Association between novel PLCE1variants identified in published esophageal cancer genome-wide association studies and risk of squamous cell carcinoma of the head and neck

BACKGROUND: Phospholipase C epsilon 1 (PLCE1) (an effector of Ras) belonging to the phospholipase family plays crucial roles in carcinogenesis and progression of several cancers, including squamous cell carcinoma of the head and neck (SCCHN). A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus in genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) that share similar risk factors with SCCHN. Therefore, we investigated the association between potentially functional SNPs in PLCE1 and susceptibility to SCCHN. METHODS: We genotyped three potentially functional SNPs (rs2274223A/G, rs3203713A/G and rs11599672T/G) of PLCE1 in 1,098 SCCHN patients and 1,090 controls matched by age and sex in a non-Hispanic white population. RESULTS: Although none of three SNPs was alone significantly associated with overall risk of SCCHN, their combined effects of risk alleles (rs2274223G, rs3203713G and rs11599672G) were found to be associated with risk of SCCHN in a locus-dose effect manner (P(trend )= 0.046), particularly for non-oropharyngeal tumors (P(trend )= 0.017); specifically, rs2274223 was associated with a significantly increased risk (AG vs. AA: adjusted OR = 1.29, 95% CI = 1.01-1.64; AG/GG vs. AA: adjusted OR = 1.30, 95% CI = 1.03-1.64), while rs11599672 was associated with a significantly decreased risk (GG vs. TT: adjusted OR = 0.54, 95% CI = 0.34-0.86; TG/GG vs. TT: adjusted OR = 0.76, 95% CI = 0.61-0.95). CONCLUSIONS: Our findings suggest that PLCE1 variants may have an effect on risk of SCCHN associated with tobacco and alcohol exposure, particularly for those tumors arising at non-oropharyngeal sites. These findings, although need to be validated by larger studies, are consistent with those in esophageal and gastric cancers

Knowledge About the Human Papillomavirus Vaccine Among Employees at a Tertiary Cancer Center: Room for Improvement

Introduction: The human papillomavirus (HPV) vaccine is recommended by the U.S. Centers for Disease Control and Prevention for routine vaccination of boys and girls to protect against HPV-related cancers and genital warts. To meet the Healthy People 2020 target for HPV vaccination, health care providers must understand the importance of strongly recommending the HPV vaccine to all eligible adolescents. We sought to determine HPV vaccination patterns among employees at a tertiary cancer center and their children and attitudes regarding HPV vaccination among the employees. Methods: All employees at a tertiary cancer center were invited to participate in a cross-sectional survey administered online during July and August 2015. The survey included questions about HPV vaccination of participants and their children, including reasons why vaccine-eligible employees and children had not been vaccinated. Results: Of those eligible, 13% of male and 33% of female employees and 44% of daughters and 24% of sons of employees had completed the vaccine series. The main reasons for not completing the series or not having one’s son completing the series were not knowing that the vaccine was needed and vaccine not recommended by a health care provider. The main reasons for not having one’s daughter complete the series were the two aforementioned reasons and daughter not yet sexually active. Conclusion: Opportunities exist to educate health care workers about the benefits of the HPV vaccine and to increase the number of providers who recommend HPV vaccination to their patients

Polymorphisms of the DNA repair gene MGMT and risk and progression of head and neck cancer.

Methylating agents are involved in carcinogenesis, and the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) removes methyl group from O(6)-methylguanine. Genetic variation in DNA repair genes has been shown to contribute to susceptibility to squamous cell carcinoma of the head and neck (SCCHN). We hypothesize that MGMT polymorphisms are associated with risk of SCCHN. In a hospital-based case-control study of 721 patients with SCCHN and 1234 cancer-free controls frequency-matched by age, sex and ethnicity, we genotyped four MGMT polymorphisms, two in exon 3, 16195C\u3eT and 16286C\u3eT and two in the promoter region, 45996G\u3eT and 46346C\u3eA. We found that none of these polymorphisms alone had a significant effect on risk of SCCHN. However, when these four polymorphisms were evaluated together by the number of putative risk genotypes (i.e. 16195CC, 16286CC, 45996GT+TT, and 46346CA+AA), a statistically significantly increased risk of SCCHN was associated with the combined genotypes with three to four risk genotypes, compared with those with zero to two risk genotypes (adjusted odds ratio (OR)=1.27; 95% confidence interval (CI)=1.05-1.53). This increased risk was also more pronounced among young subjects (OR=1.81; 95% CI=1.11-2.96), men (OR=1.24; 95% CI=1.00-1.55), ever smokers (OR=1.25; 95%=1.01-1.56), ever drinkers (OR=1.29; 95% CI=1.04-1.60), patients with oropharyngeal cancer (OR=1.45; 95% CI=1.12-1.87), and oropharyngeal cancer with regional lymph node metastasis (OR=1.52; 95% CI=1.16-1.89). In conclusion, our results suggest that any one of MGMT variants may not have a substantial effect on SCCHN risk, but a joint effect of several MGMT variants may contribute to risk and progression of SCCHN, particularly for oropharyngeal cancer, in non-Hispanic whites

Single Nucleotide Polymorphisms in Selected Apoptotic Genes and BPDE-Induced Apoptotic Capacity in Apparently Normal Primary Lymphocytes: A Genotype-Phenotype Correlation Analysis

Apoptotic capacity (AC) in primary lymphocytes may be a marker for cancer susceptibility, and functional single nucleotide polymorphisms (SNPs) in genes involved in apoptotic pathways may modulate cellular AC in response to DNA damage. To further examine the correlation between apoptotic genotypes and phenotype, we genotyped 14 published SNPs in 11 apoptosis-related genes (i.e., p53, Bcl-2, BAX, CASP9, DR4, Fas, FasL, CASP8, CASP10, CASP3, and CASP7) and assessed the AC in response to benzo[a]pyrene-7,8-9,10-diol epoxide (BPDE) in cultured primary lymphocytes from 172 cancer-free subjects. We found that among these 14 SNPs, R72P, intron 3 16-bp del/ins, and intron 6 G>A in p53, −938C>A in Bcl-2, and I522L in CASP10 were significant predictors of the BPDE-induced lymphocytic AC in single-locus analysis. In the combined analysis of the three p53 variants, we found that the individuals with the diplotypes carrying 0-1 copy of the common p53 R-del-G haplotype had higher AC values compared to other genotypes. Although the study size may not have the statistical power to detect the role of other SNPs in AC, our findings suggest that some SNPs in genes involved in the intrinsic apoptotic pathway may modulate lymphocytic AC in response to BPDE exposure in the general population. Larger studies are needed to validate these findings for further studying individual susceptibility to cancer and other apoptosis-related diseases

A variant at a potentially functional microRNA-binding site in BRIP1 was associated with risk of squamous cell carcinoma of the head and neck

DNA double-strand breaks (DSBs) are one of the most serious forms of DNA damage to the cell, causing genomic instability and ultimately carcinogenesis. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) at the micro RNA (miRNA)-binding sites of DSB repair genes may influence cancer risk by dysregulating target gene expression. To test our hypothesis, we firstly performed functional prediction for common SNPs in DSB genes and found 12 potentially functional SNPs located at the miRNA-binding sites. We then investigated their associations with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1087 patients and 1090 cancer-free controls in a non-Hispanic white population. As a result, SNP rs7213430 in BRIP1 was found to be significantly associated with cancer risk (Ptrend = 0.021). Compared with the AA homozygotes, the G allele carriers had an increased risk of SCCHN (adjusted OR 1.16, 95 % CI 1.02–1.31). Marginal significance was found for another SNP rs15869 in BRCA2 (P = 0.053). Further, functional analyses showed that SNP rs7213430 is within the miR-101 seed-binding region, and the variant G allele could lead to significantly lower luciferase activity and BRIP1 mRNA expression, compared to the A allele with the presence of miR-101. Our results suggested that SNP rs7213430 in the 3′-UTR of BRIP1 might contribute to SCCHN susceptibility by affecting the binding activity of miR-101 and resulting in a decreased BRIP1 expression. Additional larger population and functional studies are warranted to confirm our findings

Genetic variants of p27 and p21 as predictors for risk of second primary malignancy in patients with index squamous cell carcinoma of head and neck

<p>Abstract</p> <p>Background</p> <p>Cell cycle deregulation is common in human cancer, and alterations of <it>p27 </it>and <it>p21</it>, two critical cell cycle regulators, have been implicated in the development of many human malignancies. Therefore, we hypothesize that <it>p27 </it>T109G polymorphism individually or in combination with <it>p21 </it>(C98A and C70T) polymorphisms modifies risk of second primary malignancy (SPM) in patients with index squamous cell carcinoma of head and neck (SCCHN).</p> <p>Methods</p> <p>A cohort of 1,292 patients with index SCCHN was recruited between May 1995 and January 2007 at the M.D. Anderson Cancer Center and followed for SPM occurrence. Patients were genotyped for the three polymorphisms. A log-rank test and Cox proportional hazards models were used to compare SPM-free survival and SPM risk.</p> <p>Results</p> <p>We found that patients with <it>p27 </it>109 TG/GG, <it>p21 </it>98 CA/AA and <it>p21 </it>70 CT/TT variant genotypes had a worse SPM-free survival and an increased SPM risk than those with the corresponding <it>p27</it>109 TT, <it>p21 </it>98 CC, and <it>p21 </it>70 CC common genotypes, respectively. After combining the three polymorphisms, there was a trend for significantly increased SPM risk with increasing number of the variant genotypes (<it>P</it>_trend= 0.0002). Moreover, patients with the variant genotypes had an approximately 2.4-fold significantly increased risk for SPM compared with those with no variant genotypes (HR, 2.4, 95% CI, 1.6-3.6).</p> <p>Conclusions</p> <p>These results suggest that <it>p27 </it>T109G polymorphism individually or in combination with <it>p21 </it>(C98A and C70T) polymorphisms increases risk of SPM in patients with index SCCHN.</p

Apoptotic capacity and risk of squamous cell carcinoma of the head and neck

Tobacco smoke and alcohol drinking are the major risk factors for squamous cell carcinoma of the head and neck (SCCHN). Smoking and drinking cause DNA damage leading to apoptosis, and insufficient apoptotic capacity may favor development of cancer because of the dysfunction of removing damaged cells. In the present study, we investigated the association between camptothecin (CPT)-induced apoptotic capacity and risk of SCCHN in a North American population

Trends in Thyroid Cancer Incidence in Texas from 1995 to 2008 by Socioeconomic Status and Race/Ethnicity

Background: Thyroid cancer incidence is increasing, potentially due to enhanced diagnostic practices. However, access to healthcare may be dependent on socioeconomic status (SES) and race/ethnicity. Consequently, certain segments of the population may experience thyroid cancer overdiagnosis as a result of greater access to and use of enhanced diagnostic technology. The current study examined trends by SES in thyroid cancer incidence at the census tract level from 1995 to 2008 for the population of Texas, as well as by racial/ethnic subgroup

Reduced mRNA expression of nucleotide excision repair genes in lymphocytes and risk of squamous cell carcinoma of the head and neck

Nucleotide excision repair (NER) plays a critical role in the development of smoking-related cancers. We hypothesize that mRNA expression levels of NER genes are associated with risk of the squamous cell carcinoma of head and neck (SCCHN). To test this hypothesis, we conducted a case-control study of 260 SCCHN patients and 246 cancer-free controls by measuring the mRNA expression levels of eight core NER genes in cultured peripheral lymphocytes. Compared with the controls, cases had statistically significantly lower expression levels of DDB1 and ERCC3 (P = 0.015 and 0.041, respectively). Because DDB1 and ERCC3 expression levels were highly correlated, we used DDB1 for further multivariate analyses and modeling. After dividing the subjects by controls' quartiles of expression levels, we found an association between an increased risk of SCCHN and low DDB1 expression levels [adjusted ORs and 95% CIs: 1.92 and 1.11-3.32, 1.48 and 0.85-2.59, 2.00 and 1.15-3.45 for the 2nd-4th quartiles, respectively, compared with the 1st quartile; Ptrend = 0.026]. We also identified a multiplicative interaction between sex and DDB1 expression levels (P = 0.007). Finally, the expanded model with gene expression levels, in addition to demographic and clinical variables, on SCCHN risk was significantly improved, especially among men. In conclusion, reduced DDB1 expression levels were associated with an increased risk of SCCHN. However, these results need to be validated in larger studies

Common single nucleotide polymorphisms in genes related to immune function and risk of papillary thyroid cancer

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 (P(SNP-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 (P(Region) and P(Pathway)) were assessed by combining individual P(SNP-trend) values using the adaptive rank truncated product method. Two SNPs (rs6115, rs6112) in the SERPINA5 gene were significantly associated with risk of PTC (P(SNP-FDR)/P(SNP-trend) = 0.02/6×10(−6) and P(SNP-FDR)/P(SNP-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 (P(Region-FDR)/P(Region = )0.07/0.0003). Overall, the complement and coagulation cascade pathway was the most significant pathway (P(Pathway) = 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