oral HPV detection (≤200 vs. ≥500 T-cells/mm(3); OR=4.5, 95%CI:1.3-15.5). Detection of high-risk HPV was also associated with concurrent detection of potentially cancerous oral lesions in HIV-negative patients but not among HIV-positive patients. The observed risk factor associations with oral HPV in HIV-negative patients are consistent with sexual transmission and local immunity, whereas in HIV-positive patients, oral HPV detection is strongly associated with low CD4 count. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    Full-text Article · Feb 2015 · The Journal of Infectious Diseases
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    Nicolas F Schlecht · Miriam Ben-Dayan · Nicole Anayannis · [...] · Thomas J Belbin
    Full-text Dataset · Jan 2015
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    Nicolas F. Schlecht · Miriam Ben‐Dayan · Nicole Anayannis · [...] · Thomas J. Belbin
    [Show abstract] [Hide abstract] ABSTRACT: Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is recognized as a distinct disease entity associated with improved survival. DNA hypermethylation profiles differ significantly by HPV status suggesting that a specific subset of methylated CpG loci could give mechanistic insight into HPV-driven OPSCC. We analyzed genome-wide DNA methylation of primary tumor samples and adjacent normal mucosa from 46 OPSCC patients undergoing treatment at Montefiore Medical Center, Bronx, NY using the Illumina HumanMethylation27 beadchip. For each matched tissue set, we measured differentially methylated CpG loci using a change in methylation level (M value). From these analyses, we identified a 22 CpG loci panel for HPV+ OPSCC that included four CDKN2A loci downstream of the p16(INK4A) and p14(ARF) transcription start sites. This panel was significantly associated with overall HPV detection (P < 0.05; ROC area under the curve = 0.96, 95% CI: 0.91–1.0) similar to the subset of four CDKN2A-specific CpG loci (0.90, 95% CI: 0.82–0.99) with equivalence to the full 22 CpG panel. DNA hypermethylation correlated with a significant increase in alternative open reading frame (ARF) expression in HPV+ OPSCC primary tumors, but not to the other transcript variant encoded by the CDKN2A locus. Overall, this study provides evidence of epigenetic changes to the downstream region of the CDKN2A locus in HPV+ oropharyngeal cancer that are associated with changes in expression of the coded protein products.
    Full-text Article · Dec 2014 · Cancer Medicine
  • Christian R. Salazar · Nicole Anayannis · Richard V. Smith · [...] · Nicolas F. Schlecht
    [Show abstract] [Hide abstract] ABSTRACT: While its prognostic significance remains unclear, p16INK4a protein expression is increasingly being used as a surrogate marker for oncogenic human papillomavirus (HPV) infection in head and neck squamous cell carcinomas (HNSCC). To evaluate the prognostic utility of p16 expression in HNSCC, we prospectively collected 163 primary tumor specimens from histologically confirmed HNSCC patients who were followed for up to 9.4 years. Formalin fixed tumor specimens were tested for p16 protein expression by immunohistochemistry. HPV type-16 DNA and RNA was detected by MY09/11-PCR and E6/E7 RT-PCR on matched frozen tissue, respectively. P16 protein expression was detected more often in oropharyngeal tumors (53%) as compared with laryngeal (24%), hypopharyngeal (8%), or oral cavity tumors (4%; P<0.0001). With respect to prognosis, p16-positive oropharyngeal tumors exhibited significantly better overall survival than p16-negative tumors (log-rank test p=0.04), whereas no survival benefit was observed for non-oropharyngeal tumors. However, when both p16 and HPV DNA test results were considered, concordantly positive non-oropharyngeal tumors had significantly better disease-specific survival than concordantly negative non-oropharyngeal tumors after controlling for sex, nodal stage, tumor size, tumor subsite, primary tumor site number, smoking, and drinking (adjusted hazard ratio [HR]=0.04, 0.01–0.54). Compared with concordantly negative non-oropharyngeal HNSCC, p16(+)/HPV16(-) non-oropharyngeal HNSCC (n=13, 7%) demonstrated no significant improvement in disease-specific survival when HPV16 was detected by RNA (adjusted HR=0.83, 0.22–3.17). Our findings show that p16 immunohistochemistry alone has potential as a prognostic test for oropharyngeal cancer survival, but combined p16/HPV testing is necessary to identify HPV-associated non-oropharyngeal HNSCC with better prognosis. © 2014 Wiley Periodicals, Inc.
    Article · Nov 2014 · International Journal of Cancer

Publication Stats

3k Citations

Institutions

  • 2015
    • Albert Einstein College of Medicine
      New York, New York, United States
  • 2012
    • Albert Einstein Medical Center
      Philadelphia, Pennsylvania, United States
  • 2011-2012
    • Montefiore Medical Center
      • Albert Einstein College of Medicine
      New York City, New York, United States
  • 2005
    • University of California, San Francisco
      San Francisco, California, United States
  • 2002
    • Hospital Heliopolis
      San Paulo, São Paulo, Brazil
  • 2000
    • Ludwig Institute for Cancer Research Brazil
      San Paulo, São Paulo, Brazil
  • 1999
    • McGill University
      Montréal, Quebec, Canada