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1.  Functional Single-Nucleotide Polymorphisms in the BRCA1 Gene and Risk of Salivary Gland Carcinoma 
Oral oncology  2012;48(9):842-847.
Polymorphic BRCA1 is a vital tumor suppressor gene within the DNA double-strand break repair pathways, but its association with salivary gland carcinoma (SGC) has yet to be investigated.
Materials and Methods
In a case-control study of 156 SGC patients and 511 controls, we used unconditional logistical regression analyses to investigate the association between SGC risk and seven common functional single-nucleotide polymorphisms (A1988G, A31875G, C33420T, A33921G, A34356G, T43893C and A55298G) in BRCA1.
T43893C TC/CC genotype was associated with a reduction of SGC risk (adjusted odds ratio =0.55, 95% CI: 0.38–0.80, Bonferroni-adjusted p=0.011), which was more pronounced in women, non-Hispanic whites, and individuals with a family history of cancer in first-degree relatives. The interaction between T43893C and family history of cancer was significant (p=0.009). The GATGGCG and AACAACA haplotypes, both of which carry the T43893C minor allele, were also associated with reduced SGC risk.
Our results suggest that polymorphic BRCA1, particularly T43893C polymorphism, may protect against SGC.
PMCID: PMC3408797  PMID: 22503699
BRCA1 polymorphism; salivary gland carcinoma; genetic susceptibility; DNA repair; case-control study
2.  Functional repeats (TGYCC)n in the p53-inducible gene 3 (PIG3) promoter and susceptibility to squamous cell carcinoma of the head and neck 
Carcinogenesis  2012;34(4):812-817.
A polymorphic pentanucleotide microsatellite sequence (TGYCC)n within the p53-inducible gene 3 (PIG3) promoter is correlated with the extent of transcriptional activation by p53 and thought to modulate susceptibility to cancer. Using a PCR–silver staining-based single-strand conformation assay, we visualized variant genotypes of the PIG3 promoter (TGYCC)n motif in a subset of 100 subjects for each of four ethnic groups: non-Hispanic whites, African Americans, Hispanic Americans and Native Chinese. We found that PIG3 (TGYCC)15 was the most common allele but less frequent in non-Hispanic whites (0.660) than in Chinese (0.785) (P = 0.016). In an additional study of 616 patients with squamous cell carcinoma of the head and neck (SCCHN) and 623 cancer-free controls in a non-Hispanic white population, we found that compared with those who were PIG3 (TGYCC)15 homozygotes, subjects without the PIG3 (TGYCC)15 allele had a significantly increased SCCHN risk [adjusted odds ratio (OR) = 1.34; 95% CI = 1.04–1.73 for heterozygotes and OR = 1.69; 95% CI = 1.18–2.44 for variant homozygotes] in an allele-dose response manner (P = 0.002). Consistently, subsequent luciferase reporter assay revealed that the wild-type (TGYCC)15 allele had the highest p53-mediated transcriptional activity, compared with the other (TGYCC)n motifs. Our data suggest that the PIG3 variant polymorphic repeats alleles other than (TGYCC)15 may affect p53 binding and thus may be a marker for susceptibility to SCCHN, but our findings need to be validated in larger studies.
PMCID: PMC3616663  PMID: 23241165
3.  Phase II Trial of Induction Chemotherapy Followed by Surgery for Squamous Cell Carcinoma of the Oral Tongue in Young Adults 
Head & neck  2011;34(9):1255-1262.
We conducted a phase II clinical trial of induction chemotherapy followed by surgery ± radiotherapy for squamous cell carcinoma of the oral tongue (SCCOT) in young adults.
From September 2001 to October 2004, 23 patients aged 18–49 years with clinical T2-3N0-2M0 SCCOT and no prior radiotherapy, chemotherapy, or neck dissection underwent induction chemotherapy (paclitaxel, ifosfamide, and carboplatin) followed by glossectomy and neck dissection ± radiotherapy and chemotherapy.
On final surgical pathology, 9 (39%) patients had a complete/major (2 complete) histologic response at the primary tumor site; 8 (35%) had no response or progression. Similarly, 9 (39%) patients had a complete response in the neck or remained node negative; 6 (26%) had an increase in nodal category. No treatment-associated deaths occurred, and toxicity was modest. At a median follow-up from the end of treatment of 52 months (minimum, 23 months), 10 (43%) patients developed recurrence, and all 10 died of cancer. Crude recurrence/cancer death rates were associated with ≤ a partial response at the tongue (P = .029), poor histologic differentiation (P = .012), and multiple adverse features on final surgical pathology (P = .040).
Response rates and overall survival with this induction chemotherapy regimen were limited, but complete/major response at the tongue was associated with excellent prognosis. Additionally, improved patient selection and predictive tumor biomarkers will be needed for induction chemotherapy to be routinely incorporated into the treatment of oral tongue cancer in young adults.
PMCID: PMC3893095  PMID: 22009800
Oral tongue cancer; Young adults; Induction chemotherapy
4.  An evolution in demographics, treatment, and outcomes of oropharyngeal cancer at a major cancer center: A staging system in need of repair 
Cancer  2012;119(1):81-89.
This retrospective review examines demographic/clinical characteristics and overall survival of patients with squamous cell carcinoma of the oropharynx (SCCOP) at a tertiary cancer center and reports the characteristics influencing any observed survival trends over time.
The study included 3891 newly diagnosed, previously untreated patients presenting to our institution between 1955 and 2004.
Over time, patients presented at younger ages and were more likely to have base of tongue or tonsil tumors and to be never or former smokers. Patients diagnosed in 1995–2004 were almost half as likely to die as those diagnosed before 1995 (HR,0.6; 95% CI,0.6–0.8). In both multivariable and recursive partitioning survival analyses, the TNM staging system predicted survival of patients treated before 1995 but not of patients treated in 1995–2004.
Survival among patients with SCCOP improved substantially over the past 50 years. The main contributing factors were changes in clinical characteristics, in particular surrogates for HPV positivity. The current TNM staging system for SCCOP is inadequate. Incorporation of HPV status and perhaps smoking status is encouraged.
PMCID: PMC3469778  PMID: 22736261
head and neck cancer; head and neck neoplasms; human papillomavirus; oropharyngeal cancer; neoplasm staging
5.  Human Papillomavirus Type 16 E6/E7-Specific Cytotoxic T Lymphocytes for Adoptive Immunotherapy of HPV-Associated Malignancies 
Vaccines prevent HPV-associated cancer but, although these tumors express foreign, viral antigens (E6 and E7 proteins), they have little benefit in established malignancies, likely due to negative environmental cues that block tumor recognition and induce T cell anergy in vivo. We postulated that we could identify mechanisms by which ex vivo stimulation of T cells could reactivate and expand tumor-directed T-cell lines from HPV-positive cancer patients for subsequent adoptive immunotherapy.
A total of 68 patients with HPV-associated cancers were studied. Peripheral blood T cells were stimulated with monocyte-derived dendritic cells loaded with pepmixes (peptide libraries of 15-mers overlapping by 11 amino-acids) spanning E6/E7, in the presence or absence of specific accessory cytokines. The resulting T-cell lines were further expanded with pepmix-loaded activated B-cell blasts. IFNγ release and cytotoxic responses to E6/E7 were assessed.
We successfully reactivated and expanded (>1200-fold) E6/E7-specific T cells from 8/16 cervical and 33/52 oropharyngeal cancer patients. The presence of the cytokines IL-6, -7, -12 and -15 is critical for this process. These T cell lines possess the desirable characteristics of polyclonality, multiple T-cell subset representation (including the memory compartment) and a TH1 bias, and may eliminate E6/E7-positive targets.
In conclusion, we have shown it is possible to robustly generate HPV16 E6/E7-directed T-cell lines from patients with HPV16-associated cancers. Because our technique is scalable and good-manufacturing-procedures compliant, these lines could be used for adoptive cellular immunotherapy of patients with HPV16-positive cancers.
PMCID: PMC3521877  PMID: 23211628
6.  Impact of Enhanced Detection on the Increase in Thyroid Cancer Incidence in the United States: Review of Incidence Trends by Socioeconomic Status Within the Surveillance, Epidemiology, and End Results Registry, 1980–2008 
Thyroid  2013;23(1):103-110.
In the past 3 decades, the incidence of thyroid cancer in the United States has been increasing. There has been debate on whether the increase is real or an artifact of improved diagnostic scrutiny. Our hypothesis is that both improved detection and a real increase have contributed to the increase.
Because socioeconomic status (SES) may be a surrogate for access to diagnostic technology, we compared thyroid cancer incidence trends between high- and low-SES counties within the Surveillance, Epidemiology, and End Results 9 (SEER 9) registries. The incidence trends were assessed using joinpoint regression analysis.
In high-SES counties, thyroid cancer incidence increased moderately (annual percentage change 1 [APC1]=2.5, p<0.05) before the late 1990s and more pronounced (APC2=6.3, p<0.05) after the late 1990s. In low-SES counties, incidence increased steadily with an APC of 3.5 (p<0.05) during the entire study period (1980–2008). For tumors ≤4.0 cm, incidence was higher in high-SES counties, and APC was higher for high- than low-SES counties after the late 1990s. For tumors >4.0 cm, high- and low-SES counties had similar increasing incidence trends. Similarly, for tumors ≤2.0 cm, the incidence trends differed between counties that are in or adjacent to metropolitan areas and counties that are in rural areas, whereas for tumors >2.0 cm, all counties regardless of area of residence had similar increasing trends.
Enhanced detection likely contributed to the increased thyroid cancer incidence in the past decades, but cannot fully explain the increase, suggesting that a true increase exists. Efforts should be made to identify the cause of this true increase.
PMCID: PMC3539256  PMID: 23043274
7.  Common obesity-related genetic variants and papillary thyroid cancer risk 
Epidemiologic studies have shown consistent associations between obesity and increased thyroid cancer risk, but, to date, no studies have investigated the relationship between thyroid cancer risk and obesity-related single nucleotide polymorphisms (SNPs).
We evaluated 575 tag SNPs in 23 obesity-related gene regions in a case-control study of 341 incident papillary thyroid cancer (PTC) cases and 444 controls of European ancestry. Logistic regression models, adjusted for attained age, year of birth, and sex were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) with SNP genotypes, coded as 0, 1, and 2 and modeled continuously to calculate P-trends.
Nine out of 10 top-ranking SNPs (Ptrend<0.01) were located in the FTO (fat mass and obesity associated) gene region, while the other was located in INSR (insulin receptor). None of the associations were significant after correcting for multiple testing.
Our data do not support an important role of obesity-related genetic polymorphisms in determining the risk of PTC.
Factors other than selected genetic polymorphisms may be responsible for the observed associations between obesity and increased PTC risk.
PMCID: PMC3518668  PMID: 23064004
single nucleotide polymorphisms; case-control study; obesity; body mass index; thyroid neoplasms
8.  Genetic variants of a BH3-only pro-apoptotic gene, PUMA, and risk of HPV16-associated squamous cell carcinoma of the head and neck 
Molecular carcinogenesis  2011;51(Suppl 1):E54-E64.
P53 up-regulated modulator of apoptosis (PUMA) is a critical factor in the intrinsic apoptotic pathway. Through PUMA-dependent mechanisms, human papillomavirus 16 (HPV16) oncoprotein may affect apoptosis by E6-mediated p53 degradation. To examine whether the PUMA variants modify the association between HPV16 serology and risk of squamous cell carcinoma of the head and neck (SCCHN), we genotyped two polymorphisms in the PUMA promoter (rs3810294 and rs2032809) in 380 cases and 335 cancer-free controls of non-Hispanic whites, who were frequency-matched by age (± 5 years), sex, smoking and drinking status. We found that each individual polymorphism had only a modest impact on risk of SCCHN, particularly in oropharyngeal cancer for rs3810294 and non-oropharyngeal cancer for rs2032809. After we stratified the individuals by HPV16 serology, and used those with the corresponding common homozygous genotype and HPV16 seronegativity as the reference group, for each polymorphism we found that the risk of SCCHN associated with HPV16 seropositivity was higher among those with variant genotypes than those with the corresponding common homozygous genotype. Notably, this effect modification was particularly pronounced in several subgroups including never smokers, never drinkers, younger patients, and patients with oropharyngeal cancer. Furthermore, we also characterized the functional relevance of the two polymorphisms to explore the genotype-phenotype correlation. Our results suggested that the PUMA promoter polymorphisms may be a biomarker for risk of HPV16-associated SCCHN, particularly in never smokers, never drinkers, younger patients, and patients with oropharyngeal cancer. Larger studies are needed to validate our findings.
PMCID: PMC3326219  PMID: 22086558
PUMA polymorphisms; HPV16; genetic susceptibility; molecular epidemiology; squamous cell carcinoma of the head and neck
9.  Combined effects of E2F1 and E2F2 polymorphisms on risk and early onset of squamous cell carcinoma of the head and neck 
Molecular carcinogenesis  2012;51(Suppl 1):E132-E141.
Deregulated expression of most members of the E2F family has been detected in many human cancers. We examined the association of common single nucleotide polymorphisms (SNPs) of E2F1 and E2F2 with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1,096 SCCHN patients and 1,090 cancer-free controls. We genotyped ten selected SNPs in E2F1 and E2F2, including those at the near 5′ UTR, miRNA binding sites at the near 3′ UTR and tagSNPs according to bioinfotmatics analysis. Although none of the selected SNPs alone was significantly associated with risk of SCCHN, there was a statistically significantly increased risk of SCCHN associated with the combined risk genotypes (i.e. rs3213182 AA, rs3213183 GG, rs3213180 GG, rs321318121 GG, rs2742976 GT+TT, rs6667575 GA+AA, rs3218203 CC, rs3218148 AA, rs3218211 CC, rs3218123 GT+TT). Compared with those with 0–4 risk genotypes, an increased risk was observed for those who carried 5–8 risk genotypes (adjusted OR = 1.04; 95% CI = 0.86–1.26) and 9–10 risk genotypes (adjusted OR = 1.62; 95% CI = 1.14–2.30) in a dose-response manner (P = 0.045). Furthermore, the joint effect was more pronounced among patients with oropharyngeal cancer, younger adults (≤57 years old), men, non-smokers, non-drinkers, and individuals with family history of cancer first-degree relatives. Additionally, we also observed that those with 5–10 risk genotypes had an earlier SCCHN onset than those with 0–4 risk genotypes, particularly for non-smokers and/or non-drinkers. We concluded that E2F1 and E2F2 genetic variants may jointly play important roles in head and neck carcinogenesis.
PMCID: PMC3370129  PMID: 22344756
E2F1; E2F2; head and neck cancer; polymorphisms; age at onset
10.  Functional polymorphisms in the insulin-like binding protein-3 gene may modulate susceptibility to differentiated thyroid carcinoma in Caucasian Americans 
Molecular carcinogenesis  2012;51(Suppl 1):E158-E167.
The insulin-like growth factor (IGF) pathway is believed to play a pivotal role in thyroid carcinogenesis. Polymorphisms of IGF-1 and IGF binding protein-3 (IGFBP-3) have been associated with modulation of risk for the emergence of assorted common malignancies, but studies of the influence of such polymorphisms on risk of differentiated thyroid carcinoma (DTC) are lacking.
In a case-control study of 173 DTC patients, 101 patients with benign thyroid disease, and 401 controls, an unconditional logistical regression model adjusted for age and sex was applied to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between polymorphisms of IGF-1 and IGFBP-3 and DTC risk.
IGFBP-3 rs2132572 GA/AA genotypes were associated with a decreased risk of DTC (adjusted OR=0.6, 95% CI: 0.4–0.9), particularly multifocal DTC (adjusted OR=0.3, 95% CI: 0.1–0.7). The association with DTC was more evident in subjects with a first-degree family history of cancer (adjusted OR=0.4, 95% CI: 0.2–0.7, Pinteraction=0.013) and nondrinkers (adjusted OR=0.4, 95% CI: 0.2–0.7, Pinteraction=0.028). A 4 SNP haplotype of IGFBP-3 was associated with a decreased risk of DTC (adjusted OR=0.7, 95% CI: 0.5–1.0, P=0.030).
Our study suggests that polymorphic IGFBP-3 may be involved in susceptibility to DTC.
PMCID: PMC3473095  PMID: 22415807
IGF-1; multifocal; genetic susceptibility; papillary thyroid carcinoma; case-control study
11.  A Comparison of the Demographics, Clinical Features, and Survival of Patients with Adenoid Cystic Carcinoma of Major and Minor Salivary Glands Versus Less Common Sites within the SEER Registry 
Cancer  2011;118(16):3945-3953.
The scientific literature to date lacks population-based studies on the demographics, clinical features, and survival of patients with adenoid cystic carcinoma (ACC) of different anatomic sites.
We identified 5349 ACC cases in major salivary glands (N=1850), minor salivary glands (N=2077), breast (N=696), skin (N=291), lung and bronchus (N=203), female genital system (N=132), and eye and orbit (N=100) from the Surveillance, Epidemiology, and End Results (SEER) registry. Differences in demographics, clinical features, and survival of patients were assessed.
ACC of the eye and orbit was associated with younger age at presentation (mean=49.9 years). ACC of the skin or breast tended to present with less aggressive prognostic features, while ACC of the lung and bronchus or eye and orbit tended to present with more aggressive prognostic features. In multivariate survival analysis of patients presenting with localized disease, patients with ACC of breast (HR=0.40) or skin (HR=0.40) had a significantly lower risk death than patients with ACC of major salivary glands, while patients with ACC of lung and bronchus (HR=3.72) or eye and orbit (HR=3.67) had a significantly higher risk. For patients presenting with regional disease, the only clear prognostic difference in multivariate analysis was that patients with ACC of skin did significantly better.
The demographics and clinical features of ACC differ by disease site. Site may be an important predictor of survival for patients presenting with localized disease but is less important for patients presenting with regional disease.
PMCID: PMC3412946  PMID: 22179977
Adenoid Cystic Carcinoma; SEER; Epidemiology; Site; Survival
12.  Combined p53-related genetic variants together with HPV infection increase oral cancer risk 
To explore the role of polymorphisms of p53-related genes in etiology of oral cancer, we investigated joint effects of seven putatively functional polymorphisms of p53 (codon 72 Arg/Pro), p73 (4/14 GC/AT), MDM2 (A2164G and T2580G), and MDM4 (rs11801299 G>A, rs10900598 G>T, and rs1380576 C>G) on risk of HPV16-associated oral cancer in a case-control study with 325 cases and 335 cancer-free controls. We found that HPV16 seropositivity alone was associated with an increased risk of oral cancer [adjusted odds ratio (OR), 3.1; 95% confidence interval (CI), 2.1–4.6]. After combining genotypes of seven polymorphisms and using the low-risk group (0–3 combined risk genotypes) and HPV16 seronegativity as the reference group, the medium-risk (4 combined risk genotypes) and high-risk groups (5–7 combined risk genotypes) and HPV16 seronegativity were associated with only an OR of 1.6 (95% CI, 1.1–2.5) and 1.2 (95% CI, 0.7–1.9) for oral cancer risk, respectively, while the low-risk, medium-risk, and high-risk groups and HPV16 seropositivity were significantly associated with a higher OR of 2.1 (95% CI, 1.2–3.6), 4.0 (95% CI, 1.8–9.1), and 19.1 (95% CI, 5.7–64.2), respectively. Notably, such effect modification by these combined risk genotypes was particularly pronounced in young subjects (aged < 50 years), never smokers, and patients with oropharyngeal cancer. Taken together, these findings suggest that the combined risk genotypes of p53-related genes may modify risk of HPV16-associated oral cancer, especially in young patients, never-smokers, and patients with oropharyngeal cancer. Larger studies are needed to validate our findings.
PMCID: PMC3289741  PMID: 22052649
p53; p73; MDM2; MDM4; HPV infection; oral cancer
13.  Association of tumor necrosis factor-alpha promoter variants with risk of HPV-associated oral squamous cell carcinoma 
Molecular Cancer  2013;12:80.
Tumor necrosis factor alpha (TNF-α) plays an important role in inflammation, immunity, and defense against infection and clearance of human papillomavirus (HPV). Thus, genetic variants may modulate individual susceptibility to HPV-associated oral squamous cell carcinoma (OSCC).
In this study we genotyped four common single nucleotide polymorphisms (SNPs) in the TNF-α promoter [ −308G > A(rs1800629), -857C > T (rs1799724), -863C > A (rs1800630), and -1031T > C (rs1799964)] and determined HPV16 serology in 325 OSCC cases and 335 matched controls and tumor HPV status in 176 squamous cell carcinomas of the oropharynx (SCCOP) patients. Univariate and multivariable logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).
We found that HPV16 seropositivity alone was associated with an increased risk of OSCC (OR, 3.1; 95% CI, 2.1–4.6), and such risk of HPV16-associated OSCC was modified by each SNP. Patients with both HPV16 seropositivity and variant genotypes for each SNP had the highest risk when using patients with HPV16 seronegativity and a wild-type genotype as a comparison group. Moreover, similar results were observed for the combined risk genotypes of four variants and all such significant associations were more pronounced in several subgroups, particularly in SCCOP patients and never smokers. Notably, the combined risk genotypes of four variants were also significantly associated with tumor HPV-positive SCCOP.
Taken together, these results suggest that TNF-α SNPs may individually or, more likely, jointly affect individual susceptibility to HPV16-associated OSCC, particularly SCCOP and never smokers. Validation of our findings is warranted.
PMCID: PMC3725173  PMID: 23870134
TNF-α; Polymorphism; HPV infection; Oropharyngeal cancer; Case–control study
14.  Neighborhood Deprivation and Clinical Outcomes among Head and Neck Cancer Patients 
Health & place  2012;18(4):861-868.
The unique effects of neighborhood-level economic deprivation on survival, recurrence, and second primary malignancy development were examined using adjusted Cox proportional hazards regression models among 1151 incident squamous cell carcinomas of the head and neck (SCCHN) patients. Cancer site was examined as a potential moderator. Main analyses yielded null results; however, interaction analyses indicated poorer overall survival [HR=1.59 (1.00-2.53)] and greater second primary malignancy development [HR=2.99 (1.46-6.11)] among oropharyngeal cancer patients from highly deprived neighborhoods relative to less deprived neighborhoods. Results suggest a dual focus on individual and neighborhood risk factors could help improve clinical outcomes among oropharyngeal cancer patients.
PMCID: PMC3372668  PMID: 22445028
neighborhood deprivation; head and neck cancer; survival; second primary malignancy; oropharyngeal cancer
15.  Common genetic variants in metabolism and detoxification pathways and the risk of papillary thyroid cancer 
Endocrine-Related Cancer  2012;19(3):333-344.
Relationships are unclear between polymorphisms in genes involved in metabolism and detoxification of various chemicals and papillary thyroid cancer (PTC) risk as well as their potential modification by alcohol or tobacco intake. We evaluated associations between 1647 tagging single nucleotide polymorphisms (SNPs) in 132 candidate genes/regions involved in metabolism of exogenous and endogenous compounds (Phase I/II, oxidative stress, and metal binding pathways) and PTC risk in 344 PTC cases and 452 controls. For 15 selected regions and their respective SNPs, we also assessed interaction with alcohol and tobacco use. Logistic regression models were used to evaluate the main effect of SNPs (Ptrend) and interaction with alcohol/tobacco intake. Gene- and pathway-level associations and interactions (Pgene interaction) were evaluated by combining Ptrend values using the adaptive rank-truncated product method. While we found associations between PTC risk and nine SNPs (Ptrend≤0.01) and seven genes/regions (Pregion<0.05), none remained significant after correction for the false discovery rate. We found a significant interaction between UGT2B7 and NAT1 genes and alcohol intake (Pgene interaction=0.01 and 0.02 respectively) and between the CYP26B1 gene and tobacco intake (Pgene interaction=0.02). Our results are suggestive of interaction between the genetic polymorphisms in several detoxification genes and alcohol or tobacco intake on risk of PTC. Larger studies with improved exposure assessment should address potential modification of PTC risk by alcohol and tobacco intake to confirm or refute our findings.
PMCID: PMC3394851  PMID: 22389382
16.  Prospective Imaging Biomarker Assessment of Mortality Risk in Patients Treated with Head and Neck Radiotherapy 
The optimal roles for imaging-based biomarkers in the management of head and neck cancer remain undefined. Unresolved questions include whether functional or anatomic imaging biomarkers might improve mortality risk assessment for this disease. We addressed these issues in a prospective institutional trial.
Methods and Materials
Ninety-eight patients with locally advanced pharyngolaryngeal squamous cell cancer were enrolled. Each underwent pre-and post-chemoradiotherapy contrast-enhanced CT and FDG-PET/CT imaging. Imaging parameters were correlated with survival outcomes.
Low post-radiation primary tumor FDG avidity correlated with improved survival on multivariate analysis; so too did complete primary tumor response by CT alone. Although both imaging modalities lacked sensitivity, each had high specificity and negative predictive value for disease-specific mortality risk assessment. Kaplan-Meier estimates confirmed that both CT and FDG-PET/CT stratify patients into distinct high- and low-probability survivorship groups on the basis of primary tumor response to radiotherapy. Subset analyses demonstrated that the prognostic value for each biomarker was primarily derived from patients at high risk for local treatment failure (HPV-negative disease, non-oropharyngeal primary disease, or tobacco use).
CT- and FDG-PET/CT-based biomarkers are useful clinical tools in head and neck cancer-specific mortality risk assessment following radiotherapy, particularly for high-risk HPV-unrelated disease. Focus should be placed on further refinement and corroboration of imaging-based biomarkers in future studies.
PMCID: PMC3072063  PMID: 20171802
Radiotherapy; head and neck cancer; PET; CT; survival
17.  Common genetic variants in the 8q24 region and risk of papillary thyroid cancer 
The Laryngoscope  2012;122(5):1040-1042.
Single nucleotide polymorphisms (SNPs) in the 8q24 chromosomal region identified from genome-wide scans have been associated with risk of several cancers including breast (rs1562430), prostate and colon (rs1447295 and rs6983267). A genome-wide scan in 26 families with papillary thyroid cancer (PTC) also found susceptibility loci in 8q24, supporting a closer evaluation of this chromosomal region in relation to risk of sporadic PTC.
Study Design
We evaluated 157 tag SNPs in the 8q24 chromosomal region between 120.91 Mb and 128.78 Mb (including rs1562430, rs1447295, and rs6983267) in a case-control study of 344 PTC cases and 452 age and gender frequency-matched controls.
We used logistic regression to estimate odds ratios and compute P-values of linear trend for PTC with genotypes of interest. To account for multiple comparisons, we applied the false discovery rate (FDR) method.
We did not find a significant association between rs1562430, rs1447295, or rs6983267, and PTC risk. We found that one SNP (rs4733616) was associated with PTC risk at P = 0.003, and twelve other SNPs were associated with PTC risk at P < 0.05. However, no SNPs remained significant after FDR correction.
Our findings do not support a strong association between SNPs in the 8q24 chromosomal region and risk of sporadic PTC but several SNPs with small effects might exist.
PMCID: PMC3408055  PMID: 22275265
8q24; thyroid cancer
18.  Modifying effect of MDM4 variants on risk of HPV16-associated squamous cell carcinoma of oropharynx 
Cancer  2011;118(6):1684-1692.
The p53 pathway plays a critical role in maintaining genomic stability and preventing tumor formation. Given the roles of both MDM4 and HPV16 E6 oncoproteins in inhibition of p53 activity, we tested the hypothesis that MDM4 polymorphisms are associated with the risk of HPV16-associated squamous cell carcinoma of head and neck (SCCHN).
Genotyping was conducted on three tagging single nucleotide polymorphisms (rs11801299 G>A, rs10900598 G>T, and rs1380576 C>G) in MDM4, and serology was used to determine HPV 16 exposure in 380 cases and 335 cancer-free controls that were frequency-matched by age, sex, smoking, and drinking status.
None of three MDM4 polymorphisms alone was significantly associated with risk of overall SCCHN. With further analysis stratified by HPV16 serology and tumor site, we found that each polymorphism individually modified the risk of HPV16-associated squamous cell carcinoma of the oropharynx (SCCOP), and such effect modification was particularly pronounced in never smokers and never drinkers.
The risk of HPV16-associated SCCOP could be modified by MDM4 polymorphisms. Large and prospective studies are needed to validate our findings.
PMCID: PMC3213304  PMID: 21823114
MDM4 polymorphisms; genetic susceptibility; human papillomavirus; molecular epidemiology; squamous cell carcinoma of head and neck cancer; squamous cell carcinoma of the oropharynx
19.  Common Single Nucleotide Polymorphisms in Genes Related to Immune Function and Risk of Papillary Thyroid Cancer 
PLoS ONE  2013;8(3):e57243.
Accumulating evidence suggests that alterations in immune function may be important in the etiology of papillary thyroid cancer (PTC). To identify genetic markers in immune-related pathways, we evaluated 3,985 tag single nucleotide polymorphisms (SNPs) in 230 candidate gene regions (adhesion-extravasation-migration, arachidonic acid metabolism/eicosanoid signaling, complement and coagulation cascade, cytokine signaling, innate pathogen detection and antimicrobials, leukocyte signaling, TNF/NF-kB pathway or other) in a case-control study of 344 PTC cases and 452 controls. We used logistic regression models to estimate odds ratios (OR) and calculate one degree of freedom P values of linear trend (PSNP-trend) for the association between genotype (common homozygous, heterozygous, variant homozygous) and risk of PTC. To correct for multiple comparisons, we applied the false discovery rate method (FDR). Gene region- and pathway-level associations (PRegion and PPathway) were assessed by combining individual PSNP-trend values using the adaptive rank truncated product method. Two SNPs (rs6115, rs6112) in the SERPINA5 gene were significantly associated with risk of PTC (PSNP-FDR/PSNP-trend = 0.02/6×10−6 and PSNP-FDR/PSNP-trend = 0.04/2×10−5, respectively). These associations were independent of a history of autoimmune thyroiditis (OR = 6.4; 95% confidence interval: 3.0–13.4). At the gene region level, SERPINA5 was suggestively associated with risk of PTC (PRegion-FDR/PRegion = 0.07/0.0003). Overall, the complement and coagulation cascade pathway was the most significant pathway (PPathway = 0.02) associated with PTC risk largely due to the strong effect of SERPINA5. Our results require replication but suggest that the SERPINA5 gene, which codes for the protein C inhibitor involved in many biological processes including inflammation, may be a new susceptibility locus for PTC.
PMCID: PMC3592848  PMID: 23520464
20.  Family History of Cancer and Risk of Sporadic Differentiated Thyroid Carcinoma 
Cancer  2011;118(5):1228-1235.
Thyroid cancer incidence in the United States, particularly in women, has increased dramatically since 1980s. While the causes of thyroid cancer in most patients remain largely unknown, evidence suggests the existence of an inherited predisposition to development of differentiated thyroid cancer (DTC). Therefore, we explored the association between sporadic DTC and family history of cancer.
In a retrospective hospital-based case-control study of prospectively recruited subjects who completed the study questionnaire upon enrollment, unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) as estimates of the DTC risk associated with first-degree family history of cancer.
The study included 288 patients with sporadic DTC and 591 cancer-free controls. Family history of thyroid cancer in first-degree relatives was associated with increased DTC risk (adjusted OR = 4.1, 95% CI: 1.7–9.9). All DTC cases in patients with a first-degree family history of thyroid cancer were cases of papillary thyroid carcinoma (PTC) (adjusted OR = 4.6, 95 CI%: 1.9–11.1). Notably, the risk of PTC was highest in subjects with a family history of thyroid cancer in siblings (OR = 7.4, 95% CI: 1.8–30.4). In addition, multifocal primary tumor was more common among PTC patients with first-degree family history of thyroid cancer than among PTC patients with no first-degree family history of thyroid cancer (68.8% vs. 35.5%, p = 0.01).
Our study suggests that family history of thyroid cancer in first-degree relatives, particularly in siblings, is associated with an increased risk of sporadic PTC.
PMCID: PMC3208119  PMID: 21800288
Differentiated thyroid carcinoma; papillary thyroid carcinoma; benign thyroid disease; multifocal; family history of cancer
21.  Common Genetic Variants in Sex Hormone Pathway Genes and Papillary Thyroid Cancer Risk 
Thyroid  2012;22(2):151-156.
Hormonal differences are hypothesized to contribute to the approximately ≥2-fold higher thyroid cancer incidence rates among women compared with men worldwide. Although thyroid cancer cells express estrogen receptors and estrogen has a proliferative effect on papillary thyroid cancer (PTC) cells in vitro, epidemiologic studies have not found clear associations between thyroid cancer and female hormonal factors. We hypothesized that polymorphic variation in hormone pathway genes is associated with the risk of developing papillary thyroid cancer.
We evaluated the association between PTC and 1151 tag single nucleotide polymorphisms (SNPs) in 58 candidate gene regions involved in sex hormone synthesis and metabolism, gonadotropins, and prolactin in a case-control study of 344 PTC cases and 452 controls, frequency matched on age and sex. Odds ratios and p-values for the linear trend for the association between each SNP genotype and PTC risk were estimated using unconditional logistic regression. SNPs in the same gene region or pathway were aggregated using adaptive rank-truncated product methods to obtain gene region-specific or pathway-specific p-values. To account for multiple comparisons, we applied the false discovery rate method.
Seven SNPs had p-values for linear trend <0.01, including four in the CYP19A1 gene, but none of the SNPs remained significant after correction for multiple comparisons. Results were similar when restricting the dataset to women. p-values for examined gene regions and for all genes combined were ≥0.09.
Based on these results, SNPs in selected hormone pathway genes do not appear to be strongly related to PTC risk. This observation is in accord with the lack of consistent associations between hormonal factors and PTC risk in epidemiologic studies.
PMCID: PMC3271376  PMID: 22224819
22.  Genetic variants of the p53 and p73 genes jointly increase risk of second primary malignancies in patients after index squamous cell carcinoma of the head and neck 
Cancer  2011;118(2):485-492.
Due to the structural and biochemical similarities between the anti-tumor p53 and p73 proteins, we hypothesized that individuals who carry high risk genotypes of p53 codon 72 and p73 G4C14-to-A4T14 polymorphisms have a higher risk of developing second primary malignancy (SPM) in patients after an index squamous cell carcinomas of the head and neck (SCCHN).
A cohort of 1,269 patients with index cases of SCCHN was recruited between May 1995 and January 2007 at M.D. Anderson Cancer Center and followed for SPM development. Patients were genotyped for p53 codon 72 and p73 G4C14-to-A4T14 polymorphisms. A log-rank test and Cox proportional hazard models were used to compare SPM-free survival and SPM risk among different risk groups with the combined risk genotypes of the two polymorphisms.
Our data demonstrated that patients with p53 WP + PP and p73 GC/GC genotypes had a worse SPM-free survival and an increased SPM risk compared with the corresponding p53 WW and p73 GC/AT +AT/AT genotypes. After combining the two polymorphisms, a borderline significantly or significantly reduced SPM-free survival and increased SPM risk were observed in medium-risk group (p53 WW and p73 GC/GC or p53 P carrier and p73 AT carriers) and high-risk group (p53 P carriers and p73 GC/GC) compared with low-risk group (p53 WW and p73 AT carriers), respectively.
Our results suggest an increased risk of SPM after index SCCHN with both p53 and p73 polymorphisms individually and in combination.
PMCID: PMC3184342  PMID: 21717430
p53; p73; Polymorphisms; Squamous cell carcinoma of the head and neck; Second primary malignancy
23.  Polymorphisms of XPG/ERCC5 and risk of squamous cell carcinoma of the head and neck 
Pharmacogenetics and genomics  2012;22(1):50-57.
Xeroderma pigmentosum group G (XPG) protein is essential for the nucleotide excision repair (NER) system, and genetic variations in XPG/ERCC5 that affect DNA repair capacity may contribute to the risk of tobacco-induced cancers, including squamous cell carcinoma of the head and neck (SCCHN). We investigated the association between XPG/ERCC5 polymorphisms and risk of squamous cell carcinoma of the head and neck (SCCHN).
We genotyped 12 tagging and potentially functional single nucleotide polymorphisms (SNPs) of XPG/ERCC5 in a case-control study of 1,059 non-Hispanic white patients with SCCHN and 1,066 cancer-free age-and sex matched controls and evaluated their associations with SCCHN risk.
Multivariate logistic regression showed that only an intronic tagging SNP (rs4150351A/C) of XPG/ERCC5 was associated with a decreased risk of SCCHN (adjusted OR=0.76, 95% CI=0.62–0.92 for AC vs. AA; adjusted OR=0.81, 95% CI=0.67–0.98 for AC/CC vs. AA), but this association was nonsignificnant after corrections by the permutation test (empirical P=0.105). In the genotype-phenotype correlation analysis using peripheral lymphocytes from 44 SCCHN patients, we found that rs4150351 AC/CC was associated with a statistically significant increase in XPG/ERCC5 mRNA expression.
These findings suggest that genetic variation in XPG/ERCC5 may not affect the SCCHN risk, although rs4150351 C variant genotypes were associated with the increased expression of XPG/ERCC5 mRNA and nonsignificantly decreased risk of SCCHN. Larger population-based and additional functional studies are warranted to validate our findings.
PMCID: PMC3237901  PMID: 22108238
ERCC5; polymorphism; SCCHN; risk
24.  Association of BRCA1 Functional Single Nucleotide Polymorphisms with Risk of Differentiated Thyroid Carcinoma 
Thyroid  2012;22(1):35-43.
Breast cancer 1, early onset (BRCA1) is a vital DNA repair gene, and the single nucleotide polymorphisms (SNPs) of this gene have been studied in diverse cancer types. In this study, we investigated the association between eight common BRCA1 functional SNPs and the risk of differentiated thyroid carcinoma (DTC).
This cancer center-based case–control study included 303 DTC cases and 511 controls. A polymerase chain reaction-based restriction fragment length polymorphism assay was performed for genotyping. Unconditional logistical regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) in single-SNP analysis and haplotype analysis.
A decreased risk of DTC was found for the A1988G heterozygous AG genotype (adjusted OR=0.63, 95% CI: 0.45–0.87, Bonferroni-adjusted p-value=0.036). AATAATA and ATAA haplotypes that carry C33420T variant allele were associated with reduced papillary thyroid cancer risk (adjusted OR=0.52, 95% CI: 0.33–0.84; adjusted OR=0.62, 95% CI: 0.40–0.95, respectively). Also, having a combination of ≥3 favorable genotypes was associated with a DTC risk reduction (adjusted OR=0.69, 95% CI: 0.50–0.95). The A31875G AG/GG genotype was associated with a 69% reduced risk of multifocal primary tumor in DTC patients (adjusted OR=0.31, 95% CI: 0.12–0.81).
BRCA1 genetic polymorphisms may play a role in DTC risk, while the possible associations warrant confirmation in independent studies.
PMCID: PMC3263304  PMID: 22136207
25.  Assembly And Initial Characterization Of A Panel Of 85 Genomically Validated Cell Lines From Diverse Head And Neck Tumor Sites 
Human cell lines are useful for studying cancer biology and pre-clinically modeling cancer therapy, but can be misidentified and cross contamination is unfortunately common. The purpose of this study was to develop a panel of validated head and neck cell lines representing the spectrum of tissue sites and histologies that could be used for studying the molecular, genetic, and phenotypic diversity of head and neck cancer.
A panel of 122 clinically and phenotypically diverse head and neck cell lines from head and neck squamous cell carcinoma (HNSCC), thyroid cancer, cutaneous squamous cell carcinoma, adenoid cystic carcinoma, oral leukoplakia, immortalized primary keratinocytes, and normal epithelium, was assembled from the collections of several individuals and institutions. Authenticity was verified by performing short tandem repeat (STR) analysis. Human papillomavirus (HPV) status and cell morphology were also determined.
Eighty-five of the 122 cell lines had unique genetic profiles. HPV-16 DNA was detected in 2 cell lines. These 85 cell lines included cell lines from the major head and neck primary tumor sites, and close examination demonstrates a wide range of in vitro phenotypes.
This panel of 85 genomically validated head and neck cell lines represents a valuable resource for the head and neck cancer research community that can help advance understanding of the disease by providing a standard reference for cell lines that can be utilized for biological as well as preclinical studies.
PMCID: PMC3229662  PMID: 21868764
head and neck cancer; short tandem repeat (STR) profiling; head and neck squamous cell carcinoma; thyroid cancer; human papillomavirus

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