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1.  Associations of PI3KR1 and mTOR Polymorphisms with Esophageal Squamous Cell Carcinoma Risk and Gene-Environment Interactions in Eastern Chinese Populations 
Scientific Reports  2015;5:8250.
Single nucleotide polymorphisms (SNPs) in the PI3K/PTEN/AKT/mTOR signaling pathway may contribute to carcinogenesis. We genotyped five potentially functional PIK3R1 and mTOR SNPs in 1116 esophageal squamous cell cancer (ESCC) patients and 1117 cancer-free controls to assess their associations with ESCC risk. We observed no association with ESCC risk for any of the selected SNPs. However, the combined analysis of these SNPs revealed that subjects with one-to-three risk genotypes had an increased ESCC risk. Stratified analysis by body mass index (BMI) found that ESCC risk was significantly associated with each of three mTOR SNPs among subjects with BMI < 25.0. Specifically, we found that subjects carrying ≥ 1 risk genotypes had significantly increased ESCC risk, particularly for males, ever-smokers, ever-drinkers, and those with age > 60, or BMI < 25.0. Moreover, three mTOR haplotypes were associated with an increase in ESCC risk. Our meta-analysis of mTOR rs2295080 and cancer risk provided further evidence that mTOR SNPs might modulate cancer susceptibility. In this population, such risk effects might be modified by other risk factors, highlighting the importance of gene-environment interaction in esophageal carcinogenesis. Additional, larger studies are warranted to validate our findings.
PMCID: PMC4318264  PMID: 25654238
2.  Potentially functional variants of p14 ARF are associated with HPV-positive oropharyngeal cancer patients and survival after definitive chemoradiotherapy 
Carcinogenesis  2013;35(1):62-68.
Since p14 ARF and human papillomavirus (HPV) 16 E6/E7 oncoproteins are important regulators participating in the p53/Rb pathways, genetic variations of p14 ARF may modify tumor HPV16 status and survival of HPV16-positive squamous cell carcinoma of the oropharynx (SCCOP) patients. We determined tumor HPV16 status and expression of p14/p53 and genotyped p14 ARF-rs3731217 and -rs3088440 polymorphisms in 552 incident SCCOP patients. We found that patients having variant genotypes for each p14 ARF polymorphism were approximately two or three times as likely to have HPV16-positive tumors compared with patients with corresponding common homozygous genotype, and such an association was particularly pronounced in patients with variant genotypes of both polymorphisms. After definitive chemoradiotherapy, patients having p14 ARF rs3731217 TG/GG variant genotypes had significantly better overall, disease-specific and disease-free survival than those having TT genotype, respectively. Multivariable analysis found that patients with p14 ARF-rs3731217 TT genotype had an ~7-, 11- and 3-fold increased risk for death overall, death due to SCCOP and recurrence than those with TG/GG variant genotypes, respectively. Furthermore, such significantly prognostic effect was also found when survival analysis was limited to HPV16-positive patients. Additionally, potentially functional relevance of the two variants was characterized to explore the genotype–phenotype correlation. Our findings indicate p14 ARF variants may predict tumor HPV16-positive SCCOP patients and survival.
PMCID: PMC3871940  PMID: 24104554
3.  Association of marijuana smoking with oropharyngeal and oral tongue cancers: Pooled analysis from the INHANCE Consortium 
The incidence of oropharyngeal and oral tongue cancers have increased over the last twenty years which parallels increased use of marijuana among individuals born after 1950.
Pooled analysis of individual-level data from nine case-control studies from the U.S. and Latin America in the INHANCE consortium. Self-reported information on marijuana smoking, demographic, and behavioral factors was obtained from 1,921 oropharyngeal cases, 356 oral tongue cases, and 7,639 controls.
Compared with never marijuana smokers, ever marijuana smokers had an elevated risk of oropharyngeal (adjusted odds ratio [aOR]: 1.24; 95% confidence interval [CI]: 1.06, 1.47) and a reduced risk of oral tongue cancer (aOR: 0.47; 95% CI: 0.29, 0.75). The risk of oropharyngeal cancer remained elevated among never tobacco and alcohol users. The risk of oral tongue cancer decreased with increasing frequency (ptrend=0.005), duration (ptrend=0.002), and joint-years of marijuana use (ptrend=0.004), and was reduced among never users tobacco and alcohol users. Sensitivity analysis adjusting for potential confounding by HPV exposure attenuated the association of marijuana use with oropharyngeal cancer (aOR: 0.99; 95% CI: 0.71, 1.25), but had no effect on the oral tongue cancer association.
These results suggest that the association of marijuana use with Head and Neck Carcinoma may differ by tumor site.
The associations of marijuana use with oropharyngeal and oral tongue cancer are consistent with both possible pro- and anti-carcinogenic effects of cannabinoids. Additional work is needed to rule out various sources of bias, including residual confounding by HPV infection and misclassification of marijuana exposure.
PMCID: PMC3947141  PMID: 24351902
marijuana; oropharynx; oral tongue; INHANCE; human papillomavirus
4.  A recessive variant of XRCC4 predisposes to non-BRCA1/2 breast cancer in chinese women and impairs the DNA damage response via dysregulated nuclear localization 
Oncotarget  2014;5(23):12218-12232.
XRCC4 plays a crucial role in the non-homologous end joining pathway that maintains genome stability. In this two-stage case-control study with 1,764 non-BRCA1/2 breast cancer patients and 1,623 cancer-free controls, we investigated the contribution of genetic variants of XRCC4 to breast cancer susceptibility in Chinese women. We identified a recessive missense variant, rs3734091 (c.739G>T, p.Ala247Ser), of XRCC4 that was significantly associated with an increased risk of breast cancer (odds ratio [OR] = 3.92, P = 0.007), particularly with the risk of developing triple-negative breast cancer (OR = 18.65, P < 0.0001). This p.Ala247Ser variant disturbed the nuclear localization of XRCC4 in cells homozygous for the rs3734091-T allele but not in heterozygous cells at both the cellular and tissue levels. In heterozygous cells, wild-type XRCC4 facilitated the nuclear localization of the XRCC4A247S mutant, thus compensating for the impaired localization of XRCC4A247S. This provided a biological mechanism by which rs3734091 conferred an increased susceptibility to non-BRCA1/2 breast cancer exclusively under a recessive model. Further functional analyses revealed that p.Ala247Ser impaired the DNA damage repair capacity and ultimately perturbed genomic stability. Taken together, our findings document the role of XRCC4 in non-BRCA1/2 breast cancer predisposition and reveal its underlying biological mechanism of action.
PMCID: PMC4322983  PMID: 25360583
XRCC4; homozygous variant; nuclear localization; susceptibility; breast cancer
5.  Telomere length in peripheral blood lymphocytes contributes to the development of HPV-associated oropharyngeal carcinoma 
Cancer research  2013;73(19):5996-6003.
Sexual transmission of human papillomavirus, particularly HPV16, has been associated with an increasing incidence of oropharyngeal squamous cell carcinoma (OPC). Telomere shortening results in chromosomal instability, subsequently leading to cancer development. Given that HPV16 can affect telomerase activity and telomere length (TL), we conjectured that TL in peripheral blood lymphocytes (PBLs) may affect the risk of HPV16-associated OPC and tumor HPV16 status in patients. TL in PBLs and HPV16 serological status were measured in peripheral blood samples in 188 patients with OPC, 137 patients with oral cavity cancer (OCC) and 335 controls of non-Hispanic whites. Tumor HPV status was determined in 349 OPC cases. Odds ratios and 95% confidence intervals were calculated in univariate and multivariable logistic regression models. Overall, compared with long TL, short TL was associated significantly with a moderately increased risk of OPC but no increased risk of OCC. When we stratified the data by HPV16 serological status, using long TL and HPV16 seronegativity as the reference group, we found that the risk associated with HPV16 seropositivity was higher among OPC patients with short TL. Notably, such risk was particularly pronounced in never smokers, never drinkers and those >50 years of age. Furthermore, short TL was also associated significantly with tumor HPV-positive OPC. Together, our findings suggest that TL in PBLs may be associated with higher risk of HPV16-associated OPC and tumor HPV16 status, particularly in certain patient subgroups. Larger studies are needed to validate these findings.
PMCID: PMC3790860  PMID: 23928994
telomere length; HPV; molecular epidemiology; oropharyngeal cancer
6.  Differences in Imaging Characteristics of HPV-Positive and HPV-Negative Oropharyngeal Cancers: A Blinded Matched-Pair Analysis 
Human papillomavirus–positive oropharyngeal cancers typically have younger age of onset, limited tobacco exposure, and more favorable prognosis than HPV-negative oropharyngeal cancers. We assessed whether HPV-positive and HPV-negative oropharyngeal cancers have consistent differences in pretreatment imaging characteristics.
A retrospective review of 136 pretreatment CT examinations of paired HPV-positive and HPV-negative oropharyngeal cancers matched for T stage, tumor subsite, and smoking status was performed with the reviewing radiologist blinded to HPV status and clinical stage. Demographic/clinical characteristics and imaging characteristics of primary lesions and metastatic nodal disease were compared by use of Fisher exact testing. The McNemar χ2 test was used for the matched-pair analysis.
By imaging, HPV-negative tumors were more likely to demonstrate invasion of adjacent muscle (26% versus 6%, P = .013). HPV-positive primary tumors were more likely to be enhancing and exophytic with well-defined borders, whereas HPV-negative primary tumors were more likely to be isoattenuated and demonstrate ill-defined borders, though these results were not statistically significant. HPV-positive tumors were more likely to demonstrate cystic nodal metastases than HPV-negative tumors (36% versus 9%, P = .002).
In this matched and blinded analysis of the imaging differences between HPV-positive and HPV-negative oropharyngeal cancers, HPV-positive carcinomas often had primary lesions with well-defined borders and cystic nodal metastases, whereas HPV-negative primaries more often had poorly defined borders and invasion of adjacent muscle.
PMCID: PMC3951375  PMID: 23660291
7.  Identification of prohibitin and prohibiton as novel factors binding to the p53 induced gene 3 (PIG3) promoter (TGYCC)15 motif 
The promoter of p53 induced gene 3 (PIG3) contains a variable number of tandem repeats (VNTRs) of pentanucleotides (TGYCC)n that is known as a p53 binding site. In this study, we investigated whether other potential molecules could bind to this PIG3 promoter (TGYCC)n motif. Ligand-chromatography combined with liquid chromatography–tandem mass spectrometry analyses indicated direct interactions of prohibitin and/or prohibiton with the (TGYCC)15 motif, which was confirmed by electrophoretic mobility shift assay and super-gel shift analysis with anti-prohibitin and anti-prohibiton antibodies. Using the chromatin immunopercipipation assay, we further demonstrated that prohibitin and prohibiton associated with the (TGYCC)15 motif in vivo regardless of the p53 status and apoptotic stress. We also found that prohibitin and prohibiton up-regulated PIG3 transcription independent of p53, although p53 obviously enhanced this process, and that the knock-down of prohibitin and prohibiton inhibited camptothecin-induced apoptosis. Taken together, our findings suggest that prohibitin and prohibiton contribute to PIG3-mediated apoptosis by binding to the PIG3 promoter (TGYCC)15 motif.
PMCID: PMC4155496  PMID: 24388982
PIG3; Prohibitin; Prohibiton; (TGYCC)n motif
8.  Genetic variants of the LIN28B gene predict severe radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy 
LIN28 is an RNA-binding protein that not only plays key roles in multiple cellular developmental processes and tumorigenesis, but also is involved in tissue inflammatory response. However, no published study has investigated associations between genetic variants in LIN28 and radiation-induced pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) treated with definitive radiation therapy.
We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) of LIN28A (rs11247946 T>C, rs3811464 C>T, rs11581746 T>C, and rs12728900 G>A), and LIN28B (rs314280 A>G, rs12194974 G>A, rs17065417 A>C and rs314276 C>A) in 362 patients with NSCLC, who received definitive radio (chemo) therapy. The associations between RP risk and genotypes were assessed by hazards ratio (HR) in Cox proportional hazards regression analysis with time to event considered with and without adjustment for potential confounders.
Multivariate analyses found that patients carrying LIN28B rs314280 AG and AA/AG or rs314276 AC and AA/AC genotypes had a higher risk of grade ≥3 RP (for rs314280 AG and AA/AG versus GG, adjusted HR= 2.97 and 2.23, 95% CI, 1.32–6.72 and 1.01–4.94, P = 0.009 and 0.048, respectively; for rs314276 AC and AA/AC versus CC, adjusted HR = 2.30 and 2.00, 95% CI, 1.24–4.28 and 1.11–3.62, and P = 0.008 and 0.022, respectively). Further stratified analyses showed a more profound risk in the subgroups of the age <65 years subjects, males, stage III/IV, ever smokers and MLD ≥19.0 Gy.
Genetic variants of LIN28B, but not LIN28A, may be biomarkers for susceptibility to severe RP in NSCLC patients. Large, prospective studies are needed to confirm our findings.
PMCID: PMC4155498  PMID: 24780874
LIN28; polymorphisms; inflammation; Hazards ratio; Non–small cell lung cancer; radiation pneumonitis
9.  Cigarette, Cigar, and Pipe Smoking and the Risk of Head and Neck Cancers: Pooled Analysis in the International Head and Neck Cancer Epidemiology Consortium 
American Journal of Epidemiology  2013;178(5):679-690.
Cigar and pipe smoking are considered risk factors for head and neck cancers, but the magnitude of effect estimates for these products has been imprecisely estimated. By using pooled data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium (comprising 13,935 cases and 18,691 controls in 19 studies from 1981 to 2007), we applied hierarchical logistic regression to more precisely estimate odds ratios and 95% confidence intervals for cigarette, cigar, and pipe smoking separately, compared with reference groups of those who had never smoked each single product. Odds ratios for cigar and pipe smoking were stratified by ever cigarette smoking. We also considered effect estimates of smoking a single product exclusively versus never having smoked any product (reference group). Among never cigarette smokers, the odds ratio for ever cigar smoking was 2.54 (95% confidence interval (CI): 1.93, 3.34), and the odds ratio for ever pipe smoking was 2.08 (95% CI: 1.55, 2.81). These odds ratios increased with increasing frequency and duration of smoking (Ptrend ≤ 0.0001). Odds ratios for cigar and pipe smoking were not elevated among ever cigarette smokers. Head and neck cancer risk was elevated for those who reported exclusive cigar smoking (odds ratio = 3.49, 95% CI: 2.58, 4.73) or exclusive pipe smoking (odds ratio = 3.71, 95% CI: 2.59, 5.33). These results suggest that cigar and pipe smoking are independently associated with increased risk of head and neck cancers.
PMCID: PMC3755640  PMID: 23817919
head and neck neoplasms; smoking
10.  Variants in nucleotide excision repair core genes and susceptibility to recurrence of squamous cell carcinoma of the oropharynx 
Genetically determined capacity for NER may modulate both cancer risk and prognosis. Thus, we evaluated associations of seven selected variants in the NER core genes with recurrence risk in 658 SCCOP patients treated principally by radiation. The seven polymorphisms in the core NER genes (XPC-rs2228000, XPC-rs2228001, XPD-rs1799793, XPD-rs13181, XPG-rs17655, ERCC1-rs3212986, and XPA-rs1800975) were genotyped using PCR-RFLP method and log-rank test and multivariable Cox models were used to evaluate the associations in both dominant and recessive genetic models. In a dominant model, we found that polymorphisms of XPC-rs2228000, XPD-rs1799793, and XPG-rs17655 were significantly associated with disease-free survival (log-rank, P = 0.014; P = 0.00008; and P = 0.0007, respectively), and these polymorphisms were significantly associated with recurrence risk of SCCOP (HR = 1.6, 95% CI, 1.1–2.3 for XPC-rs2228000; HR = 0.4, 95%, 0.3–0.6 for XPD-rs1799793; and HR = 0.5, 95% CI, 0.4–0.8 for XPG-rs17655) after multivariable adjustment. Moreover, the borderline significant or significant associations were also found for these three polymorphisms in HPV16/18-positive SCCOP patients (HR= 1.6, 95% CI, 1.0–4.1 for XPC-rs2228000; HR = 0.2, 95%, 0.1–0.5 for XPD-rs1799793; and HR = 0.1, 95% CI, 0.0–0.9 for XPG-rs17655). However, similarly significant associations were not found for these polymorphisms in a recessive model. These findings suggest that polymorphisms of XPC-rs2228000, XPD-rs1799793, and XPG-rs17655 in the NER core genes may contribute to recurrence risk of SCCOP, particularly HPV-positive SCCOP, in a dominant but not in a recessive model. However, validation of these results is warranted.
PMCID: PMC3663873  PMID: 23335232
genetic variants; nucleotide excision repair; human papillomavirus; oropharyngeal cancer; recurrence; DNA repair
11.  Genome-wide association studies identify several new loci associated with pigmentation traits and skin cancer risk in European Americans 
Human Molecular Genetics  2013;22(14):2948-2959.
Aiming to identify novel genetic loci for pigmentation and skin cancer, we conducted a series of genome-wide association studies on hair color, eye color, number of sunburns, tanning ability and number of non-melanoma skin cancers (NMSCs) among 10 183 European Americans in the discovery stage and 4504 European Americans in the replication stage (for eye color, 3871 males in the discovery stage and 2496 males in the replication stage). We targeted novel chromosome regions besides the known ones for replication. As a result, we identified a new region downstream of the EDNRB gene on 13q22 associated with hair color and the strongest association was the single-nucleotide polymorphism (SNP) rs975739 (P = 2.4 × 10−14; P = 5.4 × 10−9 in the discovery set and P = 1.2 × 10−6 in the replication set). Using blue, intermediate (including green) and brown eye colors as co-dominant outcomes, we identified the SNP rs3002288 in VASH2 on 1q32.3 associated with brown eye (P = 7.0 × 10−8; P = 5.3 × 10−5 in the discovery set and P = 0.02 in the replication set). Additionally, we identified a significant interaction between the SNPs rs7173419 and rs12913832 in the OCA2 gene region on brown eye color (P-value for interaction = 3.8 × 10−3). As for the number of NMSCs, we identified two independent SNPs on chr6 and one SNP on chromosome 14: rs12203592 in IRF4 (P = 7.2 × 10−14; P = 1.8 × 10−8 in the discovery set and P = 6.7 × 10−7 in the replication set), rs12202284 between IRF4 and EXOC2 (P = 5.0 × 10−8; P = 6.6 × 10−7 in the discovery set and P = 3.0 × 10−3 in the replication set) and rs8015138 upstream of GNG2 (P = 6.6 × 10−8; P = 5.3 × 10−7 in the discovery set and P = 0.01 in the replication set).
PMCID: PMC3690971  PMID: 23548203
12.  Incidence and Pattern of Second Primary Malignancies in Patients with Index Oropharyngeal Cancers versus Index Non-oropharyngeal Head and Neck Cancers 
Cancer  2013;119(14):2593-2601.
A recent review of the SEER registry suggested that patients with index squamous cell carcinoma (SCC) of the oropharynx (SCCOP) are less likely to develop second primary malignancies (SPM) than patients with index SCC of non-oropharyngeal sites (oral cavity, larynx, hypopharynx). The purpose of this study was to determine the impact of index primary tumor site on SPM risk and explore factors potentially affecting this risk within a large prospectively accrued cohort of patients with index SCC of the head and neck (SCCHN).
A cohort of 2230 patients with incident SCCHN was reviewed for development of SPM. Kaplan-Meier analysis, log-rank testing, and Cox proportional hazards models were used to detect the impact of various factors, including index tumor site, on SPM risk.
The SPM rate was lower for patients with index SCCOP than for patients with index non-oropharyngeal cancer (P<.001). Among SCCOP patients, former-smokers had a 50% greater risk of SPM and current-smokers had a 100% greater risk of SPM than never-smokers (Ptrend=.008). Among SCCOP patients, those with classic SCCHN phenotype had SPM risk similar to that of patients with index non-oropharyngeal cancers; those with typical HPV phenotype had very low SPM risk. SPM most commonly occurred at non-tobacco-related sites in patients with index SCCOP and at tobacco-related sites in patients with index non-oropharyngeal cancers.
In patients with SCCHN, index cancer site and smoking status affect the risk and distribution of SPM.
PMCID: PMC3909962  PMID: 23605777
Head and neck neoplasms; second primary malignancy; smoking; oropharyngeal cancer; oral cancer; laryngeal cancer; human papillomavirus
13.  Obesity-related genetic variants, human pigmentation, and risk of melanoma 
Human genetics  2013;132(7):793-801.
Previous biological studies showed evidence of a genetic link between obesity and pigmentation in both animal models and humans. Our study investigated the individual and joint associations between obesity-related single nucleotide polymorphisms (SNPs) and both human pigmentation and risk of melanoma. Eight obesity-related SNPs in the FTO, MAP2K5, NEGR1, FLJ35779, ETV5, CADM2, and NUDT3 genes were nominally significantly associated with hair color among 5,876 individuals of European ancestry. The genetic score combining 35 independent obesity-risk loci was significantly associated with darker hair color (beta-coefficient per ten alleles=0.12, P-value=4 10−5). However, single SNPs or genetic scores showed non-significant association with tanning ability. We further examined the SNPs at the FTO locus for their associations with pigmentation and risk of melanoma. Among the 783 SNPs in the FTO gene with imputation R-square quality metric >0.8 using the 1000 genome data set, ten and three independent SNPs were significantly associated with hair color and tanning ability respectively. Moreover, five independent FTO SNPs showed nominally significant association with risk of melanoma in 1,804 cases and 1,026 controls. But none of them was associated with obesity or in linkage disequilibrium with obesity-related variants. FTO locus may confer variation in human pigmentation and risk of melanoma, which may be independent of its effect on obesity.
PMCID: PMC3683389  PMID: 23539184
obesity; pigmentation; melanoma; genetic association; FTO gene
14.  Genetic variants in p53-related genes confer susceptibility to second primary malignancy in patients with index squamous cell carcinoma of head and neck 
Carcinogenesis  2013;34(7):1551-1557.
Because of their important roles in mediating the stabilization and expression of p53, we hypothesized that high-risk genotypes of polymorphisms in p53-related genes, including p53, p73, p14ARF, MDM2 and MDM4, may be associated with an increased risk of second primary malignancy (SPM) after index squamous cell carcinoma of the head and neck (SCCHN). We analyzed data from a cohort of 1283 patients with index SCCHN who were recruited between 1995 and 2007 at MD Anderson Cancer Center and followed for SPM development. Patients were genotyped for nine polymorphisms of p53-related genes. A log-rank test and Cox models were used to compare SPM-free survival and risk. Our results demonstrated that each p53-related polymorphism had a moderate effect on increased SPM risk, but when we combined risk genotypes of these nine polymorphisms together, we found that SPM-free survival was significantly shorter among risk groups with a greater number of combined risk genotypes. SPM risk increased with increasing number of risk genotypes (P < 0.0001 for trend). Compared with the low-risk group (0–3 combined risk genotypes), both the medium-risk (4–5 combined risk genotypes) and high-risk (6–9 combined risk genotypes) groups had significantly increased SPM risk [hazard ratio (HR): 1.6; 95% confidence interval (CI): 1.0–2.6 and HR: 3.0; 95% CI: 1.8–5.0, respectively]. Moreover, such significant associations were even higher in several subgroups. Our findings suggest that combined risk genotypes of p53-related genes may jointly modify SPM risk, especially in patients who are smokers and those with index non-oropharyngeal cancers. However, larger studies are needed to validate our findings.
PMCID: PMC3697893  PMID: 23508638
15.  Pri-miR-124 rs531564 and pri-miR-34b/c rs4938723 Polymorphisms Are Associated with Decreased Risk of Esophageal Squamous Cell Carcinoma in Chinese Populations 
PLoS ONE  2014;9(6):e100055.
MicroRNAs are a new class of small non-protein-coding RNAs that sometimes function as tumor suppressors or oncogenes. Aberrant expression and structural alteration of microRNAs have been reported to be involved in tumorigenesis and cancer development. Recently, rs531564/pri-miR-124-1, rs4938723/pri-miR-34b/c, rs7372209/pri-miR-26a-1, rs895819/pre-miR-27a, and rs11134527/pri-miR-218 were reported to be associated with risks of various cancers. In order to evaluate the relationship of these SNPs and esophageal squamous cell carcinoma (ESCC) risk, we conducted a case-control study with 1109 ESCC patients and 1275 control subjects to examine the potential association of these pri/pre-miRNA polymorphisms with ESCC susceptibility. As a result, two SNPs were associated with a significant risk of ESCC. We found that the GG genotype of pri-miR-124-1 rs531564 was associated to a significantly decreased risk of ESCC comparing with the CC/CG genotypes (p = 0.005; OR = 0.61, 95% CI = 0.43–0.86). In addition, the CC genotype of pri-miR-34b/c rs4938723 was associated with a significant decreased risk of ESCC (CC VS. TT/TC: p = 0.007, OR = 0.82, 95% CI = 0.71–0.95) in Chinese population. The present study provides the first evidence that pri-miR-124-1 rs531564 and pri-miR-34 rs4938723 were associated with the risk of ESCC in Chinese population.
PMCID: PMC4063769  PMID: 24945256
16.  Low risk of second primary malignancies among never smokers with human papillomavirus-associated index oropharyngeal cancers 
Head & neck  2012;35(6):794-799.
Among index oropharyngeal cancer patients, second primary malignancies (SPMs) may be less common in human papillomavirus (HPV)-associated tumors than HPV-negative tumors. Further modification of these SPM risks by smoking has not been reported.
SPM outcomes of 356 incident oropharyngeal cancer patients were analyzed using Cox proportional hazards and Kaplan-Meier models. SPM risk and SPM-free survival were compared in HPV-seronegative patients, HPV-seropositive never smokers, and HPV-seropositive ever smokers.
HPV-seropositive patients had a lower 5-year SPM rate than HPV-seronegative patients (5.6% vs. 14.6%, p=0.051). Compared to HPV-seronegative patients, HPV-seropositive never smokers had a 73% reduced SPM risk, and HPV-seropositive ever smokers had a 27% reduced SPM risk (trend p=0.028). While HPV-seronegative patients had SPMs in traditional locations, 70% of SPMs among HPV-seropositive patients were outside typical tobacco-related sites.
HPV serologic status and smoking may stratify patients with index oropharyngeal cancers in terms of risk and location of SPMs.
PMCID: PMC3459137  PMID: 22711172
Head and neck neoplasms; second primary; smoking; oropharyngeal cancer; human papillomavirus
17.  Variants in melanocortin 1 receptor gene contribute to risk of melanoma – a direct sequencing analysis in a Texas population 
Pigment cell & melanoma research  2013;26(3):10.1111/pcmr.12070.
In this study, we directly sequenced the Melanocortin 1 Receptor (MC1R) gene in 2,212 individuals to detect all variants and assessed their associations with cutaneous melanoma (CM) risk in a hospital-based study of 1,106 CM patients and 1,106 control subjects. Of 61 MC1R variants identified, 16 rare variants have not been previously reported by others; three MC1R variants were associated with a significant CM risk [c.451C>T (OR = 1.78, 95% CI = 1.44–2.20), c.478C>T (OR = 1.31, 95% CI = 1.05–1.63), and c.880G>C (OR = 1.69, 95% CI = 1.15–2.48)]; and two with borderline CM risk [c.942A>G (OR =1.23, 95% CI =1.00–1.51, and c.274G>A (OR = 1.23,95% CI = 0.99–1.53)] under a dominant model. When combined these five MC1R variants for cumulative effect analysis, we found that subjects with an increased number of variant genotypes from any of these five variants had significantly increased risk of CM with ORs of 1.68 (95% CI = 1.39–2.04), 1.61 (95% CI = 1.27–2.04), and 2.64 (95% CI = 1.72–4.05) for one, two, and three or more variant genotypes, respectively (trend test: P <0.001). Further haplotype and diplotype analyses based on the above-mentioned five SNPs suggested that the c.451T allele contributed to the high risk of CM and that the five variants may have joint effects on the risk of CM. Additional analysis suggests that the three most significant SNPs may be the molecular mechanisms underlying the known risk factors of the colors of the eyes, skin and hair in this study population. In conclusion, our study provided confirmatory evidence that both common and rare variants in the MC1R coding region may be biomarkers for susceptibility to CM in US populations.
PMCID: PMC3721512  PMID: 23360207
melanocortin 1 receptor gene; direct sequencing; interaction; melanoma; case-control
18.  Association between putative functional variants in the PSMB9 gene and risk of melanoma - re-analysis of published melanoma genome-wide association studies 
Pigment cell & melanoma research  2013;26(3):10.1111/pcmr.12069.
To mine possibly hidden causal single nucleotide polymorphisms (SNPs) in the etiology of melanoma, we investigated the association of SNPs in 76 M/G1 transition genes with melanoma risk using our published genome-wide association study (GWAS) dataset with 1804 melanoma cases and 1,026 cancer-free controls. We found multiple SNPs with P < 0.01 and performed validation studies for 18 putative functional SNPs in PSMB9 in other two GWAS datasets. Two SNPs (rs1351383 and rs2127675) were associated with melanoma risk in the GenoMEL dataset (P = 0.013 and 0.004, respectively), but failed validation in the Australia dataset. Genotype-phenotype analysis revealed these two SNPs were significantly correlated with mRNA expression levels of PSMB9. Further experiments revealed that the promoter SNP rs2071480, which is in high LD with rs1351383 and rs2127675, involved in influencing transcription factor binding and gene expression. Taken together, our data suggested that functional variants in PSMB9 may contribute to melanoma susceptibility.
PMCID: PMC3721546  PMID: 23360169
GWAS; Cell cycle; PSMB9; Polymorphism; melanoma
19.  Significance of MDM2 and P14ARF polymorphisms in susceptibility to differentiated thyroid carcinoma 
Surgery  2012;153(5):711-717.
Murine double minute 2 (MDM2) oncoprotein and p14ARF tumor suppressor play pivotal roles in regulating p53 and function in the MAPK pathway, which is frequently mutated in differentiated thyroid carcinoma (DTC). We hypothesized that functional polymorphisms in the promoters of MDM2 and p14ARF contribute to the inter-individual difference in predisposition to DTC.
MDM2-rs2279744, MDM2-rs937283, p14ARF-rs3731217, and p14ARF-rs3088440 were genotyped in 303 patients with DTC and 511 cancer-free controls. Multivariate logistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs).
MDM2-rs2279744 and p14ARF-rs3731217 were associated with a significantly increased risk of DTC (MDM2-rs2279744: TT vs. TG/GG, OR = 1.5, 95% CI, 1.1–2.0; p14ARF-rs3731217: TG/GG vs. TT, OR = 1.7, 95% CI, 1.2–2.3). No association was found for MDM2-rs937283 or p14ARF-rs3088440. Individuals carrying 3–4 risk genotypes of MDM2 and p14ARF had 2.2 times (95% CI, 1.4–3.5) the DTC risk of individuals carrying 0–1 risk genotypes (Ptrend = 0.021). The combined effect of MDM2 and p14ARF on DTC risk was confined to young subjects (≤45 years), non-smokers, non-drinkers, and subjects with a first-degree family history of cancer. These associations were quite similar in strength when cases were restricted to those with papillary thyroid cancer.
Our results suggest that polymorphisms of MDM2 and p14ARF contribute to the inter-individual difference in susceptibility to DTC, either alone or more likely jointly. The observed associations warrant further confirmation in independent studies.
PMCID: PMC3610784  PMID: 23218882
papillary thyroid carcinoma; p53 pathway; case-control study
20.  Gene variants in angiogenesis and lymphangiogenesis and cutaneous melanoma progression 
Angiogenesis and lymphangiogenesis are important in the progression of melanoma. We investigated associations between genetic variants in these pathways with sentinel lymph node (SLN) metastasis and mortality in two independent series of melanoma patients.
Participants at Moffitt Cancer Center were 552 patients, all Caucasian, with primary cutaneous melanoma referred for SLN biopsy. A total of 177 patients had SLN metastasis, among whom 60 died from melanoma. Associations between 238 SNPs in 26 genes and SLN metastasis were estimated as odds ratios and 95%CI using logistic regression. Competing risk regression was used to estimate hazard ratios and 95%CI for each SNP and melanoma-specific mortality. We attempted to replicate significant findings using data from a genome-wide association study comprising 1,115 melanoma patients, who were referred for SLN biopsy from MD Anderson Cancer Center (MDACC), among whom 189 patients had SLN metastasis and 92 patients died from melanoma.
In the Moffitt dataset, we observed significant associations in 18 SNPs with SLN metastasis and 17 SNPs with mortality. Multiple SNPs in COL18A1, EGFR, FLT1, IL10, PDGFD, PIK3CA and TLR3 were associated with risk of SLN metastasis and/or patient mortality. The MDACC data set replicated an association between mortality and rs2220377 in PDGFD. Further, in a meta-analysis, three additional SNPs were significantly associated with SLN metastasis (EGFR rs723526 and TLR3 rs3775292) and melanoma specific death (TLR3 rs7668666).
These findings suggest that genetic variation in angiogenesis and lymphangiogenesis contributes to regional nodal metastasis and progression of melanoma.
Additional research attempting to replicate these results is warranted.
PMCID: PMC3708315  PMID: 23462921
SNP; lymph/angiogenesis; melanoma; sentinel lymph node
21.  Gastric Cancer: Molecular and Clinical Dimensions 
Nature reviews. Clinical oncology  2013;10(11):643-655.
Gastric cancer (GC) imposes a significant health burden around the globe despite its declining incidence. GC is often diagnosed in advanced stages and carries a poor prognosis. In depth understanding of molecular underpinnings of GC has lagged behind many other cancers of its magnitude, as a result our knowledge base for identifying germline susceptibility traits for risk and somatic drivers of progression (to identify novel therapeutic targets) is limited. A few germline (PLCE1) and somatic (ERBB2, ERBB3, PTEN, PI3K/AKT/mTOR, FGF, TP53, CDH1, and c-MET) alterations are emerging and some are being pursued in the clinic. Novel somatic gene targets, Arid1a, FAT4, and MLL/MLL3 are of interest. Clinically, variations in the therapeutic approaches for localized GC are evident by geographic regions. These are driven by preferences for the adjunctive strategies and the extent of surgery coupled with philosophical divides. However, there is a greater uniformity in approaches to metastatic cancer, an incurable condition. Having realized only modest successes, the momentum is building for carrying out more phase 3 comparative trials and some are using biomarker-based patient selection. Overall, rapid progress in biotechnology is improving our molecular understanding and can help with new drug discovery. The future prospects are excellent for defining biomarker-based subsets of patients and application of specific therapeutics. However, many challenges remain to be tackled. Here we review representative molecular and clinical dimensions of GC.
PMCID: PMC3927982  PMID: 24061039
22.  Pre-microRNA variants predict HPV16-positive tumors and survival in patients with squamous cell carcinoma of the oropharynx 
Cancer letters  2012;330(2):233-240.
To identify non-tumor biomarkers for prediction of tumor HPV status and prognosis of patients with squamous cell carcinoma of the oropharynx (SCCOP), we evaluated the association of single nucleotide polymorphisms (SNPs) in pre-miRNAs with HPV16 status and survival for SCCOP patients. We analyzed HPV16 status in tumor specimens and genotyped four SNPs in pre-miRNAs (hsa-mir-146a rs2910164 G>C, hsa-mir-149 rs2292832 G>T, hsa-mir-196a2 rs11614913 C>T, and hsa-mir-499 rs3746444 A>G) in 309 SCCOP patients. Unconditional logistic regression models were used for calculation of odds ratio (OR) and 95% confidence intervals (CIs), and Kaplan-Meier analysis and Cox proportional hazards regression were used to evaluate associations. We found that statistically significant associations with HPV16-positive SCCOP and survival were found for hsa-mir-146a rs2910164 and hsa-mir-196a2 rs11614913, while such similar associations were not observed for hsa-mir-149 rs2292832 and hsa-mir499 rs3746444. Compared with those with corresponding hsa-mir-146a CG/CC and has-mir-196a2 CC genotypes, the hsa-mir-146a GG and hsa-mir-196a2 CT/TT wild-type genotypes were significantly associated with HPV16-positive tumor status (adjusted OR, 2.4; 95% CI, 1.4–4.1 and adjusted OR, 2.1, 95% CI, 1.2–3.6), respectively. Patients having hsa-mir-146a rs2910164 GG and hsa-mir196a2 rs11614913 CT/TT genotypes had significantly better overall, disease-specific, and disease-free survival compared with those having the corresponding CG/CC and CC genotypes, respectively. Furthermore, these genotypes were significantly associated with reduced risk of overall death, death owing to disease, and recurrence after adjustment for important prognostic confounders including HPV status, smoking, and stage. Our findings indicate pre-miRNA polymorphisms may predict tumor HPV16-positive SCCOP cases and may be prognostic biomarkers for SCCOP.
PMCID: PMC3563870  PMID: 23219900
MicroRNA polymorphisms; genetic susceptibility; oropharyngeal cancer; molecular epidemiology; survival
23.  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
24.  Association between functional polymorphisms in genes involved in the MAPK signaling pathways and cutaneous melanoma risk 
Carcinogenesis  2013;34(4):885-892.
Genome-wide association studies (GWASs) have mainly focused on top significant single nucleotide polymorphisms (SNPs), most of which did not have clear biological functions but were just surrogates for unknown causal variants. Studying SNPs with modest association and putative functions in biologically plausible pathways has become one complementary approach to GWASs. To unravel the key roles of mitogen-activated protein kinase (MAPK) pathways in cutaneous melanoma (CM) risk, we re-evaluated the associations between 47 818 SNPs in 280 MAPK genes and CM risk using our published GWAS dataset with 1804 CM cases and 1026 controls. We initially found 105 SNPs with P ≤ 0.001, more than expected by chance, 26 of which were predicted to be putatively functional SNPs. The risk associations with 16 SNPs around DUSP14 (rs1051849) and a previous reported melanoma locus MAFF/PLA2G6 (proxy SNP rs4608623) were replicated in the GenoMEL dataset (P < 0.01) but failed in the Australian dataset. Meta-analysis showed that rs1051849 in the 3ʹ untranslated regions of DUSP14 was associated with a reduced risk of melanoma (odds ratio = 0.89, 95% confidence interval: 0.82–0.96, P = 0.003, false discovery rate = 0.056). Further genotype–phenotype correlation analysis using the 90 HapMap lymphoblastoid cell lines from Caucasians showed significant correlations between two SNPs (rs1051849 and rs4608623) and messenger RNA expression levels of DUSP14 and MAFF (P = 0.025 and P = 0.010, respectively). Gene-based tests also revealed significant SNPs were over-represented in MAFF, PLA2G6, DUSP14 and other 16 genes. Our results suggest that functional SNPs in MAPK pathways may contribute to CM risk. Further studies are warranted to validate our findings.
PMCID: PMC3616673  PMID: 23291271
The ataxia telangiectasia mutated (ATM) gene mediates detection and repair of DNA damage. We investigated associations between ATM polymorphisms and severe radiation-induced pneumonitis (RP).
Methods and Materials
We genotyped three potentially functional single nucleotide polymorphisms (SNPs) of ATM (rs1801516 [D1853N/5557G>A], rs189037 [−111G>A] and rs228590) in 362 patients with non-small cell lung cancer (NSCLC), who received definitive radio(chemo)therapy. The cumulative severe RP probabilities by genotypes were evaluated using the Kaplan-Meier analysis. The associations between severe RP risk and genotypes were assessed by both logistic regression analysis and Cox proportional hazard model with time to event considered.
Of 362 patients with 82% of non-Hispanic whites, 56 (15.5%) experienced grade ≥ 3 RP. Patients carrying ATM rs189037 AG/GG or rs228590 TT/CT genotypes, or rs189037G/rs228590T/rs1801516G (G-T-G) haplotype had a lower risk of severe RP (rs189037: GG/AG vs. AA, adjusted hazard ratio [HR] = 0.49, 95% confidence interval [CI], 0.29–0.83, P = 0.009; rs228590: TT/CT vs. CC, HR=0.57, 95% CI, 0.33–0.97, P =0.036; haplotype: G-T-G vs. A-C-G, HR=0.52, 95% CI, 0.35–0.79, P =0.002). Such positive findings remained in non-Hispanic whites.
ATM polymorphisms may serve as biomarkers for susceptibility to severe RP in non-Hispanic whites. Large prospective studies are required to confirm our findings.
PMCID: PMC3594431  PMID: 23154078
Non–small cell lung cancer; radiation pneumonitis; single-nucleotide polymorphisms; ataxia telangiectasia mutated gene

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