Clinic-based Case-control Study Research Articles

Multiple variants of TERT and CLPTM1L constitute risk factors for lung adenocarcinoma

Recent studies have shown that 5p15.33 is one of the chromosomal regions that is most consistently altered in lung cancer; common variants that are located in this region have been genotyped in various populations. However, the genetic contribution of these variants to carcinogenesis is relatively unknown. A clinic-based case-control study in Shanghai was undertaken on 196 patients with lung cancer and 229 healthy individuals. TERT rs2736100 and CLPTM1L rs401681 and rs402710 were genotyped using the ABI TaqMan Allelic Discrimination assay. For rs2736100, the G variant and the GG genotype were more frequent, whereas the TT genotype was less frequent in patients with lung adenocarcinoma than in controls. The CT genotype at rs401681 was more common and the TT genotype was rare in patients, and the differences were significant between lung adenocarcinoma patients and controls. This was also true for rs402710. Moreover, the frequency of the GGCTCT haplotype was higher and the TTTTTT frequency was lower in patients, especially those with lung adenocarcinoma. Aberrant linkage disequilibrium among the three SNPs was found in patients with lung adenocarcinoma. We conclude that multiple variants at 5p15.33 contribute to susceptibility to lung adenocarcinoma.

Case–control study of smoking and non-melanoma skin cancer

To investigate the association between cigarette smoking and basal and squamous cell carcinomas (BCC and SCC) of the skin, a clinic-based case-control study was conducted in Tampa, FL. Patients with histologically confirmed BCC/SCC were recruited from a university dermatology clinic (n = 215 BCC, 165 SCC). Controls were comprised of individuals with no history of skin cancer who screened negative for skin cancer upon physical examination at the affiliated cancer screening or primary care clinics (n = 315). Information on smoking and other risk factors was obtained from self-administered questionnaires. After adjustment for age, sex, and other skin cancer-risk factors, ever smoking was not associated with BCC (odds ratio (OR) = 1.26, 95% confidence interval (CI) = 0.83-1.92), but was statistically significantly associated with SCC (OR = 1.97, 95% CI = 1.19-3.26), with significant trends observed for SCC associated with increasing cigarettes per day (p = 0.01) and pack-years smoked (p = 0.01). Among men, smoking ≥20 pack-years was associated with non-significant increased risks of BCC (OR = 1.90, 95% CI = 0.88-4.12) and SCC (OR = 1.97, 95% CI = 0.84-4.66), whereas among women, no association was observed with BCC (OR = 0.98, 95% CI = 0.39-2.46) while a statistically significant three-fold risk was observed with SCC (OR = 3.00, 95% CI = 1.02-8.80). Cigarette smoking is more strongly associated with SCC than BCC, particularly among women.

Aspirin, Nonsteroidal Anti-inflammatory Drugs, Acetaminophen, and Pancreatic Cancer Risk: a Clinic-Based Case–Control Study

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAID) show indisputable promise as cancer chemoprevention agents. However, studies have been inconsistent as to whether aspirin has a protective effect in development of pancreatic cancer. To further evaluate the association between aspirin, NSAID, and acetaminophen use with pancreatic cancer risk, we used a clinic-based case-control study of 904 rapidly ascertained histologically or clinically documented pancreatic ductal adenocarcinoma cases, and 1,224 age- and sex-matched healthy controls evaluated at Mayo Clinic from April 2004 to September 2010. Overall, there is no relationship between non-aspirin NSAID or acetaminophen use and risk of pancreatic cancer. Aspirin use for 1 d/mo or greater was associated with a significantly decreased risk of pancreatic cancer (OR = 0.74, 95% CI: 0.60-0.91, P = 0.005) compared with never or less than 1 d/mo. Analysis by frequency and frequency-dosage of use categories showed reduced risk (P = 0.007 and 0.022, respectively). This inverse association was also found for those who took low-dose aspirin for heart disease prevention (OR = 0.67, 95% CI: 0.49-0.92, P = 0.013). In subgroup analyses, the association between aspirin use and pancreatic cancer was not significantly affected by pancreatic cancer stage, smoking status, or body mass index. Our data suggest that aspirin use, but not non-aspirin NSAID use, is associated with lowered risk of developing pancreatic cancer.

Fruit and vegetable consumption is inversely associated with having pancreatic cancer

Studies on fruit, vegetable, fiber, and grain consumption and pancreatic cancer risk are inconclusive. We used a clinic-based case-control study specifically designed to address limitations of both cohort and case-control studies to examine the relationship. Participants were excluded who reported changing their diet within 5years prior to study entry. And 384 rapidly ascertained cases and 983 controls (frequency matched on age (±5years), race, sex, and residence) completed epidemiologic surveys and 144-item food frequency questionnaires. Odds ratios (OR) and 95% confidence intervals were calculated using logistic regression adjusted for age, sex, smoking, body mass index, energy intake, and alcohol consumption. Comparing highest to lowest quintiles, we observed significant inverse associations (OR<0.8) with significant trends (p (trend)<0.05) for citrus, melon, and berries, other fruits, dark green vegetables, deep yellow vegetables, tomato, other vegetables, dry bean and pea, insoluble fiber, soluble fiber, whole grains, and orange/grapefruit juice, and an increased association with non-whole grains. Results were similar after adjusting for diabetes or total sugar intake. We provide evidence that lower consumption of fruits, vegetables, whole grains, and fiber is associated with having pancreatic cancer. This may have a role in developing prevention strategies.

P2-S9.07 Economic risk factors for syphilis infection among pregnant women in rural Haiti

BackgroundOf the 12 million global adult syphilis infections occurring globally each year, syphilis disproportionately affects women in low-income countries. WHO estimates about 80% of syphilis positive pregnancies go untreated, often...

Abstract 1896: Simple mediation analysis to determine if MSMB is a prostate specific antigen (PSA) or prostate cancer (PC) gene

Abstract Background: PC genome-wide association studies have identified MSMB as a candidate susceptibility gene in European populations screened and unscreened for PC. Studies have also shown an association between MSMB (rs10993994) and PSA levels in men without PC diagnoses, suggesting that the association between MSMB and PC may be a reflection of disease screening with PSA. The goal of this study was to determine whether MSMB is a prostate cancer gene or a PSA gene by testing the hypothesis that PSA at diagnosis mediates the relationship between MSMB and PC risk and severity in European Americans. Methods: Using 772 PC cases and 194 controls from our clinic-based case-control study, we conducted a simple mediation analysis using 4 Steps and the Sobel test. In step 1 we tested the significance of MSMB(rs10993994) on PC risk and severity. We then tested the significance of MSMB and PSA at diagnosis (Step 2). In Step 3, tested whether there was a relationship between PSA and PC not accounted for by MSMB. Since Steps 2/3 were passed, we had evidence consistent with a nonzero indirect effect, leading to Step 4, where we compared the observed values and the significance of the relationship between MSMB and PC unadjusted (Step 1) and adjusted for PSA. A Sobel Test was then conducted to determine if the indirect effect of MSMB on PC risk and severity via PSA was significant. Results were stratified by prostate cancer severity: Aggressive prostate cancer (Tumor stage &amp;gt;II and/or Gleason &amp;gt;7); Nonaggressive prostate cancer (Tumor stage &amp;lt;II and/or Gleason &amp;lt;7). For Steps 1,3,4, odds ratios (OR) and 95% confidence intervals(95%CI) were calculated using unconditional logistic regression, adjusted by age. For Step 2, linear regression coefficients were calculated adjusted by age. Results: Step 1: MSMB was significantly associated with PC risk(OR=1.40,95%CI=1.02-1.93) and nonaggressive PC(OR=1.52,95%CI=1.08-2.16), particularly for the risk genotype(TT)(PC OR=1.91,95%CI=1.01-3.66; nonaggressive OR=2.27,95%CI=1.13-4.55). Step 2: MSMB, particularly the TT genotype, and LogPSA were significantly associated (p=0.04). Step 3: LogPSA was associated with PC risk (OR=13.1,95%CI=8.24-20.9) and nonaggressive PC(OR=8.47,95%CI=5.33-13.5), adjusting for MSMB. Step 4: The association between MSMB and PC risk(OR=1.37,95%CI=0.88-2.14; TT OR=1.66,95%CI=0.70-3.97) and nonaggressive PC(OR=1.47,95%CI=0.93-2.33; TT OR=1.98,95%CI=0.81-4.89) was lower and no longer significant after adjusting for LogPSA, suggesting that PSA is a complete mediator. The Sobel test showed the indirect effect of MSMB on PC (p=0.048) and nonaggressive PC(p=0.049) was significant. Discussion: Our results show that PSA screening is a mediator of the relationship between MSMB and PC risk and nonaggressive PC, suggesting that MSMB is more a PSA gene than a PC risk gene. Our study has limited power and would need to be validated in larger studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1896. doi:10.1158/1538-7445.AM2011-1896

Abstract 874: Genetic variation in the NOTCH stem cell signaling network in relation to risk of adult-onset glioma

Abstract The Notch signaling network is an evolutionarily conserved intercellular signaling pathway that plays a fundamental role during cell-fate specification in the developing mammalian nervous system. Mounting evidence suggest that this signaling network plays a critical oncogenic role in the development and progression of glioma. Stem-like cells in brain tumors require Notch for their survival and growth. Moreover, Notch-1 and its ligands, Delta-like-1 and Jagged-1 are overexpressed in both glioma cell lines and primary human gliomas. Down-regulation of Notch-1, Delta-like-1, or Jagged-1 by RNA interference induces apoptosis and inhibits proliferation in multiple glioma cell lines. Finally, pretreatment of glioma cells with Notch-1 or Delta-like-1 small interfering RNA significantly prolongs survival in experimental models of brain tumors. In the present study, we tested whether single nucleotide polymorphisms (SNPs) in the genes encoding Notch-1 (NOTCH1 at 9q34) and its ligands, Delta-like-1 (DLL1 at 6q27) and Jagged-1 (JAG1 at 20p12-p11) are associated with the risk of glioma onset in a clinic-based case-control study conducted at medical centers in the southeastern US. A total of 29 candidate and haplotype tagging SNPs (10 SNPs in NOTCH1; 2 in DLL1 and 17 in JAG1) were genotyped using the Illumina Goldengate assay in 563 newly diagnosed (eg. nonrecurrent) glioma cases (including 324 WHO grade IV glioblastomas (GBM); 145 WHO grade II or III astrocytomas and 94 oligoastrocytomas and oligodendrogliomas) and 629 healthy controls with no history of brain tumor. DNA was isolated from saliva samples. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for individual SNPs adjusting for age and gender. No consistent associations were observed for either examined variant in DLL1. An intronic SNP (rs3013300) in NOTCH1 located 9.2kb from the start codon was associated with an increased risk of astrocytomas (per variant “T” allele OR: 1.48; 95% CI: 1.12-1.96; p=0.006; MAF: 0.31), though not other glioma subtypes. Another intronic SNP in NOTCH1 (rs11574903) in weak linkage with the rs3013300 variant (r2: 0.10) was significantly associated with risk of oligodendrogliomas (per variant ‘T” allele OR: 1.68; 95% CI: 1.18-2.40; p=0.004; MAF: 0.22). This SNP is located 62bp downstream of a nonsynonymous SNP (rs115563691; V1671I) in NOTCH1. A SNP in the 3’UTR of the NOTCH1 ligand, JAG1 (rs8708), located in a putative micro-RNA binding site, was significantly associated with the risk of GBM (per variant “A” allele OR: 1.30; 95% CI: 1.06-1.59; p=0.010; MAF: 0.45). To our knowledge, this is the first study implicating genetic variants in the Notch stem cell signaling network with cancer risk. Further research is needed to confirm these findings and to elucidate putative causal variants in this pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 874. doi:10.1158/1538-7445.AM2011-874

Abstract 950: Merkel cell polyomavirus infection in cutaneous squamous cell carcinomas

Abstract Objective: Merkel cell polyomavirus (MCV) DNA has been reported previously in 0-25% of squamous cell carcinomas (SCC) occurring in immunocompetent individuals. No studies have investigated MCV seroreactivity in individuals with SCC. We conducted a clinic-based case-control study to investigate the association between MCV seroreactivity and SCC, overall and stratified by MCV DNA status of the SCC tumor tissue. Methods: Patients with histologically-confirmed cutaneous SCC (n=173) were recruited from a university dermatology clinic. Controls were patients undergoing skin cancer screening exams who screened negative for and had no history of skin or other cancers (n=300). Levels of antibodies against capsid antigens for MCV and other polyomavirus controls (JC virus (JCV) and KI virus (KIV)) were determined by fluorescent bead-based multiplex serology. Fresh-frozen tumor tissues were obtained from 145 SCC cases, and DNA from six polyomaviruses (MCV, JCV, KIV, WU virus (WUV), BK virus (BKV) and simian virus 40 (SV40)) was measured using multiplexed PCR. Polyomavirus seropositivity, based on binary cutpoints, and quartiles of seroreactivity, based on the control distribution, were compared between SCC cases and controls, overall and stratified by the presence or absence of MCV DNA in SCC tumor tissues. Associations were estimated by calculating odds ratios (OR) and 95% confidence intervals (CI) using logistic regression to adjust for age, sex, and skin reaction to the sun. Results: MCV seropositivity was associated with a statistically significant increased risk of SCC (OR=1.80, 95% CI=1.03-3.12), whereas no association was observed for JCV (OR=1.17, 95% CI=0.72-1.92) or KIV (OR=0.88, 95% CI=0.37-2.09) seropositivity. MCV DNA was detected in 55 (38%) of SCC tumor tissues, whereas all tissues were negative for DNA from the other five polyomaviruses. Using controls as the reference group, MCV DNA-positive SCC cases were three times as likely to be MCV seropositive (OR=3.15, 95% CI=1.11-8.92) and almost six times as likely to have MCV antibody levels in the fourth versus first quartile (OR=5.94, 95% CI=1.79-19.74, ptrend=0.001). No associations were observed between MCV seropositivity and MCV DNA-negative SCC (OR=1.40, 95% CI=0.78-2.77) or between JCV or KIV seropositivity and MCV DNA-negative or DNA-positive SCC. Conclusion: SCC patients were significantly more likely than controls to exhibit MCV seroreactivity, particularly if they had MCV DNA in their SCC tumor tissue. This association was specific to MCV, with no associations observed for the other polyomaviruses studied. These results suggest that past exposure to MCV may be a risk factor for SCC in immunocompetent individuals. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 950. doi:10.1158/1538-7445.AM2011-950

Abstract 877: Genetic variation in podoplanin in relation to glioma risk and outcome

Abstract Gliomas are highly invasive tumors that invariably disseminate throughout the brain. The mechanisms of glioma cell migration are still poorly understood. Human PDPN (eg. podoplanin) is a novel transmembrane glycoprotein and a lymphatic endothelial marker thought to play a role in wound healing and frequently upregulated in human neoplasia. Although its physiologic function is still unknown, the recent observation of restricted expression at the leading invasive edge of solid tumors in experimental systems has raised the possibility that PDPN plays a role in tumor cell migration and invasion. Microarray-based gene expression analysis has recently identified PDPN as a novel candidate gene in glioma pathogenesis (Clin Cancer Res. 2009 15:6541-50). In this study, we examined whether polymorphisms in the gene encoding PDPN (located at 1p36.21) are associated with glioma risk and outcome in a clinic-based case-control study encompassing 563 newly diagnosed (eg. nonrecurrent) glioma cases (including 324 WHO grade IV glioblastomas (GBM); 145 WHO grade II or III astrocytomas and 94 oligoastrocytomas and oligodendrogliomas) and 629 healthy controls with no history of brain cancer. DNA was isolated from saliva samples. A total of 22 candidate and haplotype tagging SNPs in PDPN including the 5’ and 3’ UTR region of PDPN were genotyped using the Illumina Goldengate assay. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for glioma risk in relation to individual SNPs adjusting for age and gender. Proportional hazards regression was used to estimate age- and gender-adjusted hazard ratios (HR) for GBM-related death (203 deaths; median follow up: 11.2 months) according to PDPN genotypes. No consistent associations were observed for any examined PDPN variant with glioma risk, overall, or according to glioma histological subtype. In contrast, 3 intronic SNPs (rs92406, rs2487643 and rs4391657) in moderately high linkage disequilibrium (r2: 0.57-0.96) residing in a haplotype block spanning 8kb were significantly associated with GBM mortality with the strongest signal observed in rs4391657 (NT_004610.19:g.617369T&amp;gt;C) (per variant “T” allele HR: 1.62; 95% CI: 1.28-2.05; P=0.00006; allele frequency: 0.20). The magnitude of association was similar for deaths occurring within 12 months (per variant allele HR: 1.51; 95% CI: 1.13-2.02; P=0.005) and greater than 12 months (per variant allele HR: 1.84; 95% CI: 1.21-2.80; P=0.004) following GBM diagnosis. The median survival times were 14.4, 11.4 and 8.9 months in those carrying 0, 1, or 2 at-risk “T” alleles in PDPN rs4391657 (log rank P value 0.0018), irrespective of therapy. To our knowledge this is the first report of an association of a PDPN genetic variant predicting survival times in malignancy. Further studies are needed to confirm this observation and to identify the putative causal variant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 877. doi:10.1158/1538-7445.AM2011-877

Abstract 1894: Early adulthood sun exposure, vitamin D related gene variants, and risk of non-Hodgkin lymphoma

Abstract Background. Several recent studies have reported an inverse relationship between sun exposure and non-Hodgkin (NHL) risk. One hypothesis is that vitamin D mediates this effect. We evaluated the association of sun exposure at various ages and common variants in vitamin D related genes with risk of NHL and its major subtypes. Methods. Newly diagnosed NHL cases (N=1023) and frequency matched controls (N=1254) were enrolled in a clinic-based case-control study conducted at the Mayo Clinic. Thirty-eight single nucleotide polymorphisms (SNPs) from 5 candidate genes relevant to vitamin D metabolism and sun sensitivity (IRF4, RXR, VDR, CYP24A1, CYP27B1) were genotyped. Participants also completed a detailed questionnaire, including self-reported sun exposure at ages 13-21, 22-40, and 41+ years. Odds ratios (OR), 95% confidence intervals (CI), and tests for trend and effect modification were estimated using unconditional logistic regression adjusted for age and gender. ORs are reported for the highest vs. lowest exposure category or as the ordinal OR for SNPs. Results. The mean age of diagnosis/enrollment was 61 years for cases and 60 years for controls. The most common subtypes were chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; 34%), follicular (FL; 24%), and diffuse large B-cell (DLBCL; 18%) lymphomas. There was a significant decrease in NHL risk with increased sun exposure at ages 13-21 years (OR=0.66, 95% CI 0.44-1.00; ptrend=0.04), which attenuated with increasing age at exposure. Exploratory analysis by NHL subtype indicated a trend toward a protective effect of sun exposure at ages 13-21 years for each of the major subtypes, though these estimates did not reach statistical significance. Of the 38 SNPs evaluated, there was a significant association for 3 SNPs in VDR and 1 SNP in CYP24A1: rs3819545 (OR=1.24, 95% CI 1.10-1.40, p=0.0004), rs2239186 (OR=1.22, 95% CI 1.05-1.41, p=0.009), and rs886441 (OR=0.82, 95% CI 0.70-0.96, p=0.02) for VDR and rs2762939 (OR=0.85, 95% CI 0.75-0.98, p=0.02) for CYP24A1. Both the VDR and CYP24A1 associations were observed for CLL/SLL, FL, but were attenuated for DLBCL. There was no evidence of any significant effect modification of sun exposure at ages 13-21 years by genotype in these four SNPs for NHL overall, or for NHL subtypes. Conclusions. We observed an inverse association between the frequency of sun exposure at ages 13-21 years and NHL risk, which attenuated for sun exposure at older ages, suggesting that early life exposure may be more relevant. While genetic variation in VDR and CYP24A1 were associated with NHL risk, there was no evidence for an interaction of sun exposure with these genes, suggesting that a sun association may not act through the vitamin D metabolism pathway. This would be consistent with a lack of association of circulating vitamin D with NHL risk recently published from the Cohort Consortium pooling project. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1894. doi:10.1158/1538-7445.AM2011-1894

Abstract 876: Genetic variation in the voltage-gated chloride channel family members CLCN2 and CLCN3 in relation to glioma risk and outcome

Abstract Gliomas account for the majority of primary brain neoplasias and are among the most lethal human tumors. Tumor cells diffusely infiltrate surrounding brain tissue. The invasion of glioma cells into normal brain is thought to be facilitated by ion channels which dynamically regulate cell volume and the ability of tumor cells to shrink and invade through tortuous extracellular spaces in the brain. To shrink, glioma cells release K+ and Cl- through ion channels, which induce water to leave the cells through aquaporins. Recent evidence suggests that CL- transport in glioma cells is mediated primarily by the voltage-gated chloride channel family members, CLCN2 and CLCN3, making them attractive candidate genes in glioma pathogenesis. In the present study, we tested whether single nucleotide polymorphisms (SNPs) in CLCN2 (3q27) and CLCN3 (4q33) are associated with glioma risk or patient outcome in a clinic-based case-control study conducted at medical centers in the southeastern US. A total of 15 candidate and haplotype tagging SNPs (4 SNPs in CLCN2 and 11 SNPs in CLCN3) were genotyped using the Illumina Goldengate assay in 563 newly diagnosed (eg. nonrecurrent) glioma cases (including 324 WHO grade IV glioblastomas (GBM); 145 WHO grade II or III astrocytomas and 94 oligoastrocytomas and oligodendrogliomas) and 629 healthy controls. DNA was isolated from saliva samples. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for glioma risk in relation to individual genotypes adjusting for age and gender. Proportional hazards regression was used to estimate age and gender-adjusted hazard ratios (HR) for GBM-related death (203 deaths; median follow up: 11.2 months) for each SNP. No consistent associations were observed for any examined variant in CLCN2. In contrast, 6 of the examined SNPs in CLCN3, all in moderate linkage disequilibrium (r2: 0.30-0.80), were significantly associated with glioma risk. Among them, the strongest signal was observed in rs3797040 (NT_016354.19:g.95088578C&amp;gt;T), a SNP located in a putative transcription binding site (per variant “T” allele OR: 1.25; 95% CI:1.05-1.47; p=0.0095; allele frequency: 0.49); the observed excess risk associated with the variant rs3797040 allele was consistent in GBM (per allele OR: 1.23; 95% CI: 1.01-1.51; p=0.042), astrocytomas (per allele OR: 1.15; 95% CI: 0.88-1.49; p=0.312) and oligodendrogliomas (per allele OR: 1.75; 95% CI: 1.23-2.44; p=0.001). The ancestral “C” allele in CLCN3 rs3797040 was associated with increased mortality rates among the patients with GBM (per allele HR: 1.31; 95% CI: 1.06-1.62; p=0.011). To our knowledge this is the first report suggesting that genetic variation in plasma membrane ion channels may be a determinant of glioma risk. Further studies are needed to confirm these observations and identify the putative causal variant. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 876. doi:10.1158/1538-7445.AM2011-876

Association study between methylenetetrahydrofolate reductase gene polymorphisms and Graves' disease

5,10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the metabolism of folate and nucleotides, which are essential for DNA synthesis and methylation. It is highly polymorphic, and its variant genotypes result in lower enzymatic activity and higher plasma homocysteine. Previous studies have provided evidence that a high prevalence of MTHFR gene polymorphisms is frequently detected in patients with autoimmune disease, suggesting a novel genetic association with autoimmune disorders. However, the genetic association between MTHFR and Graves' disease (GD), one of the most common autoimmune diseases, has not been studied. Here, we designed a clinic-based case-control study including 199 GD cases and 235 healthy controls to examine the associations between three common MTHFR polymorphisms (i.e., C677T, A1298C, and G1793A) and GD. Surprisingly, logistic regression analysis shows MTHFR 677CT + TT genotypes are associated with an approximately 42% reduction in the risk of GD in women (adjusted OR = 0.58, 95% CI = 0.3-0.9), compared to the CC genotype, indicating a significant protective effect of 677CT + TT genotypes. Our result provides epidemiological evidence that MTHFR mutation (C677T) protects women from GD. The protective effect, possibly obtained by influencing DNA methylation, should be confirmed in a large number of cohorts.

A case–control study of ultraviolet radiation exposure, vitamin D, and lymphoma risk in adults

Recent research suggests that ultraviolet radiation exposure (UVRE), our major source of vitamin D, is associated with reduced lymphoma risk. Animal and human studies support an association between vitamin D (vitD) insufficiency and increased risk of some malignancies. We conducted a clinic-based case-control study (140 lymphoma cases, 139 controls; 2002-2005, Rochester, NY) to evaluate UVRE and vitD insufficiency in relation to lymphoma risk. Subjects completed a survey and provided a blood sample. We used multivariable logistic regression to estimate lymphoma risk in relation to past (5-10 years prior) UVRE and current vitD insufficiency (determined by serum 25(OH)D). Possible differences in effect by lymphoma subtype were explored, but statistical power was limited. We confirmed the previously reported decrease in lymphoma risk with past UVRE, specifically sunbathing (>once/week versus never); adjusted odds ratio (OR(adj)), = 0.28, 95% confidence interval (CI): 0.10-0.79. Current vitD insufficiency was not associated with lymphoma risk (OR(adj) = 0.89, 95% CI: 0.47-1.72). However, current sunbathing frequency was correlated with measured serum 25(OH)D values. Therefore, while our data do not support an association with current vitD status, development of accurate methods for past vitD assessment to further investigate its role in the association between past UVRE and lymphoma risk is warranted.

No association between a candidate TCF7L2 variant and risk of breast or ovarian cancer

BackgroundTCF7L2 is a transcription factor involved in Wnt/β-catenin signaling which has a variant known to be associated with risk of Type 2 diabetes and, in some studies, with risk of certain cancers, including familial breast cancer. No studies of ovarian cancer have been reported to date.MethodsTwo clinic-based case-control studies at the Mayo Clinic were assessed including 798 breast cancer cases, 843 breast cancer controls, 391 ovarian cancer cases, and 458 ovarian cancer controls. Genotyping at TCF7L2 rs12255372 used a 5' endonuclease assay, and statistical analysis used logistic regression among participants as a whole and among a priori-defined subsets.ResultsNo associations with risk of breast or ovarian cancer were observed (ordinal model, p = 0.62 and p = 0.75, respectively). In addition, no associations were observed among sub-groups defined by age, BMI, family history, stage, grade, histology, or tumor behavior.ConclusionAlthough the biology of the Wnt/β-catenin signaling pathway and prior association between rs12255372 and numerous phenotypes warranted examination of this TCF7L2 SNP, no compelling evidence for association with breast or ovarian cancer was observed.

Polymorphic Variants in Hereditary Pancreatic Cancer Genes Are Not Associated with Pancreatic Cancer Risk

Inherited risk of pancreatic cancer has been associated with mutations in several genes, including BRCA2, CDKN2A (p16), PRSS1, and PALB2. We hypothesized that common variants in these genes, single nucleotide polymorphisms (SNP), may also influence risk for pancreatic cancer development. A clinic-based case-control study in non-Hispanic white persons compared 1,143 patients with pancreatic adenocarcinoma with 1,097 healthy controls. Twenty-eight genes directly and indirectly involved in the Fanconi/BRCA pathway (includes BRCA1, BRCA2, and PALB2) were identified and 248 tag SNPs were selected. In addition, 11 SNPs in CDKN2A, PRSS1, and PRSS2 were selected. Association studies were done at the gene level by principal components analysis, whereas recursive partitioning analysis was used to investigate pathway effects. At the individual SNP level, adjusted additive, dominant, and recessive models were investigated, and gene-environment interactions were also assessed. Gene level analyses showed no significant association of any genes with altered pancreatic cancer risk. Multiple single SNP analyses showed associations, which will require replication. Exploratory pathway analyses by recursive partitioning showed no association between SNPs and risk for pancreatic cancer. In a candidate gene and pathway SNP association study analysis, common variations in the Fanconi/BRCA pathway and other candidate familial pancreatic cancer genes are not associated with risk for pancreatic cancer.

Nucleotide Excision Repair Pathway Polymorphisms and Pancreatic Cancer Risk: Evidence for role of MMS19L

Nucleotide excision repair is a vital response to DNA damage, including damage from tobacco exposure. Single nucleotide polymorphisms (SNP) in the nucleotide excision repair pathway may encode alterations that affect DNA repair function and therefore influence the risk of pancreatic cancer development. A clinic-based case-control study in non-Hispanic white persons compared 1,143 patients with pancreatic adenocarcinoma with 1,097 healthy controls. Twenty-seven genes directly and indirectly involved in the nucleotide excision repair pathway were identified and 236 tag-SNPs were selected from 26 of these (one had no SNPs identified). Association studies were done at the gene level by principal components analysis, whereas recursive partitioning analysis was utilized to identify potential gene-gene and gene-environment interactions within the pathway. At the individual SNP level, adjusted additive, dominant, and recessive models were investigated, and gene-environment interactions were also assessed. Gene level analyses showed an association of the MMS19L genotype (chromosome 10q24.1) with altered pancreatic cancer risk (P = 0.023). Haplotype analysis of MMS19L also showed a significant association (P = 0.0132). Analyses of seven individual SNPs in this gene showed both protective and risk associations for minor alleles, broadly distributed across patient subgroups defined by smoking status, sex, and age. In a candidate pathway SNP association study analysis, common variation in a nucleotide excision repair gene, MMS19L, was associated with the risk of pancreatic cancer.

Risk Factors for Barrett's Esophagus Among Patients With Gastroesophageal Reflux Disease: A Community Clinic-Based Case–Control Study

Our aim was to measure the relative risks of Barrett's esophagus (BE) associated with demographic factors, measures of adiposity, and smoking among patients with gastroesophageal reflux disease (GERD). Patients newly diagnosed with specialized intestinal metaplasia (SIM) (n=197) were compared with patients with GERD (n=418) in a community clinic-based case-control study. Case subgroups included those with any visible columnar epithelium (VBE) (n=97), and those with a long segment (>or=2 cm) of columnar epithelium (LSBE) (n=54). Risks increased with older age (adjusted odds ratio (aOR) per decade for SIM=1.3, 95% confidence interval (CI)=1.1-1.5; VBE aOR=1.4, CI=1.1-1.6; LSBE aOR=1.5, CI=1.2-1.9), male gender (SIM aOR=1.5, CI=1.1-2.2; VBE aOR=2.7, CI=1.6-4.5; LSBE aOR=3.9, CI=1.9-8.1), and possibly Asian race. Increased risk of BE was observed with high waist-to-hip ratio (WHR, male high: >or=0.9, female high: >or=0.8) (SIM aOR=1.3, CI=0.9-2.1; VBE aOR=1.9, CI=1.0-3.5; LSBE aOR=4.1, CI=1.5-11.4). These associations were independent of body mass index (BMI) for the VBE and LSBE case groups but not for SIM, which was the only case group in which BMI was a significant risk factor. Ever having smoked cigarettes increased risk similarly for all case groups (SIM aOR=1.8, CI=1.2-2.6; VBE aOR=1.6, CI=1.0-2.6; LSBE aOR=2.6, CI=1.3-4.9), although a dose-response relationship was not detected for duration or intensity of smoking. Older age, male gender, and history of smoking increased risk of SIM and BE among GERD patients independent of other risk factors for BE. Central adiposity was most strongly related to risk of VBE and LSBE. These results may be useful in the development of risk profiles for screening GERD patients.

Texture features from mammographic images and risk of breast cancer.

Mammographic percent density (PD) is a strong risk factor for breast cancer, but there has been relatively little systematic evaluation of other features in mammographic images that might additionally predict breast cancer risk. We evaluated the association of a large number of image texture features with risk of breast cancer using a clinic-based case-control study of digitized film mammograms, all with screening mammograms before breast cancer diagnosis. The sample was split into training (123 cases and 258 controls) and validation (123 cases and 264 controls) data sets. Age-adjusted and body mass index (BMI)-adjusted odds ratios (OR) per SD change in the feature, 95% confidence intervals, and the area under the receiver operator characteristic curve (AUC) were obtained using logistic regression. A bootstrap approach was used to identify the strongest features in the training data set, and results for features that validated in the second half of the sample were reported using the full data set. The mean age at mammography was 64.0+/-10.2 years, and the mean time from mammography to breast cancer was 3.7+/-1.0 (range, 2.0-5.9 years). PD was associated with breast cancer risk (OR, 1.49; 95% confidence interval, 1.25-1.78). The strongest features that validated from each of several classes (Markovian, run length, Laws, wavelet, and Fourier) showed similar ORs as PD and predicted breast cancer at a similar magnitude (AUC=0.58-0.60) as PD (AUC=0.58). All of these features were automatically calculated (unlike PD) and measure texture at a coarse scale. These features were moderately correlated with PD (r=0.39-0.76), and after adjustment for PD, each of the features attenuated only slightly and retained statistical significance. However, simultaneous inclusion of these features in a model with PD did not significantly improve the ability to predict breast cancer.

Comparing the Reliability of Responses to Telephone-Administered versus Self-Administered Web-Based Surveys in a Case-Control Study of Adult Malignant Brain Cancer

To determine whether a Web-based survey was an acceptable method of data collection for a clinic-based case-control study of adult brain cancer, the authors compared the reliability of paired responses to a main and resurvey for participants completing surveys by telephone (n=74) or self-administered on the Web (n=465) between 2003 and 2006. Recruitment of cases was done at the Evanston Northwestern Healthcare Kellogg Cancer Care Center and the Duke University Medical Center Cancer Control division, and controls were friends and siblings of cases. Twenty-five variables were examined, including smoking, oral contraceptive and residential histories, water sources, meat preparation, fruit and vegetable consumption, and pesticide use. Weighted and simple kappa's were estimated for categorical and binary variables, respectively. The number of concordant paired responses was summed for use in linear regression. Respondents were 97% White and 85% had postsecondary education. Kappa's for individual questions ranged from 0.31 (duration of residence in a single family house) to 0.96 (ever smoked), with a median of 0.57 (95% confidence interval, 0.47-0.64). The median number of concordant responses was 16.2 (range, 5-22). Reliability was greater for controls than cases, Web-based versus telephone responders, females, and higher-income responders. Frequency of e-mail and Internet use was not associated with reliability. A self-administered, Web-based survey was a feasible and appropriate mode of interview in this study. The comparable reliability of Web compared with telephone responses suggest that Web-based self-interviews could be a cost-effective alternative to traditional modes of interview.

Migraine

Migraine is a primary chronic-intermittent headache disorder that affects ≈12% of the population, with women being 3 to 4 times more likely to have migraine than men at any given age.1 Migraine typically starts before age 40, and its 1-year prevalence peaks in midlife. The pain character is moderate to severe and of pulsating quality, and headache attacks are accompanied by various combinations of gastrointestinal, autonomic nervous system dysfunction, as well as sensitivity to light and sound. In some patients, transient neurological symptoms occur that mostly involve the visual field and include flickering light, light spots or lines, or partial vision loss but can also involve the sensory or motor system. These symptoms, known as migraine aura, usually last for <30 minutes and affect as many as one third of migraine patients. The pathophysiology of migraine has been explored in detail, and it is known that a dysfunction of brain cells and brain arteries is a major component of this disorder.2 Article p 1419 In recent decades, migraine, and specifically migraine with aura, has been consistently associated with increased risk of ischemic stroke, particularly among young women.3–6 Despite several hypotheses, the mechanisms explaining this association are not fully understood.7 Because patent foramen ovale (PFO) can be a cause of ischemic stroke among young individuals, it has been suggested that this congenital heart defect may be involved in the association between migraine with aura and ischemic stroke. PFO is an often-asymptomatic condition that is present in ≈25% of the general population, and at first glance migraine and PFO have little in common. In recent years, however, several clinic-based case-control studies have suggested that PFO is more common among individuals with migraine with aura and that migraine with aura is more common among individuals with PFO.8–12 This …