Modifying effect of MDM4 variants on risk of HPV16-associated squamous cell carcinoma of oropharynx

BACKGROUND:

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).

METHODS:

Genotyping was conducted on 3 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.

RESULTS:

None of 3 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.

CONCLUSION:

The risk of HPV16‐associated SCCOP could be modified by MDM4 polymorphisms. Large and prospective studies are needed to validate our findings. Cancer 2011;. © 2011 American Cancer Society.     

p53 codon 72 polymorphism associated with risk of human papillomavirus-associated squamous cell carcinoma of the oropharynx in never-smokers

The tumor suppressor p53 protein can be bound, degraded andinactivated by the human papillomavirus (HPV) E6 oncoprotein.The p53 protein's susceptibility to this oncoprotein may beinfluenced by the p53 codon 72 polymorphism, but the role ofsuch a polymorphism in the development of HPV16-associated squamouscell carcinoma of the oropharynx (SCCOP) has not been established.To investigate the role of the p53 codon 72 polymorphism inthe risk of HPV16-associated SCCOP, we conducted a hospital-basedcase–control study of 188 non-Hispanic white patientswith newly diagnosed SCCOP and 342 cancer-free control subjectsfrequency matched by age (±5 years), sex, tobacco smokingstatus and alcohol drinking status. We found that HPV16 seropositivitywas associated with an increased risk of SCCOP [adjusted oddsratio (OR), 5.7; 95% confidence interval (CI), 3.7–8.7],especially among never-smokers (adjusted OR, 14.1; 95% CI, 6.0–32.9)and among subjects with the p53 codon 72 variant genotypes [Arginine(Arg)/Proline (Pro) and Pro/Pro] (adjusted OR, 9.2; 95% CI,4.7–17.7). A significant multiplicative interaction onthe risk of SCCOP was also found between the p53 codon 72 polymorphismand HPV16 seropositivity (P = 0.05). Among never-smokers, therisk of SCCOP for those who had both HPV16 seropositivity andp53 codon 72 variant genotypes (Arg/Pro + Pro/Pro) was particularlyhigh (adjusted OR, 22.5; 95% CI, 4.8–106.2). These findingssuggest that p53 codon 72 variant genotypes modify the riskof HPV16-associated SCCOP and may be markers of genetic susceptibilityto HPV16-associated SCCOP, especially among never-smokers. Abbreviations: Arg, Arginine; CI, confidence interval; HPV, human papillomavirus; MDACC, M. D. Anderson Cancer Center; OR, odds ratio; PCR, polymerase chain reaction; Pro, Proline; SCCOP, squamous cell carcinoma of the oropharynx Received October 22, 2007; revised January 10, 2008; accepted January 29, 2008.     

Combined effects of the p53 codon 72 and p73 G4C14-to-A4T14 polymorphisms on the risk of HPV16-associated oral cancer in never-smokers

Because p53 and p73 are associated with critical cellular processes and can be inactivated or degraded by the human papillomavirus (HPV) E6 oncoprotein, we investigated the combined effects of p53 codon 72 and p73 G4C14-to-A4T14 polymorphisms on the risk of HPV16-associated oral cancer. We analyzed genotype data from 326 patients with squamous cell carcinoma of the oral cavity or oropharynx and 349 cancer-free controls. We found that HPV16 seropositivity was associated with an increased risk of oral cancer [adjusted odds ratio (OR), 3.42; 95% confidence interval (CI), 2.28-5.13], especially among never-smokers (adjusted OR, 8.20; 95% CI, 3.66-18.4) and subjects with variant genotypes [adjusted OR for p53 Arg/Pro + Pro/Pro (Pro carriers), 5.00; 95% CI, 2.72-9.21; adjusted OR for p73 GC/AT + AT/AT (AT carriers), 3.83; 95% CI, 1.98-7.41]. HPV16 seropositivity was also associated with an significantly increased risk of oral cancer in all three risk groups with combined genotypes [adjusted ORs (95% CIs) were 2.28 (1.15-4.54) for p53 Arg/Arg and p73 GC/GC, the low-risk group; 3.97 (2.14-7.36) for p53 Arg/Arg and p73 AT carriers or p53 Pro carriers and p73 GC/GC, the medium-risk group and 5.11 (2.00-13.0) for p53 Pro carriers and p73 AT carriers, the high-risk group]. Moreover, HPV16-seropositive never-smokers in the high-risk group exhibited an approximately 11-fold greater risk of oral cancer (adjusted OR, 11.3; 95% CI, 1.22-106.0) than did HPV16-seronegative never-smokers in the low-risk group. These findings suggest that the combined variants of p53 and p73 significantly increase the risk of HPV16-associated oral cancer, especially among never-smokers.     

A TGF‐β1 genetic variant at the miRNA187 binding site significantly modifies risk of HPV16‐associated oropharyngeal cancer

TGF‐β1rs1982073 polymorphism at the miRNA‐187 binding site may alter TGF‐β1 expression and function, and thereby this polymorphism (genotype CT/CC) increases cancer susceptibility. HPV16 L1 seropositivity is associated with the risk of oral squamous cell carcinoma (OSCC), including oropharyngeal squamous cell carcinoma (OPSCC) and oral cavity squamous cell carcinoma (OCSCC). Thus, we hypothesized that TGF‐β1rs1982073 polymorphism at the miRNA‐187 binding site combined with HPV16 L1 seropositivity may have a joint effect on OSCC susceptibility. We determined the genotypes of TGF‐β1rs1982073 and HPV16 status in 325 OSCC subjects and 335 cancer‐free controls in the non‐Hispanic white population, and used logistic regression models to evaluate the joint effects on OSCC susceptibility. TGF‐β1rs1982073 polymorphism (CT/CC genotype) combined with HPV16 L1 seropositivity increased the risk of OSCC via joint effects, particularly in OPSCC subjects who were never‐smokers (OR, 165.9; 95% CI, 28.6–960.4) or never‐drinkers (OR, 196.0; 95% CI, 28.2–1,000.0), respectively. Younger subjects had a higher risk of OPSCC than older subjects (OR, 23.5; 95% CI, 6.3–87.0 vs. OR, 6.0; 95% CI, 1.7–17.9, respectively). The significant associations between this polymorphism and HPV16‐associated OSCC and OPSCC were also observed. However, OCSCC subjects did not have similar results. Our findings suggest that the joint effects of TGF‐β1rs1982073 and HPV16 L1 seropositivity can increase risk of HPV16‐associated oral cancer, particularly in OPSCC subjects who are never‐smokers, never‐drinkers and young. This result may help us understand the tumorigenesis process and improve early detection, which are critical for prevention and intervention strategies. However, larger studies are needed to validate our findings.     

A genetic variant within MDM4 3′UTR miRNA binding site is associated with HPV16‐positive tumors and survival of oropharyngeal cancer

As mouse double minute 4 (MDM4) and HPV16 E6 oncoproteins play important roles in inhibition of p53 activity, a functional polymorphism (rs4245739) in the 3′ untranslated regions of MDM4 targeted by microRNA‐191 may alter its expression level or functional efficiency, thus affecting tumor status and survival in human papillomavirus (HPV)‐positive squamous cell carcinoma of oropharynx (SCCOP). A total of 564 incident SCCOP patients with definitive radiotherapy were included for determination of tumor HPV16 status and genotypes of the polymorphism. Univariate and multivariable Cox models were performed to assess the associations between the polymorphism and outcomes. We found that MDM4 rs4245739 had statistically significant associations with tumor HPV‐positivity and survival of SCCOP patients. Patients with AC/CC variant genotypes of MDM4 rs4245739 were approximately 3‐fold more likely to be HPV16‐positive tumors among SCCOP patients compared with common homozygous AA genotype (adjusted odds ratio = 3.2, 95% confidence interval = 1.9‐5.5). Moreover, patients with MDM4 rs4245739 AC/CC variant genotypes had significantly better overall, disease‐specific, and disease‐free survival compared with those with the corresponding common homozygous AA genotype (all log‐rank = P < .05); and these genotypes were significantly associated with an approximately three to four times reduced risk of overall death, death owing to disease, and recurrence after multivariable adjustment. Finally, the significant effects of MDM4 rs4245739 polymorphism on survival were found among HPV16‐positive SCCOP patients only after the stratified analyses by tumor HPV status. We concluded that MDM4 rs4245739 polymorphism is significantly associated with tumor HPV status and survival of SCCOP, especially in HPV16‐positive SCCOP patients treated with definitive radiotherapy; nevertheless, prospective larger studies are warranted.     

Combined p53-related genetic variants together with HPV infection increase oral cancer risk

To explore the role of polymorphisms of p53-related genes in etiology of oral cancer, we investigated joint effects of seven putatively functional polymorphisms of p53 (codon 72 Arg/Pro), p73 (4/14 GC/AT), murine double minute 2 gene (MDM2; A2164G and T2580G) and MDM4 (rs11801299 G > A, rs10900598 G > T and rs1380576 C > G) on risk of human papillomavirus (HPV)16-associated oral cancer in a case-control study with 325 cases and 335 cancer-free controls. We found that HPV16 seropositivity alone was associated with an increased risk of oral cancer [adjusted odds ratio (OR), 3.1; 95% confidence interval (CI), 2.1-4.6]. After combining genotypes of seven polymorphisms and using the low-risk group (0-3 combined risk genotypes) and HPV16 seronegativity as the reference group, the medium-risk (4 combined risk genotypes) and high-risk groups (5-7 combined risk genotypes) and HPV16 seronegativity were associated with only an OR of 1.6 (95% CI, 1.1-2.5) and 1.2 (95% CI, 0.7-1.9) for oral cancer risk, respectively, whereas the low-risk, medium-risk and high-risk groups and HPV16 seropositivity were significantly associated with a higher OR of 2.1 (95% CI, 1.2-3.6), 4.0 (95% CI, 1.8-9.1) and 19.1 (95% CI, 5.7-64.2), respectively. Notably, such effect modification by these combined risk genotypes was particularly pronounced in young subjects (aged < 50 years), never smokers and patients with oropharyngeal cancer. Taken together, these findings suggest that the combined risk genotypes of p53-related genes may modify risk of HPV16-associated oral cancer, especially in young patients, never-smokers and patients with oropharyngeal cancer. Larger studies are needed to validate our findings.     

Genetic variants in microRNA‐binding sites of DNA repair genes as predictors of recurrence in patients with squamous cell carcinoma of the oropharynx

The incidence of squamous cell carcinoma of the oropharynx (SCCOP) continues to rise because of increasing rates of human papillomavirus (HPV) infection. Inherited polymorphisms in DNA repair pathways may influence the risk of SCCOP development and the prognosis of SCCOP. We sought to determine whether polymorphisms in microRNA (miRNA)‐binding sites within 3′‐untranslated regions (3'UTRs) of genes in DNA repair pathways modulate the risk of SCCOP recurrence. We evaluated the associations between nine such polymorphisms and SCCOP recurrence in 1,008 patients with incident SCCOP using the log‐rank test and multivariable Cox models. In an analysis of all the patients, patients with variant genotypes of BRCA1 rs12516 and RAD51 rs7180135 had better disease‐free survival (log‐rank, p = 0.0002 and p = 0.0003, respectively) and lower risk of SCCOP recurrence (hazard ratio [HR], 0.5, 95% confidence interval [CI], 0.2–0.8, and HR, 0.5, 95% CI, 0.3–0.9, respectively) than patients with common homozygous genotypes of the two polymorphisms after multivariable adjustment. Moreover, in tumor HPV16‐positive patients, patients with variant genotypes of the same two polymorphisms also had better disease‐free survival (log‐rank, p = 0.004 and p = 0.003, respectively) and lower recurrence risk (HR, 0.2, 95% CI, 0.1–0.6, and HR, 0.2, 95% CI, 0.0–0.7, respectively) than patients with common homozygous genotypes of the two polymorphisms. No such significant associations were found for other polymorphisms. These findings support significant roles of BRCA1 rs12516 and RAD51 rs7180135 in modifying the risk of recurrence of SCCOP, particularly HPV16‐positive SCCOP. However, these results must be validated in larger studies.     

p73 G4C14‐to‐A4T14 polymorphism and risk of second primary malignancy after index squamous cell carcinoma of head and neck

P73 plays an important role in modulating cell‐cycle control, inducing apoptosis, and inhibiting cell growth. A novel noncoding p73 G4C14‐to‐A4T14 exon 2 polymorphism was associated with risk of squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that p73 G4C14‐to‐A4T14 polymorphism modulates risk of second primary malignancies (SPM) in patients after index SCCHN. We followed a cohort of 1,384 patients diagnosed with incident SCCHN between May 1995 and January 2007 for SPM development. Log‐rank test and Cox proportional hazard models were used to compare SPM‐free survival and SPM risk between the different genotype groups. Our results showed that patients carrying the p73 variant AT allele were less likely to develop SPM compared with the patients with p73 GC/GC genotype (Log‐rank test, p = 0.013). Compared with the p73 GC/GC genotype, there was a significantly reduced risk of SPM associated with the p73 GC/AT genotype (HR, 0.61, 95% CI, 0.40–0.93) and the combined p73 GC/AT+AT/AT genotypes (HR, 0.59, 95% CI, 0.39–0.89), but a nonsignificantly reduced risk for p73 AT/AT genotype (HR, 0.44, 95% CI, 0.14–1.41). The p73 AT allele was significantly associated with risk of SPM in an allele dose‐response manner (p = 0.011 for trend). The risk of SPM associated with p73 variant genotypes (GC/AT+AT/AT) was more pronounced in several subgroups (e.g., older patients, men, minorities, ever smokers, and ever drinkers). Our results support that this p73 polymorphism may be a marker for risk of SPM among patients with an incident SCCHN. © 2009 UICC     

The p73 G4C14‐to‐A4T14 polymorphism is associated with risk of lung cancer in the Han nationality of North China

p73, a structural and functional homolog of p53, plays an important role in tumor carcinogenesis. Previous studies have suggested that the association between the p73 G4C14‐to‐A4T14 polymorphism and the risk of lung cancer, but the results have not been entirely consistent. We examined whether the p73 G4C14‐to‐A4T14 polymorphism was related to the risk of developing lung cancer in a Chinese population. The p73 G4C14‐to‐A4T14 polymorphism was genotyped in 293 lung cancer patients and 380 cancer‐free controls of Han nationality in North China using PCR‐RFLP. Multivariate logistic regression analysis was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). We observed that compared with the GC/GC genotype, the genotypes containing AT allele (GC/AT + AT/AT genotypes) were associated with significantly increased susceptibility to lung cancer (OR, 1.48; 95% CI, 1.08–2.02; P = 0.014). In addition, compared with the GC/GC genotype, the GC/AT genotype was also significantly associated with increased susceptibility to lung cancer (OR, 1.46; 95% CI, 1.06–2.02; P = 0.046). Our findings suggest that the p73 G4C14‐to‐A4T14 polymorphism contributes to the risk of developing lung cancer in Chinese population. © 2012 Wiley Periodicals, Inc.     

p73 G4C14-to-A4T14 polymorphism and risk of lung cancer

Genetic variants in genes controlling cellular processes such as cell cycle, DNA repair, and apoptosis may modulate lung cancer risk. p73 has some p53-like activity and plays an important role in modulating these processes. The noncoding region of exon 2 of the p73 gene has two polymorphisms that are in complete linkage disequilibrium with one another, which may alter translation efficiency of the p73 protein. To test the hypothesis that this p73 polymorphism plays a role in the etiology of lung cancer, we conducted a hospital-based case-control study of 1054 patients newly diagnosed with lung cancer and 1139 cancer-free controls and evaluated the association between the p73 variant AT allele and risk of lung cancer. Cancer-free controls were frequency matched to the cases by age (+/-5 years), sex, and smoking status, and all subjects were non-Hispanic whites. The variant AT allele and genotypes were more common among the cases than among the controls (P = 0.0007 and P < 0.001, respectively). Compared with the GC/GC genotype, the variant GC/AT and AT/AT genotypes were associated with a statistically significantly increased risk for lung cancer [adjusted odds ratio (OR) = 1.32, 95% confidence interval (CI), 1.10-1.59 and OR = 1.54, 95% CI, 1.05-2.26, respectively] in an allele dose-effect relationship (trend test: P < 0.001). The risk associated with the AT allele (GC/AT+AT/AT) was more pronounced in younger (相似文献   

Pre-microRNA variants predict HPV16-positive tumors and survival in patients with squamous cell carcinoma of the oropharynx

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.     

Genetic variants in TNF‐α promoter are predictors of recurrence in patients with squamous cell carcinoma of oropharynx after definitive radiotherapy

The promoter variants of TNF‐α, a major regulator of immune and inflammation responses, have been implicated in cancer development and prognosis. Thus, we investigated associations between four TNF‐α promoter variants and risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated associations of four TNF‐α polymorphisms with risk of recurrence in a cohort of 846 patients with SCCOP. Log‐rank test and multivariable Cox models were used to evaluate associations. Compared with patients with variant genotypes of the TNF‐α ‐308 and TNF‐α ‐863 polymorphisms, patients with common homozygous genotypes had worse disease‐free survival (log‐rank p = 0.0002 and p < 0.0001, respectively) and increased risk of SCCOP recurrence (HR, 1.9, 95% CI, 1.3–2.8 and HR, 1.9, 95% CI, 1.3–2.7, respectively) after multivariable adjustment. Furthermore, among patients with HPV16‐positive tumors, those with common homozygous genotypes of the TNF‐α ‐308 and ‐863 polymorphisms had worse disease‐free survival (log‐rank p = 0.005 and p = 0.007, respectively) and higher recurrence risk than patients with variant genotypes of these polymorphisms (HR, 5.1, 95% CI, 1.4–18.4 and HR, 3.7, 95% CI, 1.5–9.1, respectively), while no such significant associations were found for TNF‐α ‐857 or ‐1031 polymorphisms. Our findings suggest that TNF‐α ‐308 and ‐863 polymorphisms may modulate the risk of SCCOP recurrence in patients with HPV16‐positive tumors. However, larger studies are needed to validate these results.     

Cyclooxygenase‐2 gene polymorphisms reduce the risk of oral premalignant lesions

BACKGROUND:

Oral premalignant lesions (OPLs) have the potential to transform into malignant oral cancers. Overexpression of the cyclooxygenase‐2 gene (COX‐2) is observed frequently in OPLs and oral cancers, suggesting that this gene may play an important role in the progression of oral cancer. Single‐nucleotide polymorphisms of COX‐2 have been associated with the risk of multiple cancers; however, to date, their effects on OPL susceptibility have not been evaluated sufficiently.

METHODS:

The authors conducted a case‐control study that included 147 patients with OPL and a group of 147 healthy, matched controls. The effects of 3 potentially functional COX‐2 polymorphisms on the risk of OPL were evaluated: the ?765 G→C polymorphism (rs20417), the exon 10 +837 T→C polymorphism (rs5275), and the exon 10 ?90 C→T polymorphism (rs689470).

RESULTS:

The variant‐containing genotypes of COX‐2 exon 10 +837T→C variant were associated with a significantly reduced risk of OPL (odds ratio [OR], 0.48; 95% confidence interval [95% CI], 0.28‐0.80). This protective effect also was significant in men, younger individuals, ever smokers, and ever drinkers. Consistently, a common halotype WMW (in the following order: ?765G→C, exon 10 +837T→C, and exon 10 ?90C→T; w, widetype; M, variable allele) and a common diplotype (WWW/WMW) that contained the variant allele of exon 10 +837T→C, both were associated with a reduced risk of OPL (WMW: OR, 0.55; 95% CI, 0.33‐0.93; WWW/WMW: OR, 0.44; 95% CI, 0.22‐0.89). In addition, using never smokers with the variant‐containing genotypes as the reference group, interaction effects were observed between specific COX‐2 variants and tobacco smoking in the modulation of OPL risk.

CONCLUSIONS:

Overall, the current results provided the first epidemiologic evidence indicating that potentially functional polymorphisms of the COX‐2 gene may have an impact on individual susceptibility to OPLs. Cancer 2009. © 2009 American Cancer Society.     

The functional cytotoxic T lymphocyte-associated Protein 4 49G-to-A genetic variant and risk of pancreatic cancer

BACKGROUND:

Antitumor T lymphocytes play an essential part in immune surveillance of cancer cells. Cytotoxic T lymphocyte–associated Protein 4 (CTLA‐4) is a negative regulator of T cell activation and proliferation and therefore influences immune surveillance of carcinogenesis of pancreas. Thus, this study examined the association between functional CTLA‐4 49G‐to‐A (49G>A) single‐nucleotide polymorphism and pancreatic cancer risk.

METHODS:

Genotypes were determined in 368 patients with pancreatic cancer and 926 controls, and odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression.

RESULTS:

A significant increased risk of pancreatic cancer was found to be associated with the CTLA‐4 49G>A single‐nucleotide polymorphism. Compared with noncarriers, the OR of developing pancreatic cancer for CTLA‐4 49 GA or AA carriers was 1.75 (95% CI = 1.34‐2.30, P = 4.83 × 10^?5) or 2.54 (95% CI = 1.67‐3.87, P = 1.36 × 10^?5), respectively. In stratified analyses, the association was more pronounced in GA and AA carriers aged ≤60 years (OR = 3.10, 95% CI = 2.15‐4.47, P_interaction = .002), smokers with GA and AA genotypes (OR = 3.92, 95% CI = 2.39‐6.43, P_interaction = .037), and drinkers with GA and AA genotypes (OR = 4.55, 95% CI = 2.65‐7.82, P_interaction = .042), compared with GG carriers. Moreover, a supermultiplicative interaction between the CTLA‐4 49AA genotype and smoking plus drinking was also evident in intensifying risk of pancreatic cancer (P_interaction = 5.64 × 10^?12).

CONCLUSIONS:

These results suggest that CTLA‐4 49G>A polymorphism is involved in susceptibility to developing pancreatic cancer, alone and in a gene–environment interaction manner. Cancer 2012. © 2012 American Cancer Society.     

Passive and active smoking and breast cancer risk in Canada, 1994–97

Background: Studies comparing ever smokers with never smokers have found little increase in breast cancer risk. However, the five published studies examining passive smoking and breast cancer have all suggested associations with both passive and active smoking, particularly premenopausal risk. Methods: We analyzed data collected through the Canadian National Enhanced Cancer Surveillance System, from 805 premenopausal and 1512 postmenopausal women with newly diagnosed (incident), histologically confirmed, primary breast cancer and 2438 population controls. The mailed questionnaire included questions on breast cancer risk factors and a lifetime residential and occupational history of exposure to passive smoking. Results: Among premenopausal women who were never active smokers, regular exposure to passive smoke was associated with an adjusted breast cancer odds ratio (OR) of 2.3 (95% confidence interval [CI] 1.2–4.6). Passive exposure showed a strong dose–response trend (test for trend p=0.0007) with an OR of 2.9 (95% CI 1.3–6.6) for more than 35 years of passive residential and/or occupational exposure. When premenopausal women who had ever actively smoked were compared with women never regularly exposed to passive or active smoke, the adjusted OR for breast cancer was also 2.3 (95% CI 1.2–4.5). Among postmenopausal women who were never-active smokers, regular exposure to passive smoke was associated with an adjusted breast cancer OR of 1.2 (95% CI 0.8–1.8) and an OR of 1.4 (95% CI 0.9–2.3) for the most highly exposed quartile of women. The adjusted OR for postmenopausal breast cancer risk for ever-active smokers compared with women never regularly exposed to passive or active smoke was 1.5 (95% CI 1.0–2.3). Statistically significant dose–response relationships were observed with increasing years of smoking, increasing pack-years and decreasing years since quitting. Women with 35 or more years of smoking had an adjusted OR of 1.7 (95% CI 1.1–2.7). Conclusions: Active and passive smoking may be associated with increased breast cancer risk, particularly premenopausal risk.     

Associations of human leukocyte antigen class II genotypes with human papillomavirus 18 infection and cervical intraepithelial neoplasia risk

BACKGROUND:

Only a small proportion of women infected with human papillomavirus type 18 (HPV18) may progress to persistent infection and cervical neoplasia. This community‐based cohort study aimed to assess associations with human leukocyte antigen (HLA) class II genotypes for natural infection of HPV18 and subsequent risk of cervical neoplasia.

METHODS:

Among 10,190 cytologically normal participants, 125 with HPV18 infection were identified by HPV blot kit. HPV18 viral load at study entry was examined by real‐time polymerase chain reaction; persistent infection was defined as HPV18 infection at 2 consecutive examinations.

RESULTS:

There was a significant association between HLA‐DRB1*0403 allele and high HPV18 viral load (>1000 copies in 50 ng of total DNA) at study entry (odds ratio [OR], 7.2; 95% confidence interval [CI], 2.0‐25.2). After adjustment for age and viral load at study entry, haplotype HLA‐DRB1*0405‐DQA1*0301‐DQB1*0302 was significantly associated with persistent HPV18 infection (OR, 13.3; 95% CI, 1.7‐105.9). HLA‐DRB1*0403 allele was also associated with a significantly increased risk of high‐grade squamous intraepithelial lesion or cancer, showing a multivariate‐adjusted hazard ratio (95% CI) of 18.1 (2.6‐128.5).

CONCLUSIONS:

HLA‐DRB1*0403 allele and HLA‐DRB1*0405‐DQA1*0301‐DQB1*0302 haplotype may play important roles in determination of high viral load and persistent infection of HPV18 and subsequent cervical neoplasia risk. Cancer 2012;. © 2011 American Cancer Society.     

Impact of smoking on patients with stage III colon cancer

BACKGROUND:

Cigarette smoking has been shown to increase the risk of developing colorectal cancer, particularly smoking early in life. Little is known about the impact of tobacco use on colon cancer recurrence among colon cancer survivors.

METHODS:

The authors prospectively collected lifetime smoking history from stage III colon cancer patients enrolled in a phase 3 trial via self‐report questionnaires during and 6 months after completion of adjuvant chemotherapy. Smoking status was defined as never, current, or past. Lifetime pack‐years were defined as number of lifetime packs of cigarettes. Patients were followed for recurrence or death.

RESULTS:

Data on smoking history were captured on 1045 patients with stage III colon cancer receiving adjuvant therapy (46% never smokers; 44% past; 10% current). The adjusted hazard ratio (HR) for disease‐free survival (DFS) was 0.99 (95% confidence interval [CI], 0.70‐1.41), 1.17 (95% CI 0.89‐1.55), and 1.22 (95% CI 0.92‐1.61) for lifetime pack‐years 0‐10, 10‐20, and 20+, respectively, compared with never smoking (P = .16). In a preplanned exploratory analysis of smoking intensity early in life, the adjusted HR for 12+ pack‐years before age 30 years for DFS was 1.37 (95% CI, 1.02‐1.84) compared with never smoking (P = .04). The adjusted HR for DFS was 1.18 (95% CI, 0.92‐1.50) for past smokers and 1.10 (95% CI, 0.73‐1.64) for current smokers, compared with never smokers.

CONCLUSIONS:

Total tobacco usage early in life may be an important, independent prognostic factor of cancer recurrences and mortality in patients with stage III colon cancer. Cancer 2010. © 2010 American Cancer Society.     

5,10-Methylenetetrahydrofolate reductase polymorphisms and the risk of pancreatic cancer.

To test the hypothesis that 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms modify the risk of pancreatic cancer, we conducted a hospital-based, case-control study involving 347 patients with newly diagnosed pancreatic adenocarcinoma and 348 healthy controls, frequency matched by age, sex, and race. MTHFR polymorphisms were determined using the PCR-RFLP method. Association of these polymorphisms with the risk of pancreatic cancer was estimated by unconditional logistic regression analysis. We found that the C667T (but not the A1298C) polymorphism had a significant main effect on the risk of pancreatic cancer. The frequencies of the MTHFR 667CC, 667CT, and 667TT genotypes were 49.5%, 38.6%, and 11.9%, respectively, among cases compared with 48.5%, 45.0%, and 6.5%, respectively, among controls. Individuals with the 667TT genotype displayed a 2-fold increased risk for pancreatic cancer compared with those with the CC/CT genotypes [adjusted odds ratio (OR), 2.14; 95% confidence interval (95% CI), 1.14-4.01]. Multivariate analyses found that the effect of the 677TT genotype on the risk of pancreatic cancer was present among ever smokers (OR, 5.53; 95% CI, 2.0-15.3) and ever alcohol drinkers (OR, 3.16; 95% CI, 1.30-7.69) but not in never smokers (OR, 0.82; 95% CI, 0.33-2.06) and never drinkers (OR, 1.42; 95% CI, 0.56-3.62). Furthermore, a positive interaction between the MTHFR TT genotype and heavy smoking or heavy alcohol consumption was detected. The OR (95% CI) of pancreatic cancer was 6.83 (1.91-24.38) for heavy smokers among the TT carriers compared with never smokers with the CC/CT genotypes and 4.23 (0.88-20.3) for heavy drinkers with the TT genotype compared with nondrinkers with the CC/CT genotypes. These observations support a role for folate metabolism in pancreatic cancer, especially among smokers and heavy drinkers.     

Etiologic role of human papillomavirus infection in bladder carcinoma

BACKGROUND:

The authors elucidated an etiologic role of human papillomavirus (HPV) infection in carcinoma of the bladder.

METHODS:

One hundred seventeen of 224 patients with bladder carcinoma who were treated between 1997 and 2009 were enrolled in this study. The presence of HPV DNA was tested on frozen carcinoma tissues that were obtained by transurethral resection using a polymerases chain reaction‐based method. Localization of HPV was observed on archival tissue specimens by in situ hybridization (ISH) for high‐risk HPV DNA. Cyclin‐dependent kinase (CDK) inhibitor 2A (inhibits CDK4) (p16‐INK4a) and minichromosome maintenance protein‐7 (mcm‐7)—surrogate markers for high‐risk HPV‐E7 oncoprotein—and HPV‐L1 (capsid) protein expression were evaluated by immunohistochemistry.

RESULTS:

HPV types 16, 18, 31, 33, 52, and 58, and an unknown HPV type were detected in 18 of 117 samples (15%) from patients with bladder carcinoma. HPV16 was identified in 6 samples, HPV18 was identified in 4 samples, and HPV33 was identified in 3 samples. All were single HPV type infections. HPV was detected in 38% (12 of 28) of histologic grade 1 bladder carcinomas, 8.5% (6 of 71) of grade 2 bladder carcinomas, and in 0% (0 of 18) of grade 3 bladder carcinomas. Multivariate analysis indicated that younger age (<60 years; odds ratio [OR], 10.9; 95% confidence interval [CI], 2.6‐45.3) and grade 1 tumors (OR, 4.5; 95% CI, 1.2‐17.0) were associated with HPV infection. ISH analysis indicated that high‐risk HPV DNA was localized in the nuclei of tumor cells of all HPV‐positive samples. p16‐INK4a and mcm‐7 were expressed in 94% and 89% of HPV‐positive carcinoma cells, respectively. HPV‐L1 protein expression, which suggested reproductive HPV infection, was not observed in any carcinoma.

CONCLUSIONS:

The current results indicated that high‐risk HPV is likely to be a causative agent of some low‐grade bladder carcinomas that develop in younger patients. Cancer 2011. © 2010 American Cancer Society.