Mouse double minute 4 (MDM4), a homolog of MDM2, is a key negative regulator of p53, and its amplification or over-expression contributes to carcinogenesis by inhibiting the p53 tumor suppressor activity. We investigated the association between MDM4 polymorphisms and risk of squamous cell carcinoma of the head and neck (SCCHN).
We genotyped three MDM4 tagging polymorphisms, two in the 3′ untranslated region (3′ UTR: rs11801299G>A and rs10900598G>T) and one in intron 1 (rs1380576C>G), in a case-control study of 1,075 non-Hispanic white SCCHN patients and 1,084 cancer-free controls and evaluated their associations with SCCHN risk.
Although none of these three polymorphisms individually had a statistically significant effect on risk of SCCHN, nor did their combined number of putative risk genotypes (i.e., rs11801299GG, rs1380576CG+GG, and rs10900598GG) (OR = 1.16 and 95% CI=0.93–1.45), we found that individuals with 1–3 risk genotypes had statistically significantly increased risk of oropharyngeal cancer (OR = 1.32 and 95% CI = 1.00–1.73), particularly for those with T1–2 stage (OR = 1.40; 95% CI = 1.02–1.94), those with regional lymph node metastases (N1–3) (OR = 1.44; 95% CI = 1.07–1.95), and those with late stages (III and IV) (OR = 1.34; 95% CI = 1.01–1.77).
Our results suggest that the joint effect of MDM4 variants may contribute to the risk of oropharyngeal cancer in non-Hispanic whites. Additional studies are warranted to unravel whether the particular stage distribution of oropharyngeal cancer with the strongest association (T1–2, N1–3, and III–IV) is a possible link with human papillomavirus-related oropharyngeal cancers.
MDM4 polymorphism; case-control; genetic susceptibility; molecular epidemiology; head and neck neoplasms; oropharyngeal cancer
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.
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.
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 (Ptrend = 0.046), particularly for non-oropharyngeal tumors (Ptrend = 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).
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.
PLCE1; polymorphism; SCCHN; risk; susceptibility
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.
E2F1; E2F2; head and neck cancer; polymorphisms; age at onset
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.
MDM4 polymorphisms; genetic susceptibility; human papillomavirus; molecular epidemiology; squamous cell carcinoma of head and neck cancer; squamous cell carcinoma of the oropharynx
Single-nucleotide polymorphisms (SNPs) of TERT-rs2736098 (C > T) and CLPTM1L-rs401681(C > T) at the 5p15.33 locus are significantly associated with cancer risk as reported in genome-wide association studies (GWAS), but there are no reported studies for squamous cell carcinoma of the head and neck (SCCHN). In a case–control study of 1079 SCCHN cases and 1115 cancer-free controls of non-Hispanic whites who were frequency matched by age and sex, we genotyped for these two SNPs and assessed their associations with SCCHN risk. Compared with the CC genotypes of each polymorphism, the associations of a slightly reduced risk of SCCHN with the variant genotypes of CT + TT of both polymorphisms were approaching statistical significance [Odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.76–1.08 for TERT-rs2736098 and OR = 0.86, 95% CI = 0.71–1.04 for CLPTM1L-rs401681, respectively]. When the two SNPs were combined, the variant genotypes of the two SNPs were significantly associated a moderately reduced risk of SCCHN (OR = 0.82, 95% CI = 0.67–0.99), and the number of variant genotypes was associated with a significantly reduced risk in a dose–response manner (P = 0.028). Furthermore, the reduced risk was more pronounced in ever smokers, ever drinkers and patients with oropharyngeal cancer. Our results suggested that these two SNPs at the 5p15.33 locus may be associated with a reduced risk of SCCHN, particularly for their combined effect. Although we added additional evidence for the association of the two SNPs with cancer risk as reported in GWAS, additional studies are needed to replicate our findings.
Recent studies reported associations of the relative telomere length (RTL) and TERT variants with risk of several cancers, which has not been comprehensively investigated in squamous cell carcinoma of the head and neck (SCCHN).
We detected RTL in peripheral blood lymphocytes and genotyped six selected functional single nucleotide polymorphisms (SNPs) of the TERT gene in 888 SCCHN cases and 885 cancer-free controls of non-Hispanic whites.
Overall, we did not observe significant associations between RTL and SCCHN risk (adjusted OR, 0.97; 95% CI, 0.80–1.17 for below versus above the median; Ptrend = 0.618) nor between the six TERT SNPs and SCCHN risk. We also found no associations between RTL and TERT SNPs.
Our results suggest that RTL and TERT functional polymorphisms may not play a major role in the etiology of SCCHN. Large prospective studies are needed to validate our findings.
Although our results suggest no association among RTL, TERT functional polymorphisms, and SCCHN risk, this study may contribute to future meta-analysis.
genetic polymorphisms; Telomere length; TERT; head and neck cancer; molecular epidemiology
Methylating agents are involved in carcinogenesis, and the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) removes methyl group from O6-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 1,234 cancer-free controls frequency-matched by age, sex and ethnicity, we genotyped four MGMT polymorphisms, two in exon 3, 16196C>T and 16286C>T and two in the promoter region, 45996G>T and 46346C>A. 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 = 1.16-2.01). 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.
oral cancer; DNA repair; methylation; genetic susceptibility; molecular epidemiology
Single-nucleotide polymorphisms within TP53 gene (codon 72 exon 4, rs1042522, encoding either arginine or proline) and MDM2 promoter (SNP309; rs2279744), have been independently associated with increased risk of several cancer types. Few studies have analysed the role of these polymorphisms in the development of hepatocellular carcinoma.
Genotype distribution of TP53 codon 72 and MDM2 SNP309 in 61 viral hepatitis-related hepatocellular carcinoma cases and 122 blood samples (healthy controls) from Italian subjects were determined by PCR and restriction fragment length polymorphism (RFLP).
Frequencies of TP53 codon 72 alleles were not significantly different between cases and controls. A significant increase of MDM2 SNP309 G/G and T/G genotypes were observed among hepatocellular carcinoma cases (Odds Ratio, OR = 3.56, 95% Confidence Limits, 95% CI = 1.3-9.7; and OR = 2.82, 95% CI = 1.3-6.4, respectively).
These results highlight a significant role of MDM2 SNP309 G allele as a susceptibility gene for the development of viral hepatitis-related hepatocellular carcinoma among Italian subjects.
Genetic Polymorphisms; TP53 codon 72; MDM2 SNP309; hepatocellular carcinoma
Single nucleotide polymorphisms (SNPs) in the promoter region of the FAS and FASLG may alter the transcriptional activity of these genes. We, therefore, investigated the association between the FAS and FASLG polymorphisms and risk of second primary tumor (SPM) after index squamous cell carcinoma of the head and neck (SCCHN).
We used Log-rank test and Cox proportional hazard models to assess the association of the four SNPs (FAS -1377G>A, FAS -670A>G, FASLG -844C>T and FASLG -124 A>G) with the SPM-free survival and SPM risk among 1,286 incident SCCHN patients.
Compared to patients having the FAS -670 AA or the FASLG -844CC genotypes, the patients having variant genotypes of FAS -670 AG/GG or FASLG -844 CT/TT genotypes had a significantly increased risk of SPM, respectively. A trend for significantly increased SPM risk with increasing number of risk genotypes of the four polymorphisms was observed in a dose-response manner. Moreover, the patients with three or four combined risk genotypes had an appropriately 1.8- or 2.5-fold increased risk for developing SPM compared with patients with zero or one risk genotypes, respectively.
Our results suggest a modestly increased risk of SPM after index SCCHN with FAS -670 A>G and FASLG -844 C>T polymorphisms and an even greater risk of SPM with multiple combined FAS and FASLG risk genotypes.
The FAS and FASLG polymorphisms may serve as a susceptible marker for SCCHN patients at high SPM risk.
FAS/FASLG; Squamous cell carcinoma of head and neck; Second primary malignancy; Genetic susceptibility; Polymorphism
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.
ERCC5; polymorphism; SCCHN; risk
AIM: To investigate the risk association and compare the onset age of hepatocellular carcinoma (HCC) patients in Taiwan with different genotypes of MDM2-SNP309.
METHODS: We analyzed MDM2-SNP309 genotypes from 58 patients with HCC and 138 cancer-free healthy controls consecutively. Genotyping of MDM2-SNP309 was conducted by restriction fragment length polymorphism assay.
RESULTS: The proportion of homozygous MDM2-SNP309 genotype (G/G) in cases and cancer-free healthy controls was similar (17.2% vs 16.7%). Multivariate analysis showed that the risk of G/G genotype of MDM2-SNP309 vs wild-type T/T genotype in patients with HCC was not significant (OR = 1.265, 95% CI = 0.074-21.77) after adjustment for sex, hepatitis B or C virus infection, age, and cardiovascular disease/diabetes. Nevertheless, there was a trend that GG genotype of MDM2-SNP309 might increase the risk in HCC patients infected with hepatitis virus (OR = 2.568, 95% CI = 0.054-121.69). Besides, the homozygous MDM2-SNP309 genotype did not exhibit a significantly earlier age of onset for HCC.
CONCLUSION: Current data suggest that the association between MDM2-SNP309 GG genotype and HCC is not significant, while the risk may be enhanced in patients infected by hepatitis virus in Taiwan.
MDM2 protein; Hepatocellular carcinoma; Taiwan; Tumor suppressor protein p53
The nucleotide excision repair (NER) pathway is central in response to damage induced by environmental carcinogens. Efficiency of this pathway, probably genetically determined, may modulate individual risk of developing squamous cell carcinoma of the head and neck (SCCHN) as well as second primary malignancy (SPM) after the index tumor. We hypothesized that common non-synonymous and regulatory single-nucleotide polymorphisms (SNPs) in the NER core genes individually, and more probably collectively, associated with the risk of SPM. We genotyped for seven selected SNPs in 1376 incident SCCHN patients who were prospectively recruited between 1995 and 2006 and followed for SPM development. We found that 110 patients (8%) developed SPM: 43 (39%) second SCCHN; 38 (35%) other tobacco-associated sites and 29 (26%) other non-tobacco-associated sites. The associations of these SNPs with SPM risk were assessed assuming a recessive genetic model. We did not find any significant associations of each or in combination of the seven SNPs with SPM risk in the recessive models. However, when we explored the combined effect based on an alternatively dominant genetic model, we found that the number of observed risk genotypes was associated with a significantly increased SPM risk in a dose-response manner (P = 0.005) and patients with five to seven risk genotypes had a significantly 2.4-fold increased SPM risk compared with patients with zero to two risk genotypes. These findings suggest that a profile of NER core gene polymorphisms might collectively contribute to risk of SPM not in a recessive model but in a dominant model among patients with an index primary SCCHN. These findings need to be validated in future studies with larger sample sizes and longer follow-up time.
The MDM2 oncoprotein is a key negative regulator of the tumor suppressor p53. A functional MDM2 single nucleotide polymorphism (SNP309) in the promoter region increases the affinity of transcription activator Sp1 for the MDM2 gene promoter, resulting in higher expression of MDM2 and thus inhibition of p53 transcriptional activity. UV-induced p53 activation promotes cutaneous transient pigmentation, and the common p53 Arg72Pro polymorphism alters the protein’s transcriptional activity. We evaluated the effect of the MDM2 SNP309 and its interaction with the p53 Arg72Pro polymorphism on pigmentary phenotypes and skin cancer risk in a nested case-control study within the Nurses’ Health Study (NHS) among 219 melanoma cases, 286 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 873 controls, and among controls from other studies. We found that the G allele of the MDM2 SNP309 was inversely associated with the presence/absence of moles on the arm among 3207 women pooled from controls of three nested case-control studies within the NHS. Compared with the MDM2 SNP309 T/T genotype, adjusted odds ratios (ORs) of having moles on the arms for T/G and G/G genotypes were 0.92 (95% confidence interval (CI), 0.78–1.08) and 0.68 (95%CI, 0.53–0.87), respectively (P, trend, 0.005). We observed suggestive evidence of the association between the carriage of the MDM2 SNP309 G allele and childhood tanning tendency (adjusted OR, 1.30; 95% CI, 1.01–1.68). No significant associations were found between the MDM2 SNP309 and any of the three types of skin cancer. For SCC, the trend of increased risk across the three genotypes of MDM2 was stronger among p53 Pro carriers (p, trend, 0.05) than p53 Arg/Arg wildtype group (p, trend, 0.99; p, interaction, 0.07). These results provide evidence for the potential involvement of MDM2 SNP309 in pigmentary traits.
MDM2; p53; pigmentary phenotypes; skin cancer
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.
PUMA polymorphisms; HPV16; genetic susceptibility; molecular epidemiology; squamous cell carcinoma of the head and neck
Cyclooxygenase-2 (COX-2) is involved in inflammation and carcinogenesis. Interleukin-10 (IL-10) is also regarded as anti-inflammatory factors with the multi-functional ability to positively and negatively influence functional immunity and tumor development. Genetic polymorphisms of COX-2 and IL-10 might contribute to the development of squamous cell carcinoma of the head and neck (SCCHN). The purpose of this study was to evaluate the association of COX-2 and IL-10 single nucleotide polymorphisms (SNPs) with the risk of SCCHN in a Korean sample. We analyzed the COX-2 SNPs, -1329A>G, +1266C>T, and +6365T>C, and the IL-10 SNPs, -1082A>G, +920T>G, and +3917T>C, in 290 Korean SCCHN patients and 358 healthy controls. There was no significant association between the risk of SCCHN and the three COX-2 or three IL-10 SNPs. We analyzed three haplotypes (ht1, ht2, ht3) for COX-2 and found that COX-2 ht3+/+ was associated with a decreased risk of SCCHN in a Korean sample, compared with the COX-2 ht3 -/- genotype (P=0.03). Two haplotypes (ht1, ht2) of IL-10 were analyzed and there was no statistical significance in the distribution of haplotypes. Based on these results, the COX-2 haplotype ht3 can be used as a molecular biomarker to predict low risk groups of SCCHN in a Korean sample.
Carcinom, Squamous Cell; Head and Neck Neoplasms; Cyclooxygenase 2; Interleukin-10; Polymorphism, Genetic; Polymorphism, Single Nucleotide
The polymorphism SNP309 (rs2279744) in the promoter region of the MDM2 gene has been shown to alter protein expression and may play a role in the susceptibility to lung cancer. The MDM2 protein is a key inhibitor of p53 and several mechanisms of MDM2/p53 interactions are presently known: modulating DNA-repair, cell-cycle control, cell growth and apoptosis.
We used 635 Caucasian patients diagnosed with lung cancer before 51 years of age and 1300 healthy gender and age frequency matched population Caucasian controls to investigate the association between the MDM2 SNP309 and the risk of developing early onset lung cancer. Conditional logistic models were applied to assess the genotype-phenotype association, adjusted for smoking.
Compared to the GG genotype, the adjusted ORs for the TG and TT genotype were 0.9 (95% CI: 0.7–1.5) and 1.0 (95% CI: 0.7–1.5), respectively. Also no association was found for histological subtypes of lung cancer. The strength of this study is that within young cases the genetic component to develop lung cancer may be greater. Our results indicate that the MDM2 SNP309 is not significantly associated with lung carcinogenesis but point towards gender-specific differences.
Single nucleotide polymorphisms (SNPs) in alcohol metabolism genes are associated with squamous cell carcinoma of the head and neck (SCCHN), and may influence cancer risk in conjunction with alcohol. Genetic variation in the oxidative stress pathway may impact the carcinogenic effect of reactive oxygen species produced by ethanol metabolism. We hypothesized that alcohol interacts with these pathways to affect SCCHN incidence.
Interview and genotyping data for 64 SNPs were obtained from 2552 European- and African-American subjects (1227 cases, 1325 controls) from the Carolina Head and Neck Cancer Epidemiology study, a population-based case-control study of SCCHN conducted in North Carolina from 2002–2006. We estimated odds ratios and 95% confidence intervals for SNPs and haplotypes, adjusting for age, sex, race, and duration of cigarette smoking. P-values were adjusted for multiple testing using Bonferroni correction.
Two SNPs were associated with SCCHN risk: ADH1B rs1229984 A allele (OR=0.7, 95%CI=0.6–0.9) and ALDH2 rs2238151 C allele (OR=1.2, 95%CI=1.1–1.4). Three were associated with sub-site tumors: ADH1B rs17028834 C allele (larynx, OR=1.5, 95%CI=1.1–2.0), SOD2 rs4342445 A allele (oral cavity, OR=1.3, 95%CI=1.1–1.6), and SOD2 rs5746134 T allele (hypopharynx, OR=2.1, 95%CI=1.2–3.7). Four SNPs in alcohol metabolism genes interacted additively with alcohol consumption: ALDH2 rs2238151, ADH1B rs1159918, ADH7 rs1154460, and CYP2E1 rs2249695. No alcohol interactions were found for oxidative stress SNPs.
Conclusions and Impact
Previously unreported associations of SNPs in ALDH2, CYP2E1, GPX2, SOD1, and SOD2 with SCCHN and sub-site tumors provide evidence that alterations in alcohol and oxidative stress pathways influence SCCHN carcinogenesis, and warrant further investigation.
Head and Neck Neoplasms; Head and Neck Neoplasms/epidemiology; Gene-environment interaction; Alcohol Drinking/metabolism; Oxidative Stress
p14ARF plays a critical role in crosstalk between p53 and Rb pathways and in cellular anticancer mechanisms. We, therefore, investigated the association between the single nucleotide polymorphisms (SNPs) of p14ARF and risk of second primary Malignancy (SPM) after index squamous cell carcinoma of the head and neck (SCCHN).
We used Log-rank test and Cox proportional hazards models to assess the association of the two p14ARF SNPs (rs3731217 and rs3088440) with the SPM-free survival and SPM risk among 1,287 incident SCCHN patients.
We found that patients with either p14ARF variant genotypes of the two polymorphisms had a significantly reduced SPM-free survival, compared with patients with no variant genotypes (Log-rank test, P = 0.006). Compared with p14ARF TT and GG genotypes, the variant genotypes of p14ARF TG/GG and GA/AA were associated with significantly moderately increased risk of developing SPM [adjusted hazard ratio (aHR), 1.48, 95% confidence interval (CI), 1.00–2.19 for p14ARF-rs3731217 and aHR, 1.61, 95% CI, 1.07–2.43 for p14ARF-rs3088440), respectively]. Moreover, after combining the variant genotypes of the two SNPs, patients with variant genotypes had a significantly greater risk for SPM compared to patients with no variant genotypes (aHR, 3.07, 95% CI, 1.54–6.12), and the risk was particularly pronounced in several subgroups.
Our results suggest a modestly increased risk of SPM after index SCCHN with each p14ARF polymorphism and an even greater risk of SPM with combined variant genotypes of the two SNPs. Therefore, p14ARF polymorphisms may be a susceptible marker to SPM risk for SCCHN patients.
p14ARF; Squamous cell carcinoma of head and neck; Second primary malignancy; Genetic susceptibility; Polymorphism
Previous studies have shown that MDM2 SNP309 and p53 codon 72 have modifier effects on germline P53 mutations, but those studies relied on case-only studies with small sample sizes. The impact of MDM4 polymorphism on tumor onset in germline mutation carriers has not previously been studied.
We analyzed 213 p53 germline mutation carriers including 168(78.9%) affected with cancer and 174 who had genotypic data. We analyzed time to first cancer using Kaplan-Meier and Cox proportional hazards methods, comparing risks according to polymorphism genotypes. For MDM2 SNP309, a significant difference of 9.0 years in the average age of cancer diagnosis was observed between GG/GT and TT carriers (18.6 versus 27.6 years, P = 0.0087). The hazards ratio was 1.58 (P = 0.03) comparing risks among individuals with GG/GT to risk among TT, but this effect was only significant in females (HR = 1.60, P = 0.02). Compared to other genotypes, P53 codon 72 PP homozygotes had a 2.24 times (P = 0.03) higher rate for time to develop cancer. We observed a multiplicative joint effect of MDM2 and p53 codon72 polymorphism on risk. The MDM4 polymorphism had no significant effects.
Our results suggest that the MDM2 SNP309 G allele is associated with cancer risk in p53 germline mutation carriers and accelerates time to cancer onset with a pronounced effect in females. A multiplicative joint effect exists between the MDM2 SNP309 G allele and the p53 codon 72 G allele in the risk of cancer development. Our results further define cancer risk in carriers of germline p53 mutations.
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.
p53; p73; Polymorphisms; Squamous cell carcinoma of the head and neck; Second primary malignancy
DNA-methyltransferase-3B (DNMT3B) may play an oncogenic role during tumorigenesis, and its genetic variants have been reportedly to be associated with risk of several cancers, but few studies have investigated their roles in head and neck cancer. Here we report a hospital-based case-control study with 832 SCCHN patients and 843 cancer-free controls of non-Hispanic whites that evaluated the association between two DNMT3B single nucleotide polymorphisms (SNPs) DNMT3B-149C>T (rs2424913) and DNMT3B-579G>T (rs2424909) in the promoter region and risk of squamous cell carcinoma of the head and neck (SCCHN). We found that compared with C-allele carriers, the DNMT3B-149 TT genotype was statistically significantly associated with increased risk of SCCHN (adjusted OR, 1.35, 95% CI, 1.01-1.80, P = 0.043), whereas the DNMT3B-579 TT genotype showed only a non-statistically significant risk compared with G-allele carriers. Further analysis of the effects of combined genotypes suggested that subjects with either DNMT3B-149 TT or DNMT3B-579 TT homozygous genotypes had statistically significantly increased risk of SCCHN (adjusted OR = 1.36, 95% CI = 1.07-1.73, P = 0.013). Stratification analysis showed a more profound risk in the subgroups of the young (≤57 years, the median age of the controls), males, current smokers, current drinkers, and patients with primary tumor sites of pharynx and larynx. This large study provides reliable risk estimates for associations between DNMT3B variants and SCCHN risk in non-Hispanic whites, and our findings are consistent with that of previously reported cancer case-control studies of other cancers. Further mechanistic studies are needed to unravel the underlying molecular mechanisms.
Polymorphism; Methylation; DNMT3B; Molecular epidemiology; Cancer risk
No studies have evaluated roles of insulin-like growth factor binding protein 5 (IGFBP-5) polymorphisms in risk of squamous cell carcinoma of the head and neck (SCCHN).
A hospital-based study of 1082 SCCHN patients and 1120 cancer-free controls was performed to investigate associations between two functional polymorphisms -1195T>C and -709G>C in the IGFBP5 promoter region and SCCHN risk.
We demonstrated that the transcription factor AP-1 differentially bound to T or C variants at -1195 in the promoter to regulate the IGFBP5 promoter activity and that the C variant genotypes were associated with deferential risk of late-stage SCCHN, compared with the TT genotype, particularly for HPV-unrelated sites (adjusted OR, 2.21; 95% CI, 1.19-4.11 for CC vs. TT).
The IGFBP5 -1195T>C polymorphism is functional and may potentially be a biomarker for susceptibility to late-stage SCCHN.
IGFBP5; head neck cancer; TNM stage; polymorphism; association
Excision repair cross-complementation group 4 gene (ERCC4/XPF) plays an important role in nucleotide excision repair and participates in removal of DNA interstrand cross-links and DNA double-strand breaks. Single nucleotide polymorphisms (SNPs) in ERCC4 may impact repair capacity and affect cancer susceptibility.
In this case-control study, we evaluated associations of four selected potentially functional SNPs in ERCC4 with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1,040 non-Hispanic white patients with SCCHN and 1,046 cancer-free matched controls. We found that the variant GG genotype of rs2276466 was significantly associated with a decreased risk of SCCHN (OR = 0.69, 95% CI 0.50–0.96), and that the variant TT genotype of rs3136038 showed a borderline significant decreased risk with SCCHN (OR = 0.76, 95% CI: 0.58–1.01) in the recessive model. Such protective effects were more evident in oropharyngeal cancer (OR = 0.61, 95% CI: 0.40–0.92 for rs2276466; OR = 0.69, 95% CI: 0.48–0.98 for rs3136038). No significant associations were found for the other two SNPs (rs1800067 and rs1799798). In addition, individuals with the rs2276466 GG or with the rs3136038 TT genotypes had higher levels of ERCC4 mRNA expression than those with the corresponding wild-type genotypes in 90 Epstein-Barr virus-transformed lymphoblastoid cell lines derived from Caucasians.
These results suggest that these two SNPs (rs2276466 and rs3136038) in ERCC4 may be functional and contribute to SCCHN susceptibility. However, our findings need to be replicated in further large epidemiological and functional studies.
Although the role of TNFAIP2 is still unclear, it is an important gene involved in apoptosis, and there are single-nucleotide polymorphisms (SNPs) at its microRNA (miRNA)-binding sites that could modulate miRNA target gene function. In this study, we evaluated associations of four selected SNPs (rs8126 T > C, rs710100 G > A, rs1052912 G > A and rs1052823 G > T) in the miRNA-binding sites of the 3′ untranslated region (UTR) with squamous cell carcinoma of the head and neck (SCCHN) risk in 1077 patients with SCCHN and 1073 cancer-free controls in a non-Hispanic White population. We found that, compared with the rs8126 TT genotype, the variant C allele were associated with increased SCCHN risk in an allele dose–response manner (adjusted odds ratio = 1.48 and 95% confidence interval = 1.06–2.05 for CC, respectively; Ptrend = 0.009). No significant associations were seen for the other three SNPs (rs710100 G > A, rs1052912 G > A and rs1052823 G > T). Additionally, we identified that the rs8126 T > C SNP is within the miR-184 seed binding region in the 3′ UTR of TNFAIP2. Further functional analyses showed that the rs8126 variant C allele led to significantly lower luciferase activity, compared with the T allele. In the genotype–phenotype correlation analysis of peripheral blood mononuclear cells from 64 SCCHN patients, the rs8126 CC genotype was associated with reduced expression of TNFAIP2 messenger RNA. Taken together, these findings indicate that the miR-184 binding site SNP (rs8126 T > C) in the 3′ UTR of TNFAIP2 is functional by modulating TNFAIP2 expression and contributes to SCCHN susceptibility. Larger replication studies are needed to confirm our findings.
Glutathione S-transferases (GSTs) detoxify carcinogens in tobacco smoke, which plays a major role not only in development of squamous cell carcinoma of the head and neck (SCCHN) but also second primary malignancy (SPM) after index SCCHN.
We hypothesized that GSTM1 null, GSTT1 null, GSTP1 Ile105Val, and GSTP1 Ala114Val polymorphisms would individually, and more likely, collectively demonstrate an association with risk of SPM after index SCCHN. 1,376 incident SCCHN patients were prospectively recruited between May 1996 and December 2006, genotyped, and followed for SPM development.
110 patients (8%) developed SPM: 43 (39%) second SCCHN, 38 (35%) other tobacco-associated sites, and 29 (26%) other non tobacco-associated sites. Patients with GSTP1 Ile105Val polymorphism had a statistically significant association with risk of SPM development [adjusted hazard ratio (HR),1.7; 95% confidence interval (CI),1.1-2.5)]. However, no statistically significant associations were observed with GSTM1, GSTT1, or GSTP1 Ala114Val polymorphisms. After combining risk genotypes for all four polymorphisms, rates of SPM development with 0-1, 2, 3, and 4 risk genotypes were 6.4%, 8.4%, 10.9%, and 15.1%, respectively, and a step-wise increase in SPM risk was observed with increasing number of risk genotypes (P = 0.004 for trend). Patients with 3-4 risk genotypes had a 1.7-fold increased risk for SPM compared to patients with 0-2 risk genotypes (HR, 1.70; 95% CI,1.2-2.5).
This large prospective cohort study supports a modestly increased risk of SPM after index SCCHN with GSTP1 Ile105Val polymorphism, and an even greater risk of SPM with multiple combined GST risk genotypes.
Glutathione S-transferase; Polymorphisms; Squamous cell carcinoma of the head and neck; Second primary malignancy