bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphisms in DNA Repair Genes, Medical Exposure to Ionizing Radiation, and Breast Cancer Risk
Authors: Millikan Robert C. , Player Jon S. , deCotret Allan Rene , Tse Chiu-Kit , Keku Temitope
Published: March 2006

An epidemiologic study was conducted to determine whether polymorphisms in DNA repair genes modify the association between breast cancer risk and exposure to ionizing radiation. Self-reported exposure to ionizing radiation from medical sources was evaluated as part of a population-based, case-control study of breast cancer in African-American (894 cases and 788 controls) and White (1,417 cases and 1,234 controls) women. Genotyping was conducted for polymorphisms in four genes involved in repair of radiation-induced DNA damage, the double-strand break repair pathway: X-ray cross-complementing group 3 (XRCC3) codon 241 Thr/Met, Nijmegen breakage syndrome 1 (NBS1) codon 185 Glu/Gln, X-ray cross-complementing group 2 (XRCC2) codon 188 Arg/His, and breast cancer susceptibility gene 2 (BRCH2) codon 372 Asn/His. Allele and genotype frequencies were not significantly different in cases compared with controls for all four genetic polymorphisms, and odds ratios for breast cancer were close to the null. Combining women with two, three, and four variant genotypes, a positive association was observed between breast cancer and number of lifetime mammograms (Ptrend < 0.0001). No association was observed among women with zero or one variant genotype (P = 0.86). Odds ratios for radiation treatments to the chest and number of lifetime chest X-rays were slightly elevated but not statistically significant among women with two to four variant genotypes. The study has several limitations, including inability to distinguish between diagnostic and screening mammograms or reliably classify prediagnostic mammograms and chest X-rays in cases. Prospective studies are needed to address whether common polymorphisms in DNA repair genes modify the effects of low-dose radiation exposure from medical sources.
Variation of the Killer Cell Immunoglobulin-Like Receptors andHLA-CGenes in Nasopharyngeal Carcinoma
Authors: Butsch Kovacic Melinda , Martin Maureen , Gao Xiaojiang , Fuksenko Tatyana , Chen Chien-Jen , Cheng Yu-Juen , Chen Jen-Yang , Apple Raymond , Hildesheim Allan , Carrington Mary
Published: March 2006

Nasopharyngeal carcinoma (NPC) is an Epstein-Barrvirus (EBV)-associated malignancy. Previous studies have shown that NPC is associated with specific human leukocyte antigen (HLA) alleles which function in adaptive immunity to present viral and other antigens to the immune system. The role of innate immunity in NPC development is unknown. To determine whether innate immunity is associated with NPC, a case-control study was conducted among 295 Taiwanese NPC cases (99% EBV seropositive) and 252 community controls (29% EBV seropositive). Using high-resolution genotyping, we evaluated the variation of HLA class I alleles and killer cell immunoglobulin-like receptor (KIR) alleles. Located on the surface of natural killer (NK) cells and a subset of T cells, inhibitory KIRs diminish NK cytolysis of target cells upon binding to their HLA class I ligands and activating KIRs are thought to stimulate NK destruction of target cells. Our results suggest that an increasing number of activating KIRs may be associated with increasing NPC risk, particularly in individuals seropositive for anti-EBV antibodies known to be linked to NPC susceptibility (Ptrend = 0.07). Among EBV-seropositive individuals, carriers of ≥5 activating KIRs had a 3.4-fold increased risk of disease (95% confidence interval, 0.74-15.7) compared with individuals with no functional activating KIRs. In contrast, there was no clear evidence of risk associated with increasing numbers of inhibitory KIRs. When evaluating HLA-Cw alleles, we observed that carriers of HLA-Cw*0401 alleles were at a significantly reduced NPC risk (odds ratio, 0.46; 95% confidence intervals, 0.23-0.92), an effect that could not be explained by linkage disequilibrium with other NPC-associated HLA alleles. Our results suggest that KIR-mediated activation may be associated with NPC risk. As this finding is consistent with a recent report examining cervical cancer, a malignancy caused by human papillomavirus, the data raises the possibility that KIRs, and more generally innate immunity, may be involved in the pathogenesis of viral-associated cancers.
Variation of theN-Acetyltransferase 2Gene in a Romanian and a Kyrgyz Population
Authors: Rabstein Sylvia , Unfried Klaus , Ranft Ulrich , Illig Thomas , Kolz Melanie , Rihs Hans-Peter , Mambetova Chinara , Vlad Mariana , Brüning Thomas , Pesch Beate
Published: March 2006

As part of a project on environmental disasters in minority populations, this study aimed to evaluate differences in the sequence of N-acetyltransferase 2 (NAT2) as a metabolic susceptibility gene in yet unexplored ethnicities. Eight single nucleotide polymorphisms (SNP) in the NAT2 coding region and a variant in the 3′ flanking region were analyzed in 290 unrelated Kyrgyz and 140 unrelated Romanians by SNP-specific PCR analysis. The variants 341C, 481T, and 803G were less and 857A more prevalent in Kyrgyz (P < 0.0001). The variant at site 857 indicates Asian descent. 282C>T and 590G>A showed no significant variation by ethnicity. 364G>A and 411A>T turned out to be monomorphic. Database comparisons of the NAT2 minor allele frequencies support that Romanians belong to Caucasians and Kyrgyz are in between Caucasians and East Asians. The distributions of predicted haplotypes differed significantly between the two ethnicities where the Kyrgyz showed a higher genetic diversity. The haplotype without mutations was more common in Kyrgyz (40.1% in Kyrgyz, 29.3% in Romanians). Accordingly, the imputed slow acetylator phenotype was less prevalent in Kyrgyz (35.2% versus 51.4% in Romanians). We found pronounced ethnic differences in NAT2 genotypes with yet unknown effect on the health risks for environmental or occupational exposures in minority populations. (Cancer Epidemiol Biomarkers Prev 2006;(15)1:138–41)
Expression of Vitamin D Receptor and 25-Hydroxyvitamin D3-1α-Hydroxylase in Normal and Malignant Human Colon
Authors: Matusiak Damien , Murillo Genoveva , Carroll Robert E. , Mehta Rajendra G. , Benya Richard V.
Published: March 2006

Considerable evidence exists to support the use of vitamin D to prevent and/or treat colorectal cancer. However, the routine use of bioactive vitamin D, 1,25-dihydroxyvitamin D3, is limited by the side effect of toxic hypercalcemia. Recent studies, however, suggest that colonic epithelial cells express 25-hydroxyvitamin D3-1α-hydroxylase, an enzyme that converts nontoxic pro-vitamin D, 25-hydroxycholecalciferol [25(OH)D3], to its bioactive form. Yet, nothing is known as to the cellular expression of 1α-hydroxylase and the vitamin D receptor (VDR) in the earliest histopathologic structures associated with malignant transformation such as aberrant crypt foci (ACF) and polyps [addressing the possibility of using nontoxic 25(OH)D3 for chemoprevention], nor is anything known as to the expression of these proteins in colorectal cancer as a function of tumor cell differentiation or metastasis [relevant to using 25(OH)D3 for chemotherapy]. In this study, we show that 1α-hydroxylase is present at equal high levels in normal colonic epithelium as in ACFs, polyps, and colorectal cancer irrespective of tumor cell differentiation. In contrast, VDR levels were low in normal colonic epithelial cells; were increased in ACFs, polyps, and well-differentiated tumor cells; and then declined as a function of tumor cell de-differentiation. Both 1α-hydroxylase and VDR levels were negligible in tumor cells metastasizing to regional lymph nodes. Overall, these data support using 25(OH)D3 for colorectal cancer chemoprevention but suggest that pro-vitamin D is less likely to be useful for colorectal cancer chemotherapy.
Reliability and Validity of a Telephone Questionnaire for Estimating Lifetime Personal Sun Exposure in Epidemiologic Studies
Authors: Kricker Anne , Vajdic Claire M. , Armstrong Bruce K.
Published: March 2006

Our Australia-wide case-control study of ocular melanoma diagnosed in 1996 to 1997 needed a short telephone interview on sun exposure. We constructed one by examining data from 700 controls ages 40 to 64 years in the Geraldton Skin Cancer Survey in 1988; they had answered a “whole-of-life” questionnaire in a face-to-face interview. Sun exposure in their first 4 decade years of age best predicted their lifetime annual average sun exposure, so the shortened questionnaire asked about sun exposure in these 4 decade years only. Retesting 60 participants 1 year later with the whole-of-life questionnaire gave an intraclass correlation coefficient of 0.65 (95% confidence interval, 0.48-0.78) for ranked total sun exposure between the two interviews; the intraclass correlation coefficient was higher in men (0.73) than in women (0.54). Correlations were also high between parallel measurements of sun exposure on working days in the decade years and in outdoor occupations throughout life in the telephone interview of the ocular melanoma study (Spearman's R = 0.75) and in another study of non-Hodgkin's lymphoma (R = 0.71). Agreement between simultaneous parallel measures of total exposure (nonworking + working day and recreational + occupational exposure) was slightly weaker and of nonworking day and recreational exposure much weaker. Occupational exposure in women was much less strongly correlated with total exposure than it was in men possibly because of their frequently combined work and family roles, which the questionnaires did not try to separate. Research is needed into how this might be done to improve sun exposure measurement in women.
Interest in Testing for Genetic Susceptibility to Lung Cancer among Black College Students “At Risk” of Becoming Cigarette Smokers
Authors: McBride Colleen M. , Lipkus Isaac M. , Jolly David , Lyna Pauline
Published: March 2006

Receptivity to genetic testing for lung cancer susceptibility was assessed among African American college freshmen, who held attitudes favorable towards or had experimented with cigarette smoking. Students (n = 95) completed a telephone survey that assessed beliefs about genetics and lung cancer risk, interest in genetic testing, and expectations about the test outcome. Interest in being tested was moderately high (mean, 5; SD, 2.2; scale of 1-7) and highest among those who believed lung cancer was influenced by genetics (r = 0.22, P < 0.05) and those who expected to be at high risk (r = 0.27, P < 0.05). Overall, 34% thought if tested, the result would show high risk for lung cancer. In multivariate analyses, students' test result expectation was the only significant predictor of interest in testing. Those who believed the test would show them to be at higher risk were thrice more likely to be interested in testing than those who thought the test would show that they were at lower risk (odds ratio, 2.99; confidence interval, 1.03-8.64; P = 0.04). Future research is needed to understand how young adults will respond to genetic susceptibility feedback that confirms or contradicts their expectations about personal risks of smoking. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2978–81)
Uptake of the Tobacco-Specific Lung Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-Butanone by Moldovan Children
Authors: Stepanov Irina , Hecht Stephen S. , Duca Gheorghe , Mardari Igor
Published: March 2006

The evidence of an association between childhood exposure to environmental tobacco smoke (ETS) and an increased risk of lung cancer is inconsistent. However, taking into account the existing association between lung cancer and adulthood ETS exposure, it is plausible that children exposed to ETS also would be at risk of developing lung cancer later in life. In this study, we investigated the uptake by Moldovan children of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by measuring total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), the sum of the NNK metabolites, NNAL, and its O-glucuronide and N-glucuronide (NNAL-Glucs) in urine. We also measured urinary cotinine and its glucuronide (total cotinine). Total NNAL was detected in 69 of 80 samples, including those that were low in cotinine (<5 ng/mL). The mean ± SD level of total NNAL (0.09 ± 0.077 pmol/mL) was comparable with those observed in previous studies of children and adults exposed to ETS. Total NNAL correlated with total cotinine (r = 0.8, P < 0.0001). The mean ± SD levels of total NNAL and total cotinine were higher in children who were exposed to ETS (0.1 ± 0.08 and 109 ± 126 pmol/mL, respectively) than in those who were classified as unexposed to ETS based on questionnaire data (0.049 ± 0.016 pmol/mL and 0.043 ± 0.040 nmol/mL). The results of this study for the first time show widespread and considerable uptake of nicotine and the tobacco-specific lung carcinogen NNK in Moldovan children. These results should be useful in heightening the awareness of the dangers of smoking and ETS exposure in this eastern European country. (Cancer Epidemiol Biomarkers Prev 2006;15(1):7–11)
Evaluating Bias due to Population Stratification in Epidemiologic Studies of Gene-Gene or Gene-Environment Interactions
Authors: Wang Yiting , Localio Russell , Rebbeck Timothy R.
Published: March 2006

Confounding by ethnicity (i.e. population stratification) can result in bias and incorrect inferences in genotype-disease association studies, but the effect of population stratification in gene-gene or gene-environment interaction studies has not been addressed. We used logistic regression models to fit multiplicative interactions between two dichotomous variables that represented genetic and/or environmental factors for a binary disease outcome in a hypothetical cohort of multiple ethnicities. Biases in main effects and interactions due to population stratification were evaluated by comparing regression coefficients in mis-specified models that ignored ethnicities with their counterparts in models that accounted for ethnicities. We showed that biases in main effects and interactions were constrained by the differences in disease risks across the ethnicities. Therefore, large biases due to population stratification are not possible when baseline disease risk differences among ethnicities are small or moderate. Numerical examples of biases in genotype-genotype and/or genotype-environment interactions suggested that biases due to population stratification for main effects were generally small but could become large for studies of interactions, particularly when strong linkage disequilibrium between genes or large correlations between genetic and environmental factors existed. However, when linkage disequilibrium among genes or correlations among genes and environments were small, biases to main effects or interaction odds ratios were small to nonexistent. (Cancer Epidemiol Biomarkers Prev 2006;15(1):124–32)
Androgen Receptor and Prostate-Specific Antigen Gene Polymorphisms and Breast Cancer in African-American Women
Authors: Wang Wei , John Esther M. , Ingles Sue Ann
Published: March 2006

Several previous studies have found the CAG repeat polymorphism in exon 1 of the androgen receptor (AR) gene to be associated with breast cancer risk among some groups of Caucasian and Asian women. In a population-based case-control study of 488 African-American women (239 cases and 249 controls), we examined this polymorphism along with a polymorphism (−158 G/A) in an androgen-regulated gene (PSA) whose expression has been correlated with breast cancer prognosis. Overall, we did not observe any significant association between the CAG repeat polymorphism and breast cancer risk. However, among women with a first-degree family history of breast cancer, longer CAG repeats were associated with a significantly increased risk. Women carrying at least one longer allele [(CAG)n ≥ 22] had a 3-fold increased risk compared to those with two shorter alleles (odds ratio, 3.18; 95% confidence interval, 1.08-9.36). There was no significant association between the PSA gene polymorphism and breast cancer risk, nor was there significant gene-gene interaction. In summary, our results further support that shorter CAG repeats (stronger AR transactivation activity) may reduce the risk of breast cancer, at least among some groups of women. Our data, however, are unable to provide evidence that PSA is the pathway through which the protective effect of androgens operates. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2990–4)
A Randomized Controlled Trial of Financial Incentives for Smoking Cessation
Authors: Volpp Kevin G. , Gurmankin Levy Andrea , Asch David A. , Berlin Jesse A. , Murphy John J. , Gomez Angela , Sox Harold , Zhu Jingsan , Lerman Caryn
Published: March 2006

Background: Although 435,000 Americans die each year of tobacco-related illness, only ∼3% of smokers quit each year. Financial incentives have been shown to be effective in modifying behavior within highly structured settings, such as drug treatment programs, but this has not been shown in treating chronic disease in less structured settings. The objective of this study was to determine whether modest financial incentives increase the rate of smoking cessation program enrollment, completion, and quit rates in a outpatient clinical setting.

Methods: 179 smokers at the Philadelphia Veterans Affairs Medical Center who reported smoking at least 10 cigarettes per day were randomized into incentive and nonincentive groups. Both groups were offered a free five-class smoking cessation program at the Philadelphia Veterans Affairs Medical Center. The incentive group was also offered $20 for each class attended and $100 if they quit smoking 30 days post program completion. Self-reported smoking cessation was confirmed with urine cotinine tests.

Results: The incentive group had higher rates of program enrollment (43.3% versus 20.2%; P < 0.001) and completion (25.8% versus 12.2%; P = 0.02). Quit rates at 75 days were 16.3% in the incentive group versus 4.6% in the control group (P = 0.01). At 6 months, quit rates in the incentive group were not significantly higher (6.5%) than in the control group (4.6%; P > 0.20).

Conclusion: Modest financial incentives are associated with significantly higher rates of smoking cessation program enrollment and completion and short-term quit rates. Future studies should consider including an incentive for longer-term cessation. (Cancer Epidemiol Biomarkers Prev 2006;15(1):12–8)
Does Nonsteroidal Anti-inflammatory Drug Use Modify the Effect of a Low-Fat, High-Fiber Diet on Recurrence of Colorectal Adenomas?
Authors: Hartman Terryl J. , Yu Binbing , Albert Paul S. , Slattery Martha L. , Paskett Electra , Kikendall James Walter , Iber Frank , Brewer Brenda K. , Schatzkin Arthur , Lanza Elaine ,   The Polyp Prevention Study Group
Published: March 2006

The Polyp Prevention Trial was designed to evaluate the effects of a high-fiber (18 g/1,000 kcal), high-fruit and -vegetable (3.5 servings/1,000 kcal), low-fat (20% energy) diet on recurrence of adenomatous polyps. Participants ≥35 years of age, with histologically confirmed colorectal adenoma(s) removed in the prior 6 months, were randomized to the intervention or control group. Demographic, dietary, and clinical information, including use of nonsteroidal anti-inflammatory drugs (NSAID), was collected at baseline and four annual visits. Adenoma recurrence was found in 754 of 1,905 participants and was not significantly different between groups. NSAID use was associated with a significant reduction in recurrence [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.63-0.95]. In this analysis, NSAIDs modified the association between the intervention and recurrence at baseline (P = 0.02) and throughout the trial (P = 0.008). Among participants who did not use NSAIDs, the intervention was in the protective direction but did not achieve statistical significance (OR, 0.87; 95% CI, 0.69-1.09). The intervention was protective among males who did not use NSAIDs at baseline (OR, 0.71; 95% CI, 0.54-0.94), but not among NSAIDs users (OR, 1.09; 95% CI, 0.74-1.62). For females, corresponding OR estimates were 1.28 (95% CI, 0.86-1.90) and 2.30 (95% CI, 1.24-4.27), respectively. The protective association observed for NSAID use was stronger among control (OR, 0.63; 95% CI, 0.47-0.84) than for intervention group participants (OR, 0.97; 95% CI, 0.74-1.28). These results should be interpreted cautiously given that they may have arisen by chance in the course of examining multiple associations and Polyp Prevention Trial study participants were not randomly assigned to both dietary intervention and NSAID use. Nevertheless, our results suggest that adopting a low-fat, high-fiber diet rich in fruits and vegetables may lower the risk of colorectal adenoma recurrence among individuals who do not regularly use NSAIDs.
Vitamin D Is Associated with Improved Survival in Early-Stage Non–Small Cell Lung Cancer Patients
Authors: Zhou Wei , Suk Rebecca , Liu Geoffrey , Park Sohee , Neuberg Donna S. , Wain John C. , Lynch Thomas J. , Giovannucci Edward , Christiani David C.
Published: March 2006

Vitamin D may inhibit the development and progression of a wide spectrum of cancers. We investigated the associations of surgery season and vitamin D intake with recurrence-free survival (RFS) and overall survival in 456 early-stage non–small cell lung cancer patients. The data were analyzed using log-rank test and Cox proportional hazards models. The median (range) follow-up time was 71 (0.1-140) months, with 161 recurrence and 231 deaths. Patients who had surgery in summer had a better RFS than those who had surgery in winter (adjusted hazard ratio, 0.75; 95% confidence interval, 0.56-1.01), with 5-year RFS rates of 53% (45-61%) and 40% (32-49%), respectively (P = 0.10, log-rank test). Similar association between surgery season and RFS was found among the 321 patients with dietary information (P = 0.33, log-rank test). There was no statistically significant association between vitamin D intake and RFS. Because both season and vitamin D intake are important predictors for vitamin D levels, we investigated the joint effects of surgery season and vitamin D intake. Patients who had surgery during summer with the highest vitamin D intake had better RFS (adjusted hazard ratio, 0.33; 95% confidence interval, 0.15-0.74) than patients who had surgery during winter with the lowest vitamin D intake, with the 5-year RFS rates of 56% (34-78%) and 23% (4-42%), respectively. Similar associations of surgery season and vitamin D intake with overall survival were also observed. In conclusion, the joint effects of surgery season and recent vitamin D intake seem to be associated with the survival of early-stage non–small cell lung cancer patients.
Positive Association of Farm or Rural Residence with Acute Myeloid Leukemia Incidence in a Cohort of Older Women
Authors: Sinner Penny J. , Cerhan James R. , Folsom Aaron R. , Ross Julie A.
Published: March 2006

The etiology of acute myeloid leukemia (AML) is relatively unknown. Incidence rates are highest in the agricultural Midwest region compared with other regions of the United States. Many studies have examined the relationship between farming and leukemia, but most have mainly focused on men. We examined the potential association between farm or rural residence and AML in the Iowa Women's Health Study. In 1986, 37,693 women who were free of prior cancer completed a lifestyle and health questionnaire, which included a question on the place of residence. Women were subsequently followed until 2002 for cancer incidence; 79 women developed AML during the time period. Women who lived on a farm at baseline were more likely (relative risk, 1.91; 95% confidence interval, 1.19-3.05) to develop AML compared with women who did not live on a farm. Further, women who reported living on a farm or in a rural area were twice as likely (relative risk, 2.38; 95% confidence interval, 1.33-4.26) to develop AML compared with women who lived in a city with a population of >10,000 people. These results provide evidence that women who live on farms or rural areas are at an increased risk of AML.
Risk of Second Primary Cancer and Death Following a Diagnosis of Nonmelanoma Skin Cancer
Authors: Nugent Zoann , Demers Alain A. , Wiseman Marni C. , Mihalcioiu Catalin , Kliewer Erich V.
Published: March 2006

Cancer-free patients diagnosed with a first primary nonmelanoma skin cancer (NMSC) offer an opportunity for studying the risk of a second primary cancer without the confounding effect of systemic treatment. The objective of the study was to estimate the risk of second primary cancer in people with a history of basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) and the risk of dying in cancer patients with a NMSC history. BCC and SCC cases diagnosed between 1956 and 2000 in Manitoba, Canada were followed-up for second primaries (other than NMSC). Standardized incidence and mortality ratios (SIR and SMR) were calculated. Men [SIR, 1.06; 95% confidence interval (95% CI), 1.02-1.10] and women (SIR, 1.07; 95% CI, 1.02-1.12) with a BCC history as well as men (SIR, 1.15; 95% CI, 1.08-1.22) with a SCC history were at greater risk of a second primary cancer. Overall, the increased risk was observed only in the first 4 years following a NMSC, although it remained increased for specific cancer sites. The risk remained higher in all age groups up to 75 years of age. People with a history of BCC (males: SMR, 1.09; 95% CI, 1.04-1.14; females: SMR, 1.24; 95% CI, 1.16-1.32) or SCC (males: SMR, 1.18; 95% CI, 1.09-1.27; females: SMR, 1.55; 95% CI, 1.35-1.79) had a greater risk of death following their second primaries. Even if NMSC patients are at greater risk of a second cancer, it is not recommended to follow them up beyond the generally accepted periodic examination of the skin.
Relationship of Benign Gynecologic Diseases to Subsequent Risk of Ovarian and Uterine Tumors
Authors: Brinton Louise A. , Sakoda Lori C. , Sherman Mark E. , Frederiksen Kirsten , Kjaer Susanne Kruger , Graubard Barry I. , Olsen Jorgen H. , Mellemkjaer Lene
Published: March 2006

Objective: Although endometriosis and uterine leiomyomas are common conditions, the extent to which either is associated with certain types of malignancies remains uncertain.

Methods: Using record linkage techniques, we assessed the relationships between hospital and outpatient admissions for endometriosis or leiomyomas and the development of ovarian and uterine cancers in Denmark between 1978 and 1998. Based on a population-based cohort exceeding 99,000 women, including 2,491 ovarian cancers, 860 borderline ovarian tumors, and 1,398 uterine cancers, we derived relative risks (RR) and 95% confidence intervals (95% CI) associated with overall and histology-specific tumor risks after adjustment for calendar time and reproductive characteristics.

Results: Endometriosis seemed to predispose to the development of ovarian cancer, with the association restricted to endometrioid or clear cell malignancies. Five or more years after the diagnosis of endometriosis, the RRs (95% CIs) were 2.53 (1.19-5.38) for endometrioid (7 exposed cases) and 3.37 (1.24-9.14) for clear cell (4 exposed cases) malignancies. Uterine leiomyomas were associated with increases in the risk of uterine malignancies, particularly sarcomas, where the RRs (95% CIs) were 20.80 (11.32-38.22) for women with 1 to 4 years of follow-up (11 exposed cases) and 5.70 (2.27-14.32) for those with more extended follow-up (5 exposed cases).

Conclusion: In combination with clinical, pathologic, and molecular data, our results support that some endometriotic lesions may predispose to clear cell and endometrioid ovarian cancers. Uterine leiomyomas also showed a strong connection with subsequent uterine sarcomas, although it was difficult to decipher whether this reflected detection bias, shared risk factors, or an etiologic relationship. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2929–35)
The Angiotensin I–Converting Enzyme Gene Insertion/Deletion Polymorphism Is Linked to Early Gastric Cancer
Authors: Ebert Matthias P.A. , Lendeckel Uwe , Westphal Sabine , Dierkes Jutta , Glas Jürgen , Folwaczny Christian , Roessner Albert , Stolte Manfred , Malfertheiner Peter , Röcken Christoph
Published: March 2006

The insertion/deletion polymorphism of the angiotensin I–converting enzyme (ACE) gene has recently been linked to the pathogenesis and progression of human cancers. Using genomic DNA from 88 patients with early gastric cancer confined either to mucosa (pT1a) or submucosa (pT1b), we assessed the insertion (I) and deletion (D) polymorphism by PCR analysis and compared it with a large noncancer control population (n = 145). In the noncancer control group, the II genotype was observed in 33 (23%) individuals, whereas the ID and DD genotypes were found in 72 (50%) and 40 (27%) individuals, respectively. Interestingly, in the cancer group, we found the II genotype in six (7%) patients and the ID genotype in 46 (52%) individuals, whereas the DD genotype was observed in 36 (41%) individuals (P = 0.0034). Accordingly, the odds ratio for the II genotype was 0.20 [95% confidence interval (95% CI), 0.08-0.54; P = 0.009] and 0.55 for the ID/II genotype (95% CI, 0.31-0.96; P = 0.044) using the high-activity genotype DD as the reference category. No correlation was found among tumor type, tumor stage, the presence of Helicobacter pylori, and the ACE genotype. Our study provides further evidence that the ACE insertion/deletion gene polymorphism may be linked to the development of early gastric cancer. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2987–9)
Interindividual Variation in Nucleotide Excision Repair Genes and Risk of Endometrial Cancer
Authors: Weiss Jocelyn M. , Weiss Noel S. , Ulrich Cornelia M. , Doherty Jennifer A. , Voigt Lynda F. , Chen Chu
Published: March 2006

Exposure to estrogens is a likely cause of endometrial cancer, but the means by which estrogens exert this effect are not entirely clear. One hypothesis is that certain estrogen metabolites bind to the DNA, forming bulky adducts that damage the DNA and initiate carcinogenesis. A woman's reduced capacity to repair such damage may increase her risk of endometrial cancer. We conducted a population-based case-control study in western Washington State to address the role of variation in nucleotide excision repair genes on the risk of endometrial cancer. Case women (n = 371), ages 50 to 69 years, were diagnosed with invasive endometrial cancer between 1994 and 1999. Control women (n = 420) were selected using random-digit dialing (ages 50-65 years) and by random selection from Health Care Financing Administration data files (ages 66-69 years). Genotyping assays were done for ERCC1, ERCC2 (XPD), ERCC4 (XPF), ERCC5 (XPG), XPA, and XPC. No appreciable differences between cases and controls were observed in the genotype distributions of ERCC1 (c8092a and c19007t), ERCC2 (D312N, K751Q, and c22541a), ERCC4 (R415Q and t30028c), or ERCC5 (D1104H). Carriage of at least one variant allele for XPA G23A was associated with decreased risk of endometrial cancer [odds ratio (OR), 0.70; 95% confidence interval (95% CI), 0.53-0.93]. Carriage of at least one XPC A499V variant allele was associated with a modest decrease in risk (OR, 0.79; 95% CI, 0.59-1.05). Women with variant alleles at both XPC A499V and K939Q had 58% of the risk of women with no XPC variant alleles (OR, 0.58; 95% CI, 0.35-0.96). Our data suggest that interindividual variation in XPA and XPC influences a woman's risk of endometrial cancer.
Genetic Variation and Willingness to Participate in Epidemiologic Research: Data from Three Studies
Authors: Bhatti Parveen , Sigurdson Alice J. , Wang Sophia S. , Chen Jinbo , Rothman Nathaniel , Hartge Patricia , Bergen Andrew W. , Landi Maria Teresa
Published: March 2006

The differences in common genetic polymorphism frequencies by willingness to participate in epidemiologic studies are unexplored, but the same threats to internal validity operate as for studies with nongenetic information. We analyzed single nucleotide polymorphism genotypes, haplotypes, and short tandem repeats among control groups from three studies with different recruitment designs that included early, late, and never questionnaire responders, one or more participation incentives, and blood or buccal DNA collection. Among 2,955 individuals, we compared 108 genotypes, 8 haplotypes, and 9 to 15 short tandem repeats by respondent type. Among our main comparisons, single nucleotide polymorphism genotype frequencies differed significantly (P < 0.05) between respondent groups in six instances, with 13 expected by chance alone. When comparing the odds of carrying a variant among the various response groups, 19 odds ratios were ≤0.70 or ≥1.40, levels that might be notably different. Among the various respondent group comparisons, haplotype and short tandem repeat frequencies were not significantly different by willingness to participate. We observed little evidence to suggest that genotype differences underlie response characteristics in molecular epidemiologic studies, but a greater variety of genes should be examined, including those related to behavioral traits potentially associated with willingness to participate. To the extent possible, investigators should evaluate their own genetic data for bias in response categories.
Dairy Products and Ovarian Cancer: A Pooled Analysis of 12 Cohort Studies
Authors: Genkinger Jeanine M. , Hunter David J. , Spiegelman Donna , Anderson Kristin E. , Arslan Alan , Beeson W. Lawrence , Buring Julie E. , Fraser Gary E. , Freudenheim Jo L. , Goldbohm R. Alexandra , Hankinson Susan E. , Jacobs David R. , Koushik Anita , Lacey James V. , Larsson Susanna C. , Leitzmann Michael , McCullough Marji L. , Miller Anthony B. , Rodriguez Carmen , Rohan Thomas E. , Schouten Leo J. , Shore Roy , Smit Ellen , Wolk Alicja , Zhang Shumin M. , Smith-Warner Stephanie A.
Published: March 2006

Background: Dairy foods and their constituents (lactose and calcium) have been hypothesized to promote ovarian carcinogenesis. Although case-control studies have reported conflicting results for dairy foods and lactose, several cohort studies have shown positive associations between skim milk, lactose, and ovarian cancer.

Methods: A pooled analysis of the primary data from 12 prospective cohort studies was conducted. The study population consisted of 553,217 women among whom 2,132 epithelial ovarian cases were identified. Study-specific relative risks and 95% confidence intervals were calculated by Cox proportional hazards models and then pooled by a random-effects model.

Results: No statistically significant associations were observed between intakes of milk, cheese, yogurt, ice cream, and dietary and total calcium intake and risk of ovarian cancer. Higher lactose intakes comparing ≥30 versus <10 g/d were associated with a statistically significant higher risk of ovarian cancer, although the trend was not statistically significant (pooled multivariate relative risk, 1.19; 95% confidence interval, 1.01-1.40; Ptrend = 0.19). Associations for endometrioid, mucinous, and serous ovarian cancer were similar to the overall findings.

Discussion: Overall, no associations were observed for intakes of specific dairy foods or calcium and ovarian cancer risk. A modest elevation in the risk of ovarian cancer was seen for lactose intake at the level that was equivalent to three or more servings of milk per day. Because a new dietary guideline recommends two to three servings of dairy products per day, the relation between dairy product consumption and ovarian cancer risk at these consumption levels deserves further examination. (Cancer Epidemiol Biomarkers Prev 2006;15(2):364–72)
The Relative Use of Eight Collagenous and Noncollagenous Markers for Diagnosis of Skeletal Metastases in Breast, Prostate, or Lung Cancer Patients
Authors: Leeming Diana J. , Koizumi Mitsuru , Byrjalsen Inger , Li Bo , Qvist Per , Tankó László B.
Published: March 2006

The present study was sought to assess the relative use of eight biomarkers for the detection of bone metastases in cancer forms frequently spreading to the skeleton. Participants were 161 patients with either breast, prostate, or lung cancer. The presence and extent of bone metastases was assessed by imaging techniques (computer tomography and/or magnetic resonance imaging) and Technetium-99m scintigraphy. Serum or urinary level of the bone resorption markers (ααCTX, ββCTX, NTX, and ICTP), formation marker (BSAP), and osteoclastogenesis markers (osteoprotegerin, RANKL, and TRAP5b) was measured by commercially available immunoassays. When assessed on a group basis, all biomarkers, except for osteoprotegerin and RANKL, were significantly elevated in patients compared with those without bone metastases (P < 0.05). Biomarkers had greater diagnostic value in breast and prostate cancer patients, yet ααCTX, NTx, and ICTP were able to discriminate lung cancer patients with or without bone metastases (P < 0.05). Strong linear associations were seen between the extent of skeletal infiltration and levels of the different biomarkers, except for osteoprotegerin and RANKL. Furthermore, all biomarkers (except for osteoprotegerin and RANKL) were indicative at the early stage of skeletal involvement (one to five metastases). When expressing sensitivity as the percentage increase in biomarker level relative to patients without bone metastases, ααCTX showed the largest relative increases at each stage of the metastatic disease. These results suggest that closer monitoring of cancer patients with serial measures of biomarkers might facilitate the timely diagnosis of skeletal metastases. (Cancer Epidemiol Biomarkers Prev 2006;15(1)32–8)
Associations between ERα, ERβ, and AR Genotypes and Colon and Rectal Cancer
Authors: Slattery Martha L. , Sweeney Carol , Murtaugh Maureen , Ma Khe Ni , Wolff Roger K. , Potter John D. , Caan Bette J. , Samowitz Wade
Published: March 2006

Estrogen and androgens are thought to be involved in the etiology of colorectal cancer. We evaluate genetic variants of the estrogen receptor genes (ERα and ERβ) and the androgen receptor gene (AR). We use data from two large case-control studies of colon (n = 1,580 cases and 1,968 controls) and rectal (n = 797 cases and 1,016 controls) cancer. We evaluated the 351A>G XbaI polymorphism of ERα, the 1,082 G>A and CA repeat polymorphisms of ERβ, and the CAG repeat of AR. Having two 25 or more CA repeats in ERβ was associated with an increased relative risk of colon cancer in women [odds ratio (OR), 2.13; 95% confidence interval (95% CI), 1.24-3.64] but not in men (Pinteraction relative excess risk from interaction < 0.01; multiplicative = 0.03). Increasing number of AR CAG repeats was directly associated with colon cancer among men (OR, 1.28; 95% CI, 1.06-1.54), but not women (OR, 0.83; 95% CI, 0.68-1.02); the interaction P value for AR gene × sex was <0.01. Taking hormone replacement therapy (HRT) was associated with a reduced risk of colon cancer in the presence of the R allele of the ERβ gene, whereas an R allele was associated with increased risk among postmenopausal women who did not take HRT. Postmenopausal women not using HRT who had ≥25 CA repeats of the ERβ gene had over a 6-fold increased risk of colon cancer (OR, 6.71; 95% CI, 2.89-15.6). Our results suggest that the ERβ gene is more important than ERα in the etiology of colorectal cancer. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2936–42)
Risk of Non–Hodgkin Lymphoma Associated with Polymorphisms in Folate-Metabolizing Genes
Authors: Lightfoot Tracy J. , Skibola Christine F. , Willett Eleanor V. , Skibola Danica R. , Allan James M. , Coppede Fabio , Adamson Peter J. , Morgan Gareth J. , Roman Eve , Smith Martyn T.
Published: March 2006

Genetic instability, including chromosomal imbalance, is important in the pathogenesis of lymphoproliferative disorders such as non–Hodgkin lymphoma (NHL). DNA synthesis and methylation, which are closely linked to folate metabolism and transport, may be affected by polymorphisms in genes involved in these pathways. Folate metabolism polymorphisms have been linked to acute lymphoblastic leukemia and colorectal cancer. To evaluate whether genetic variation in folate metabolism and transport may have a role in determining the risk of developing NHL, we analyzed several polymorphisms using DNA obtained as part of a large U.K. population-based case-control study of lymphoma. Polymorphisms studied include methylenetetrahydrofolate reductase (MTHFR) 677 C>T and 1298 A>C, methionine synthase (MTR) 2756 A>G, serine hydroxymethyltransferase (SHMT1) 1420 C>T, thymidylate synthase (TYMS) 1494del6 and 28–bp repeat, and reduced folate carrier (RFC) 80 G>A. Increased risks for NHL [odds ratio (OR), 1.48; 95% confidence intervals (CI), 1.12-1.97], and marginal zone lymphoma (OR, 3.38; 95% CI, 1.30-8.82) were associated with the TYMS 2R/3R variant. Marginal increased risks were also observed for diffuse large B cell lymphoma with the TYMS homozygous 6 bp deletion (OR, 1.61; 95% CI, 0.99-2.60) and for follicular lymphoma with RFC 80AA (OR, 1.44; 95% CI, 0.94-2.22) and TYMS 28–bp repeat 2R/3R (OR, 1.45; 95% CI, 0.96-2.2). We observed no association between NHL and haplotypes for MTHFR or TYMS. These findings are somewhat inconsistent with those of others, but may reflect differences in circulating folate levels between study populations. Thus, further investigations are warranted in larger series with dietary information to determine the roles that genetics and folic acid status play in the etiology of lymphoma. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2999–3003)
Claudin-4, Mitogen-Activated Protein Kinase Kinase 4, and Stratifin Are Markers of Gastric Adenocarcinoma Precursor Lesions
Authors: Cunningham Steven C. , Kamangar Farin , Kim Min P. , Hammoud Sommer , Haque Raqeeb , Iacobuzio-Donahue Christine A. , Maitra Anirban , Ashfaq Raheela , Hustinx Steven , Heitmiller Richard E. , Choti Michael A. , Lillemoe Keith D. , Cameron John L. , Yeo Charles J. , Schulick Richard D. , Montgomery Elizabeth
Published: March 2006

Approximately 23,000 new gastric cancer cases and 12,000 associated deaths occur annually in the United States. Intestinal metaplasia and gastric epithelial dysplasia are precursor lesions to gastric adenocarcinoma, but are not readily detectable clinically, radiographically, or endoscopically. A noninvasive method of precursor detection would require the ability to distinguish precursor lesions from adjacent normal mucosa. In search of such markers, tissue microarrays were prepared for 133 patients of resected gastric adenocarcinoma. Tissue microarrays contained primary cancer, normal stomach, intestinal metaplasia, and gastric epithelial dysplasia and were probed with antibodies against nine potential markers that were either identified in a database of genes overexpressed in gastric adenocarcinoma or were already of interest to our laboratory: claudin-4, mitogen-activated protein kinase kinase 4 (MKK4), 14-3-3σ (stratifin), S100A4, mesothelin, fascin, topoisomerase IIα, HER-2/neu, and epithelial growth factor receptor. Three markers discriminated gastric adenocarcinoma precursor lesions from normal gastric mucosa. Claudin-4 expression was present in 36 intestinal metaplasia lesions (100%) and 14 gastric epithelial dysplasia lesions (100%), but in only 16 normal stomach samples (15%). MKK4 expression was present in 24 intestinal metaplasia lesions (89%) and 12 gastric epithelial dysplasia lesions (100%), but in only 6 normal stomach samples (8%). Stratifin expression was present in 29 intestinal metaplasia lesions (97%) and 8 gastric epithelial dysplasia lesions (100%), but in only 2 normal stomach samples (3%). Sensitivity and specificity for detection of the precursor lesion intestinal metaplasia were 100% and 85%, respectively, for claudin-4; 89% and 92%, respectively, for MKK4; and 97% and 97%, respectively, for stratifin. In primary cancers, 123 of 125 (98.4%) were positive for claudin-4, 116 of 126 (94%) for MKK4, and 111 of 120 (92%) for stratifin. In conclusion, claudin-4, MKK4, and stratifin immunolabeling detects precursor lesions of gastric adenocarcinoma that are otherwise clinically, radiographically, and endoscopically inapparent. These findings may prove useful in the diagnosis and therapeutic targeting of gastric adenocarcinoma precursor lesions. (Cancer Epidemiol Biomarkers Prev 2006;15(2):281–7)
Telomere Length in the Colon Declines with Age: a Relation to Colorectal Cancer?
Authors: O'Sullivan Jacintha , Risques Rosa Ana , Mandelson Margaret T. , Chen Lu , Brentnall Teresa A. , Bronner Mary P. , MacMillan Melissa P. , Feng Ziding , Siebert Joseph R. , Potter John D. , Rabinovitch Peter S.
Published: March 2006

Telomeres shorten with age, which may be linked to genomic instability and an increased risk of cancer. To explore this association, we analyzed telomere length in normal colorectal tissue of individuals at different ages using quantitative-fluorescence in situ hybridization (Q-FISH) and quantitative-PCR (Q-PCR). Using Q-FISH, we also examined the histologically normal epithelium adjacent to, or distant from, colon adenomas and cancers, in addition to the neoplasms. Q-FISH and Q-PCR showed that telomere length was inversely associated with age until ∼ages 60 to 70; surprisingly, beyond this age, telomere length was positively associated with age. This association was found exclusively in epithelial, and not in stromal, cells. Peripheral blood lymphocytes showed an inverse association between telomere length and age, but without any apparent increase in telomere length in the oldest individuals. Telomere length in larger adenoma lesions (>2 cm) was significantly shorter than in normal adjacent (P = 0.004) or normal distant (P = 0.05) tissue from the same individuals. However, telomere length in histologically normal epithelium adjacent to cancers or in adenomas <2 cm was not statistically different from that of the normal distant mucosa or from normal controls, evidence that a telomere-shortening field effect was not present. We suggest that the positive association between telomere length and age in the oldest patients is a consequence of selective survival of elderly patients with long colonocyte telomeres. (Cancer Epidemiol Biomarkers Prev 2006;15(3):573–7)