bluuebunny/crossref_metadata_2025 huggingface dataset:
No Evidence for Anticipation in Lymphoproliferative Tumors in Population-Based Samples
Authors: Daugherty Sarah E. , Pfeiffer Ruth M. , Mellemkjaer Lene , Hemminki Kari , Goldin Lynn R.
Published: September 2005

Genetic anticipation in familial non–Hodgkin's lymphoma, Hodgkin's lymphoma, and chronic lymphocytic leukemia (CLL) has been consistently reported in the literature. However, most of these findings were based on data from families ascertained for genetic studies. Fecundity bias, right censoring bias, and secular trends can lead to erroneous conclusions regarding the presence of anticipation. Our report investigates anticipation in four lymphoproliferative cancers, non–Hodgkin's lymphoma, Hodgkin's lymphoma, CLL, and multiple myeloma, drawn from Swedish and Danish population-based registries. We used marginal survival methods to test for a relative difference in age at diagnosis between parents and offspring and to account for other risk factors, staggered entries, censored data, and correlations among relatives. Changes in incidence rates of lymphoproliferative tumors were accommodated in the models by using time-varying covariates for different periods of diagnosis. Whereas no anticipation was observed for Hodgkin's lymphoma, CLL, and multiple myeloma, our initial model, which controlled for gender and country, suggested a significant difference (hazard ratio, 0.5; 95% confidence interval, 0.33-0.75) in age at diagnosis between the parents and offspring in the non–Hodgkin's lymphoma sample. However, once we accounted for the significant change in non–Hodgkin's lymphoma incidence over time, the statistical difference between parents and offspring disappeared (hazard ratio, 0.99; 95% confidence interval, 0.56-1.76). Our results emphasize the importance of considering secular trends when evaluating the possibility of anticipation in lymphoproliferative cancers. This is the first study to consider the changes of incidence over time as a source of bias when evaluating anticipation in lymphoproliferative cancers.
Dietary Folate and Risk of Prostate Cancer in Italy
Authors: Pelucchi Claudio , Galeone Carlotta , Talamini Renato , Negri Eva , Parpinel Maria , Franceschi Silvia , Montella Maurizio , La Vecchia Carlo
Published: September 2005

Folate status may affect cancer risk through its role in both methylation and nucleotide synthesis of DNA. A low dietary intake of folate has been linked to risk of several cancers, but epidemiologic studies with reference to prostate cancer are scanty. We therefore analyzed data from a case-control study of prostate cancer conducted between 1991 and 2002 in various areas of Italy. Cases were 1,294 patients with incident, histologically confirmed prostate cancer and controls were 1,451 patients admitted to the same network of hospitals of cases for acute, nonneoplastic conditions. All subjects were <75 years old. Intake of folate and other nutrients was computed from a validated food frequency questionnaire. We adjusted for energy intake using the residual method, and calculated multivariate odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression. The OR of prostate cancer was 0.66 (95% CI, 0.51-0.85) for the highest versus the lowest quintile of folate intake. The relation between dietary folate and prostate cancer was consistent across strata of age, methionine, vitamin B6, and alcohol intake, and did not vary substantially according to Gleason score of prostate cancer. The combined OR for high-folate and low-alcohol intake versus low-folate and high-alcohol intake was 0.46 (95% CI, 0.29-0.75). Therefore, this study supports a favorable role of dietary folate on prostate cancer risk.
Host-Environment Interactions: Their Impact on Progression from Gastric Inflammation to Carcinogenesis and on Development of New Approaches to Prevent and Treat Gastric Cancer
Authors: Wu Ming-Shiang , Chen Chien-Jen , Lin Jaw-Town
Published: September 2005

Revelation of the connection between Helicobacter pylori infection and gastric adenocarcinoma has prompted new investigations pertaining to its basic and clinical aspects. H. pylori–induced persistent and uncontrolled gastric inflammation nearly always precedes the development of cancer and is instrumental in initiating a multistep process leading to carcinogenesis. Despite initial optimism about the potential of combination anti–H. pylori therapy to ultimately eradicate gastric adenocarcinoma, recent investigations suggest its use should be targeted and tailored to a selected patient group considering the multifaceted role of H. pylori in disease and the disease heterogeneity of gastric adenocarcinoma. The clinical spectrum of H. pylori infection ranges from asymptomatic gastritis and peptic ulcer to gastric malignancies. The occurrence of one versus another is the result of differences in the magnitude of gastritis, and the current disease paradigm suggests gastric inflammation is common to all H. pylori–associated gastroduodenal diseases. Therefore, the host inflammatory responses to environmental triggers, rather than to bacteria or environmental factors per se, would dictate the variable outcomes of H. pylori infection. Putative factors that are expected to play an important role in stimulating inflammatory pathways and modulating the cross-talk between host and environment are age at the time of infection, environmental cofactors, H. pylori virulence, and host genetics. Elucidation of the intimate relationship between host-environment interaction and gastric inflammation, although currently a formidable task, is essential in the development of new prevention and treatment strategies. Such knowledge might provide clues that allow more accurate prediction of variable outcomes of gastric inflammation and appropriate adjustment of treatment strategies, and might open up novel areas for studying gastric carcinogenesis. The evolving new technologies, such as microarray, proteomic, and functional genomic analyses, promise to shed new light on the immense complexity of the presumed host-environment interactions and will reveal more useful markers for the diagnosis and prognosis of gastric adenocarcinoma.
Monitoring Low Benzene Exposure: Comparative Evaluation of Urinary Biomarkers, Influence of Cigarette Smoking, and Genetic Polymorphisms
Authors: Fustinoni Silvia , Consonni Dario , Campo Laura , Buratti Marina , Colombi Antonio , Pesatori Angela C. , Bonzini Matteo , Bertazzi Pier A. , Foà Vito , Garte Seymour , Farmer Peter B. , Levy Leonard S. , Pala Mauro , Valerio Federico , Fontana Vincenzo , Desideri Arianna , Merlo Domenico F.
Published: September 2005

Benzene is a human carcinogen and an ubiquitous environmental pollutant. Identification of specific and sensitive biological markers is critical for the definition of exposure to low benzene level and the evaluation of the health risk posed by this exposure. This investigation compared urinary trans,trans-muconic acid (t,t-MA), S-phenylmercapturic acid, and benzene (U-benzene) as biomarkers to assess benzene exposure and evaluated the influence of smoking and the genetic polymorphisms CYP2E1 (RsaI and DraI) and NADPH quinone oxidoreductase-1 on these indices. Gas station attendants, urban policemen, bus drivers, and two groups of controls were studied (415 subjects). Median benzene exposure was 61, 22, 21, 9 and 6 μg/m3, respectively, with higher levels in workers than in controls. U-benzene, but not t,t-MA and S-phenylmercapturic acid, showed an exposure-related increase. All the biomarkers were strongly influenced by cigarette smoking, with values up to 8-fold higher in smokers compared with nonsmokers. Significant correlations of the biomarkers with each other and with urinary cotinine were found. A possible influence of genetic polymorphism of CYP2E1 (RsaI and/or DraI) on t,t-MA and U-benzene in subjects with a variant allele was found. Multiple linear regression analysis correlated the urinary markers with exposure, smoking status, and CYP2E1 (RsaI; R2 up to 0.55 for U-benzene). In conclusion, in the range of investigated benzene levels (<478 μg/m3 or <0.15 ppm), smoking may be regarded as the major source of benzene intake; among the study indices, U-benzene is the marker of choice for biomonitoring low-level occupational and environmental benzene exposure.
Decreased α-Methylacyl CoA Racemase Expression in Localized Prostate Cancer is Associated with an Increased Rate of Biochemical Recurrence and Cancer-Specific Death
Authors: Rubin Mark A. , Bismar Tarek A. , Andrén Ove , Mucci Lorelei , Kim Robert , Shen Ronglai , Ghosh Debashis , Wei John T. , Chinnaiyan Arul M. , Adami Hans-Olov , Kantoff Philip W. , Johansson Jan-Erik
Published: September 2005

α-Methylacyl CoA racemase (AMACR) is overexpressed in prostate cancer relative to benign prostatic tissue. AMACR expression is highest in localized prostate cancer and decreases in metastatic prostate cancer. Herein, we explored the use of AMACR as a biomarker for aggressive prostate cancer. AMACR protein expression was determined by immunohistochemistry using an image analysis system on two localized prostate cancer cohorts consisting of 204 men treated by radical prostatectomy and 188 men followed expectantly. The end points for the cohorts were time to prostate-specific antigen (PSA) failure (i.e., elevation >0.2 ng/mL) and time to prostate cancer death in the watchful waiting cohort. Using a regression tree method, optimal AMACR protein expression cutpoints were determined to best differentiate prostate cancer outcome in each of the cohorts separately. Cox proportional hazard models were then employed to examine the effect of the AMACR cutpoint on prostate cancer outcome, and adjusted for clinical variables. Lower AMACR tissue expression was associated with worse prostate cancer outcome, independent of clinical variables (hazard ratio, 3.7 for PSA failure; P = 0.018; hazard ratio, 4.1 for prostate cancer death, P = 0.0006). Among those with both low AMACR expression and high Gleason score, the risk of prostate cancer death was 18-fold higher (P = 0.006). The AMACR cutpoint developed using prostate cancer–specific death as the end point predicted PSA failures independent of Gleason score, PSA, and margin status. This is the first study to show that AMACR expression is significantly associated with prostate cancer progression and suggests that not all surrogate end points may be optimal to define biomarkers of aggressive prostate cancer.
Positive Correlation of Insulin-Like Growth Factor-II with Proliferating Cell Index in Patients with Colorectal Neoplasia
Authors: Zhao Ronghua , Berho Mariana , Nogueras Juan , Sands Dana , Weiss Eric , Wexner Steven , Giardiello Francis M. , Cruz-Correa Marcia
Published: September 2005

Background: Insulin-like growth factor-II (IGF-II) stimulates cell proliferation and is considered a potential risk factor for colorectal cancer. Tumor levels of IGF-II seem to positively correlate with colorectal cancer cell proliferation. This investigation examined the association of circulating IGF-II to the proliferating cell index (PCI) of tumor and matched normal mucosa in patients with colorectal neoplasia.

Methods: Circulating IGF-II level (ng/mL) was determined in the peripheral blood plasma by ELISA. The proliferating cells in tumor or matched normal mucosa were immunohistochemically stained using the primary antibody against Ki-67. Computer image analysis was used and PCI was expressed as the percentage of Ki-67–positive cells/total counted cells.

Results: Sixty-four patients were evaluated; 45 had colorectal neoplasia (27 males/18 females; mean age, 66.8 ± 11.8 years) and 19 had hyperplastic polyps (6 males and 13 females; mean age, 58.4 ± 14.4 years). Among patients with colorectal neoplasia, blood IGF-II levels were positively correlated with PCI in the matched normal mucosa (r = 0.46, P < 0.05) but not in the tumor. In patients with hyperplastic polyps, blood IGF-II levels were not correlated with the PCI in the polyps. Blood IGF-II levels were higher in colorectal cancer patients with Dukes' C/D stage (P < 0.01) or with positive lymph nodes (P < 0.01).

Conclusion: Circulating IGF-II positively correlated with PCI in normal colonic mucosa of patients with colorectal neoplasia, suggesting that IGF-II may have a role in initiating the carcinogenic pathway by stimulating cell proliferation. Blood IGF-II was increased in advanced colorectal cancer, indicating that it might enhance colorectal cancer progression and be a useful marker of poor prognosis.
Genetic Variants of DNA Repair Genes and Prostate Cancer: A Population-Based Study
Authors: Ritchey Jamie D. , Huang Wen-Yi , Chokkalingam Anand P. , Gao Yu-Tang , Deng Jie , Levine Paul , Stanczyk Frank Z. , Hsing Ann W.
Published: September 2005

As part of a population-based case-control study in Shanghai, China, we investigated whether variants in several DNA repair genes, either alone or in conjunction with other risk factors, are associated with prostate cancer risk. Genomic DNA from 162 patients newly diagnosed with prostate cancer and 251 healthy men randomly selected from the population were typed for five nonsynonymous DNA repair markers. We found that the XRCC1-Arg399Gln AA and the MGMT-Leu84Phe CT+TT genotypes were associated with an increased risk of prostate cancer [odds ratio (OR), 2.18; 95% confidence interval (CI), 0.99-4.81 and OR, 1.99; 95% CI, 1.19-3.34, respectively]. In contrast, XRCC3-Thr241Met, XPD-Lys751Gln, and MGMT-Ile143Val markers showed no significant associations with risk, although due to the much lower frequency of their variant alleles in this population we cannot rule out small to modest effects. There was a significant interaction between the MGMT-84 marker and insulin resistance (Pinteraction = 0.046). Relative to men with the MGMT-84 CC genotype and a low insulin resistance (<0.097), those having the CT-TT genotype and a greater insulin resistance had a 5.4-fold risk (OR, 5.39; 95% CI, 2.46-11.82). In addition, for the XRCC3-241 marker, relative to men with the CC genotype and a low intake of preserved foods (<12.7 g/d), those harboring the CT+TT genotype and having a higher intake of preserved foods (>12.7 g/d), which contain nitrosamines and nitrosamine precursors, had a significantly increased risk of prostate cancer risk (OR, 2.62; 95% CI, 1.13-6.06). In contrast, men with the CT+TT genotype and a low intake of preserved foods had a 69% reduction in risk (OR, 0.31; 95% CI, 0.10-0.96; Pinteraction = 0.005). These results suggest that genetic variants in the DNA repair pathways may be involved in prostate cancer etiology and that other risk factors, including preserved foods and insulin resistance, may modulate prostate cancer risk in combination with genetic susceptibility in these repair pathways. Replication in larger studies is necessary to preclude chance findings, particularly those among subgroups, and clarify the mechanisms involved.
Examining Population Stratification via Individual Ancestry Estimates versus Self-Reported Race
Authors: Barnholtz-Sloan Jill S. , Chakraborty Ranajit , Sellers Thomas A. , Schwartz Ann G.
Published: September 2005

Population stratification has the potential to affect the results of genetic marker studies. Estimating individual ancestry provides a continuous measure to assess population structure in case-control studies of complex disease, instead of using self-reported racial groups. We estimate individual ancestry using the Federal Bureau of Investigation CODIS Core short tandem repeat set of 13 loci using two different analysis methods in a case-control study of early-onset lung cancer. Individual ancestry proportions were estimated for “European” and “West African” groups using published allele frequencies. The majority of Caucasian, non-Hispanics had >50% European ancestry, whereas the majority of African Americans had <20% European ancestry, regardless of ancestry estimation method, although significant overlap by self-reported race and ancestry also existed. When we further investigated the effect of ancestry and self-reported race on the frequency of a lung cancer risk genotype, we found that the frequency of the GSTM1 null genotype varies by individual European ancestry and case-control status within self-reported race (particularly for African Americans). Genetic risk models showed that adjusting for individual European ancestry provided a better fit to the data compared with the model with no group adjustment or adjustment for self-reported race. This study suggests that significant population substructure differences exist that self-reported race alone does not capture and that individual ancestry may be confounded with disease status and/or a candidate gene risk genotype.
Genetic Variation in XPD, Sun Exposure, and Risk of Skin Cancer
Authors: Han Jiali , Colditz Graham A. , Liu Jun S. , Hunter David J.
Published: September 2005

The XPD gene is involved in the nucleotide excision repair pathway removing DNA photoproducts induced by UV radiation. Genetic variation in XPD may exert a subtle effect on DNA repair capacity. We assessed the associations between two common nonsynonymous polymorphisms (Asp312Asn and Lys751Gln) with skin cancer risk in a nested case-control study within the Nurses' Health Study (219 melanoma, 286 squamous cell carcinoma, 300 basal cell carcinoma, and 874 controls) along with exploratory analysis on the haplotype structure of the XPD gene. There were inverse associations between the Lys751Gln and Asp312Asn polymorphisms and the risks of melanoma and squamous cell carcinoma. No association was observed between these two polymorphisms and basal cell carcinoma risk. We also observed that the association of the 751Gln allele with melanoma risk was modified by lifetime severe sunburns, cumulative sun exposure with a bathing suit, and constitutional susceptibility score (P for interaction = 0.03, 0.04, and 0.02 respectively). Similar interactions were also observed for the Asp312Asn. Our data suggest these two XPD nonsynonymous polymorphisms may be associated with skin cancer risk, especially for melanoma.
Association of an Exon 1 Polymorphism in theIGFBP3Gene with Circulating IGFBP-3 Levels and Colorectal Cancer Risk: The Multiethnic Cohort Study
Authors: Le Marchand Loïc , Kolonel Laurence N. , Henderson Brian E. , Wilkens Lynne R.
Published: September 2005

Laboratory and seroepidemiologic studies have suggested that insulin-like growth factor binding protein-3 (IGFBP-3), the main binding protein for IGF-I, may be protective against colorectal cancer. We investigated the association of two polymorphisms (A-202C and G2133C) in the IGFBP3 gene with plasma IGF hormone levels among 887 randomly selected participants in the Multiethnic Cohort study. We found that these two genetic variants were in strong linkage disequilibrium and were both inversely associated with plasma IGFBP-3. However, the effect on plasma IGFBP-3 levels was stronger for the G2133C variant than the A-202C variant. Thus, we assessed the colorectal cancer risk associated with the G2133C in a case-control study of 817 cases and 1,995 controls nested within the Multiethnic Cohort study. Under the assumption of dominant genetic model, carriers of the 1233C allele were at 32% increased risk of colorectal cancer [95 % confidence interval (95% CI) for the odds ratio (OR), 1.07-1.62] and that this effect seemed stronger for the rectum (OR for the C allele, 1.95; 95% CI, 1.35-2.83) than the colon (OR, 1.16; 95% CI, 0.92-1.45). These data suggest that the exon 1 G2133C missense variant in IGFBP3 may be a susceptibility factor for colorectal cancer.
Age-Specific Incidence Rates of In situ Breast Carcinomas by Histologic Type, 1980 to 2001
Authors: Li Christopher I. , Daling Janet R. , Malone Kathleen E.
Published: September 2005

Incidence rates of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) have increased rapidly over the past several decades largely due to the increased use of mammography. However, recent data from 1987 to 1999 indicate that invasive ductal carcinoma incidence rates have remained essentially constant, whereas rates of invasive lobular carcinoma have increased 65%, with greater increases observed among postmenopausal women. Data on recent trends in DCIS and LCIS incidence rates, particularly age-specific trends, are lacking. We evaluated trends in the incidence rates of DCIS overall, noncomedo DCIS, comedo DCIS, and LCIS using data from nine Surveillance, Epidemiology, and End Results cancer registries. DCIS incidence rates increased 7.2-fold [95% confidence interval (95% CI), 6.8-7.7] from 1980 to 2001, 1.8-fold (95% CI, 1.7-1.9) over the past 10 years (1992-2001), and 1.1-fold (95% CI, 1.0-1.2) over the past 5 years (1997-2001). The magnitudes of these increases were highest among women ages ≥50 years. Furthermore, over the past 10- and 5-year periods, rates of noncomedo DCIS have generally increased across all age groups, whereas rates of comedo DCIS held constant or decreased. LCIS incidence rates increased 2.6-fold (95% CI, 2.3-2.9) from 1980 to 2001, 1.3-fold (95% CI, 1.2-1.5) over the past 10 years, and 1.1-fold (95% CI, 1.0-1.3) over the past 5 years. Similar to invasive lobular carcinoma, but unlike invasive ductal carcinoma, incidence rates of both DCIS and LCIS continue to increase in the United States primarily among older women. These trends present important public health and clinical challenges.
Dietary Benzo[a]Pyrene Intake and Risk of Colorectal Adenoma
Authors: Sinha Rashmi , Kulldorff Martin , Gunter Marc J. , Strickland Paul , Rothman Nathaniel
Published: September 2005

We carried out a clinic-based case-control study specifically designed to address the hypothesis that dietary intake of polycyclic aromatic hydrocarbons (PAH) is associated with colorectal adenoma risk. We developed a food frequency questionnaire with detailed questions on meat-cooking methods and doneness levels and a benzo[a]pyrene (BaP) database (as a surrogate for total carcinogenic PAHs) based on the collection and analysis of a wide range of food samples. We estimated BaP intake derived from meat and from all foods to test its relationship with risk of colorectal adenomas. The median (10th and 90th percentiles) BaP intake in controls was 5 ng/d (0.2 and 66 ng/d) estimated from meat and 73 ng/d (35 and 140 ng/d) from all foods. In cases, median BaP intake was 17 ng/d (0.5 and 101 ng/d) from meat and 76 ng/d (44 and 163 ng/d) from all foods. Multivariate analysis was carried out on 146 cases and 228 controls. The odds ratios (95% confidence interval) for dietary BaP from meat with the first quintile as the reference group were 1.19 (0.51-2.80) for the second quintile, 1.71 (0.76-3.83) for the third quintile, 2.16 (0.96-4.86) for the fourth quintile, and 2.82 (1.24-6.43) for the fifth quintile (Ptrend = 0.01). Increased risk of colorectal adenomas was more strongly associated with BaP intake estimated from all foods: 2.61 (1.08-6.29) for the second quintile, 4.21 (1.79-9.91) for the third quintile, 2.45 (0.98-6.12) for the fourth quintile, and 5.60 (2.20-14.20) for the fifth quintile (Ptrend = 0.002). This study provides evidence that dietary BaP plays a role in colorectal adenoma etiology.
Pregnancy Hormone Concentrations Across Ethnic Groups: Implications for Later Cancer Risk
Authors: Potischman Nancy , Troisi Rebecca , Thadhani Ravi , Hoover Robert N. , Dodd Kevin , Davis William W. , Sluss Patrick M. , Hsieh Chung-Cheng , Ballard-Barbash Rachel
Published: September 2005

A variety of in utero factors have been associated with risk of adult cancers, particularly birth weight, toxemia, and gestational age. These factors are thought to reflect hormonal exposures during pregnancy. We hypothesized that the prenatal hormonal milieu may explain part of the variation in cancer rates across ethnic groups, for example, the higher incidence of breast cancer in the Caucasian compared with Hispanic women and the higher incidence of prostate and lower incidence of testicular cancers among African-Americans compared with Caucasians. We measured hormones in early pregnancy blood samples from three ethnic groups in a health care plan in Boston, MA. Mean levels of androstenedione, testosterone, estrone, and prolactin were significantly lower in Caucasian women compared with Hispanic women. Although not statistically significant, estradiol levels were lower in Caucasian compared with Hispanic or African-American women. Concentrations of androstenedione, testosterone, and progesterone were notably higher in African-American compared with Caucasian or Hispanic women. These data are consistent with hypotheses that in utero hormonal exposures may explain some of the ethnic group differences in cancer risk.
Endometrial Cancer Incidence Trends in Europe: Underlying Determinants and Prospects for Prevention
Authors: Bray Freddie , dos Santos Silva Isabel , Moller Henrik , Weiderpass Elisabete
Published: September 2005

More than one in 20 female cancers in Europe are of the endometrium. Surveillance of incidence rates is imperative given the rapidly changing profile in the prevalence and distribution of the underlying determinants. This study presents an analysis of observed and age-period-cohort–modeled trends in 13 European countries. There were increasing trends among postmenopausal women in many Northern and Western countries. Denmark and possibly France and Switzerland were exceptions, with decreasing trends in postmenopausal women. In premenopausal and perimenopausal women, declines were observed in Northern and Western Europe, most evidently in Denmark, Sweden, and the United Kingdom, affecting consecutive generations born after 1925. These contrast with the increasing trends regardless of menopausal age in some Southern and Eastern European countries, particularly Slovakia and Slovenia. These observations provide evidence of changes in several established risk factors over time and have implications for possible primary prevention strategies. In postmenopausal women, changes in reproductive behavior and prevalence of overweight and obesity may partially account for the observed increases, as well as hormone replacement therapy use in certain countries. Combined oral contraceptive use may be responsible for the declines observed among women aged <55 years. Whereas there are some prospects for chemoprevention in premenopausal women as oral contraceptive use becomes more widespread in Europe, increases in obesity and decreases in fertility imply that endometrial cancer in postmenopausal women will become a more substantial public health problem in the future.
The Role of Cytokine Gene Polymorphisms in Colorectal Cancer and Their Interaction with Aspirin Use in the Northeast of Scotland
Authors: Macarthur Mairi , Sharp Linda , Hold Georgina L. , Little Julian , El-Omar Emad M.
Published: September 2005

The reduced risk of colorectal cancer associated with cyclooxygenase enzyme inhibitors, such as aspirin and other nonsteroidal anti-inflammatory drugs, strongly suggests that chronic inflammation is a key mediator in the development of colorectal cancer. This complements recent molecular evidence demonstrating an association between a number of proinflammatory genetic polymorphisms and risk of colorectal cancer. We assessed polymorphisms in the IL-1, IL-10, TNF-A, and TGF-B genes in a population-based case-control study of colorectal cancer cases (n = 264) and frequency-matched controls (n = 408) in the Northeast of Scotland and analyzed their interaction with regular aspirin use. There was no evidence of a relation between any of the individual polymorphisms, or pairs of polymorphisms, and risk of colorectal cancer. There was a significant interaction between the IL-10-592 C/A polymorphism and aspirin use (Pinteraction = 0.03). Carriers of the variant IL-10-592 (A) allele, who produce less of the anti-inflammatory cytokine interleukin-10, had a statistically significant 50% reduced risk of colorectal cancer when taking regular aspirin (odds ratio, 0.5; 95% confidence interval, 0.25-0.97), whereas risk was not reduced in carriers of the A allele who did not use aspirin, or among aspirin users with the CC genotype. It is possible that carriers of the mutant IL-10-592 allele are more likely to derive anti-inflammatory and chemopreventive benefits from aspirin in the presence of a lower production of their own endogenous anti-inflammatory interleukin-10. These results suggest that host genetics may play a role in predicting response to chemopreventive strategies. Confirmation of these findings in other populations is required.
Role of Cytokine Polymorphisms in the Risk of Distal Gastric Cancer Development
Authors: Perez-Perez Guillermo I. , Garza-Gonzalez Elvira , Portal Cynthia , Olivares Asalia Z.
Published: September 2005

We review the current information concerning the role of cytokine polymorphisms and the risk of develop distal gastric cancer in different populations. We have included populations colonized with Helicobacter pylori as well as populations without colonization. We found that the study of polymorphisms alone seems insufficient to assess gastric cancer risk and it is necessary to examine environmental factors in different ethnic groups and geographic areas along with the study of H. pylori strains to define better the risk factors associated with distal gastric cancer.
5,10-Methylenetetrahydrofolate Reductase Polymorphisms and the Risk of Pancreatic Cancer
Authors: Li Donghui , Ahmed Maha , Li Yanan , Jiao Li , Chou Ta-Hsu , Wolff Robert A. , Lenzi Renato , Evans Douglas B. , Bondy Melissa L. , Pisters Peter W. , Abbruzzese James L. , Hassan Manal M.
Published: September 2005

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.
Polymorphisms in Ghrelin and Neuropeptide Y Genes Are Associated with Non-Hodgkin Lymphoma
Authors: Skibola Danica R. , Smith Martyn T. , Bracci Paige M. , Hubbard Alan E. , Agana Luz , Chi Shawn , Holly Elizabeth A.
Published: September 2005

We previously reported a positive association among body mass index, single nucleotide polymorphisms (SNP) in the leptin and leptin receptor genes that are involved in body weight regulation, and non-Hodgkin lymphoma (NHL). Polymorphisms in the ghrelin (GHRL) and neuropeptide Y (NPY) genes were examined in the same population-based case-control study of NHL to further explore the role of genes involved in energy homeostasis and obesity in susceptibility to NHL. Ghrelin is an orexigenic hormone that induces NPY release and inhibits proinflammatory cytokines via its antagonistic relationship with leptin. NPY is a potent appetite stimulator controlled by ghrelin and leptin and also acts as a mediator of immune function. DNA from 458 cases and 812 controls was genotyped. Among genotyped GHRL SNPs, the variant allele for GHRL −4427G>A was inversely associated with all NHL [odds ratios (OR), 0.78; 95% confidence interval (95% CI), 0.59-1.0] and more specifically with diffuse large cell lymphoma (DLCL; homozygous variant: OR, 0.31; 95% CI, 0.13-0.74). Another SNP, GHRL 5179A>G, decreased the risk of DLCL (homozygous variant: OR, 0.35; 95% CI, 0.10-1.2). NPY −485T>C, 1258G>A, and 5671C>T were in total linkage disequilibrium (D′ = 0.99) and the homozygous variants were associated with an increased risk of NHL in NPY SNPs −485T>C (OR, 1.7; 95% CI, 1.1-2.5), 1258G>A (OR, 1.7; 95% CI, 1.1-2.5), and 5671C>T (OR, 1.9; 95% CI, 1.3-2.8). When stratified by subtype, the variant allele for NPY 1128T>C was positively associated with follicular lymphoma (OR, 2.3; 95% CI, 1.1-4.9) as were homozygous variants for NPY SNPs −485T>C (OR, 2.4; 95% CI, 1.3-4.4), 1258G>A (OR, 2.0; 95% CI, 1.1-3.5), and 5671C>T (OR, 1.8; 95% CI, 1.1-3.0). These results add further support for the hypothesis that SNPs in energy-regulating genes affect risk of NHL.
Prenatal and Postnatal Milk Supplementation and Adult Insulin-like Growth Factor I: Long-term Follow-up of a Randomized Controlled Trial
Authors: Ben-Shlomo Yoav , Holly Jeff , McCarthy Anne , Savage Paul , Davies David , Davey Smith George
Published: September 2005

Objective: Insulin-like growth factors (IGF) are increasingly recognized as important determinants of adult health, in particular risk of certain cancers. However, little is known about the determinants of adult IGFs and to what degree they may be programmed by early life influences.

Design: Randomized controlled trial of prenatal and postnatal milk supplementation among 951 subjects born in 1972 to 1974 in South Wales.

Main outcome measure: Measures of IGF-I, IGF binding protein 3, and the molar ratio.

Results: Data on adult IGFs were available from 663 subjects at a mean age of 25 years. Subjects in the intervention arm had lower IGF-I (−8.5 ng/mL; 95% confidence interval, −15.1 to −1.8, P = 0.01) and ratio (−1.20; 95% confidence interval, −2.33 to −0.04, P = 0.04). These differences could not be explained by follow-up bias or confounding factors.

Conclusions: These results provide experimental data on the role of early life programming either in the intrauterine or postnatal period that may have long-term influences on the IGF axis, with potential implications for disease risk.
Behavioral Consequences of Testing for Obesity Risk
Authors: Frosch Dominick L. , Mello Paul , Lerman Caryn
Published: September 2005

Objective: There is considerable hope that genetic susceptibility testing will motivate behavior that can prevent or reduce the risk of complex conditions such as obesity. This study examined potential behavioral consequences of such testing.

Methods: Participants (n = 249) were randomly assigned to review one of four vignettes that asked them to imagine that they had been tested for their risk of becoming overweight or obese. The experimental factors were test type (genetic versus hormone test) and risk level (increased versus average risk for obesity). Study measures included behavioral intentions and perceived behavioral control related to eating a healthy diet, as well as weight locus of control.

Results: Participants assigned to the increased risk conditions indicated greater intentions to eat a healthy diet compared with participants assigned to the average risk conditions (P < 0.02). There were significant interaction effects of risk × perceived behavioral control (P < 0.02) and risk × weight locus of control (P < 0.003) on dietary intentions. Individuals with low perceived behavioral control or an external weight locus of control who were told to imagine they were at average risk expressed significantly lower intentions to eat a healthy diet. A three-way interaction of body mass index, family history of overweight/obesity, and assigned risk level found the greatest effects of risk feedback among those who either had a family history or a higher body mass index (P < 0.007).

Conclusion: This study provides preliminary evidence that testing for susceptibility to obesity may motivate healthier behavior. However, some individuals may be susceptible to a false reassurance effect after receiving test results indicating a lack of increased risk.
Leptin, Insulin-Like Growth Factor-1, and Insulin-Like Growth Factor-2 Are Mitogens in ApcMin/+ but not Apc+/+ Colonic Epithelial Cell Lines
Authors: Fenton Jenifer I. , Hord Norman G. , Lavigne Jackie A. , Perkins Susan N. , Hursting Stephen D.
Published: September 2005

The obese state is associated with elevated circulating levels of insulin, insulin-like growth factors (IGF), and leptin. Research is contradictory regarding the role of these elevated growth factors in colon cancer risk. We hypothesized that colonic epithelial cells that were Apc deficient (ApcMin/+) but not those expressing wild-type Apc (Apc+/+) would experience a hyperproliferative and antiapoptotic phenotype when exposed to these growth factors. This hypothesis was addressed using two nontumorigenic murine colonic epithelial cell lines with distinct Apc genotypes: Apc+/+ YAMC cells and ApcMin/+ IMCE cells. Cells were treated for 48 hours with various concentrations of leptin (0.001-50 ng/mL), IGF-1 (0.1-200 ng/mL), or IGF-2 (0.1-600 ng/mL). In YAMC cells, leptin caused a significant decrease in cell proliferation (P < 0.01) compared with controls due to induction of caspase activity and apoptosis. In contrast, in the IMCE cells, leptin induced a 75% increase in cell proliferation compared with controls (P < 0.0001). IGF-1 and IGF-2 also induced 50% greater proliferation in the IMCE cells (P < 0.001) compared with controls. Cotreatment of IMCE cells with leptin and either IGF-1 or IGF-2 induced greater proliferation than either growth factor alone (P < 0.0001). IMCE cell proliferation caused by leptin only treatment was associated with activation of p42/44 mitogen-activated protein kinase (MAPK), p38 MAPK, and nuclear factor-κB nuclear translocation but not with MAPK kinase or Janus-activated kinase/signal transducers and activators of transcription activation. These data provide the first evidence that leptin may interact with IGFs to promote survival and expansion of colonic epithelial cells that were Apc deficient (ApcMin/+) but not those expressing wild-type Apc (Apc+/+).
Smoking Is a Risk Factor for Cervical Intraepithelial Neoplasia Grade 3 among Oncogenic Human Papillomavirus DNA–Positive Women with Equivocal or Mildly Abnormal Cytology
Authors: McIntyre-Seltman Kathleen , Castle Philip E. , Guido Richard , Schiffman Mark , Wheeler Cosette M. ,   for The ALTS Group
Published: September 2005

Background: Smoking is a potential risk factor for cervical cancer and its immediate precursor, cervical intraepithelial neoplasia grade 3 (CIN3), but few studies have adequately taken into account the possible confounding effect of oncogenic human papillomavirus (HPV) infection.

Methods: Women (n = 5,060) with minimally abnormal Papanicolaou smears were enrolled in the ASCUS and LSIL Triage Study, a clinical trial to evaluate management strategies, and were seen every 6 months for the 2-year duration of the study. Cervical specimens were tested for HPV DNA using both Hybrid Capture 2 and PGMY09/11 L1 consensus primer PCR with reverse line blot hybridization for genotyping. Multivariate logistics regression models were used to assess associations [odds ratio (OR) with 95% confidence intervals (95% CI)] between smoking behaviors and rigorously reviewed cases of cervical intraepithelial neoplasia grade 3 or cancer (≥CIN3) identified throughout the study (n = 506) in women with oncogenic HPV (n = 3,133).

Results: Current smoking was only weakly associated with increased HPV infection. Among infected women, current smokers (OR, 1.7; 95% CI, 1.4-2.1) and past smokers (OR, 1.7; 95% CI, 1.2-2.4) were more likely to be diagnosed with ≥CIN3 than nonsmokers. Greater smoking intensity (PTrend < 0.0005) and duration (PTrend < 0.0005) increased the strength of the association, with smoking ≥2 packs/d (OR, 3.3; 95% CI, 1.5-7.5) and smoking for ≥11 years (OR, 2.1; 95% CI, 1.5-2.9) most strongly associated with ≥CIN3 as compared to non-smokers. The effects of intensity and duration seemed additive.

Conclusions: Women with oncogenic HPV and minimally abnormal Papanicolaou smears who smoke were up to three times more likely to be diagnosed with ≥CIN3 than nonsmokers. Smoking cessation trials targeting this population might be warranted.
The Effect of Over-the-Counter Sales of the Nicotine Patch and Nicotine Gum on Smoking Cessation in California
Authors: Reed Mark B. , Anderson Christy M. , Vaughn Jerry W. , Burns David M.
Published: September 2005

The Food and Drug Administration approved over-the-counter (OTC) sale of nicotine gum and nicotine patches in 1996. We used data from the 1996 California Tobacco Survey to compare the rates of nicotine replacement therapy (NRT) use and smoking abstinence in California for each month during a period immediately preceding and immediately following the OTC availability of nicotine gum and patches. For smokers eligible to report a quit attempt, the proportion making a quit attempt using NRT and the proportion remaining abstinent was calculated for each of the 12 months prior to the survey interview. Multiple regression modeling of quit attempts and abstinence included a term for the number of months between the quit attempt and survey interview and dummy variables for the months before and after the OTC availability of NRT. Results showed a significant increase in the fraction of smokers using the patch (P < 0.01) and gum (P < 0.05) immediately following their availability OTC. There was also a significantly higher proportion of smokers reporting abstinence with gum use (P < 0.01) and a significant increase in reported abstinence with patch use (P < 0.01) during the period of time immediately following the availability of these products without a prescription. The results of this study suggest that removing the prescription status of NRT products resulted in an immediate increase in quit attempts and smoking abstinence with the use of nicotine gum or patches.
Urinary Hydroxyestrogens and Breast Cancer Risk among Postmenopausal Women: A Prospective Study
Authors: Wellejus Anja , Olsen Anja , Tjonneland Anne , Thomsen Birthe L. , Overvad Kim , Loft Steffen
Published: September 2005

Background: It has been suggested that a low level of the 2-hydroxyestrogen metabolites (2-OHE) and a high level of 16α-hydroxyestrone (16α-OHE1) are associated with an enhanced risk of breast cancer. We examined the association between the metabolite levels and breast cancer in a nested case-control study, which also addressed hormone replacement therapy (HRT) and estrogen receptor status of the tumors.

Methods: 24,697 postmenopausal Danish women were enrolled in the “Diet, Cancer and Health” cohort. During follow-up, 426 breast cancer cases were identified and controls were matched by age at diagnosis, baseline age, and HRT use. The concentrations of 2-OHE and 16α-OHE1 in spot urine were measured by an enzyme immunoassay. Incidence rate ratios (IRR) and 95% confidence intervals (95% CI) were estimated for total and estrogen receptor–specific breast cancer and were stratified according to HRT use.

Results: A higher incidence of estrogen receptor–positive breast cancer with an enhanced 2-OHE level was observed among current HRT users, IRR per doubling = 1.30 (95% CI, 1.02-1.66), whereas no association was seen among nonusers of HRT, IRR per doubling = 1.00 (95% CI, 0.69-1.45). The association between estrogen receptor–positive breast cancer and the 16α-OHE1 metabolite level was in the opposite direction but slightly weaker and statistically insignificant. For estrogen receptor–negative breast cancer, no significant associations were seen.

Conclusions: The risk of breast cancer, in particular the estrogen receptor–positive type, was enhanced among postmenopausal women using estradiol-based HRT and among those who had a high 2-OHE concentration.
Common Leptin Receptor Polymorphisms do not Modify the Effect of Alcohol Ingestion on Serum Leptin Levels in a Controlled Feeding and Alcohol Ingestion Study
Authors: Roth Mark J. , Paltoo Dina N. , Albert Paul S. , Baer David J. , Judd Joseph T. , Tangrea Joseph , Taylor Philip R.
Published: September 2005

We explored whether serum leptin response to alcohol ingestion was related to common leptin receptor gene polymorphisms, K109R (Lys109Arg), Q223R (Gln223Arg), S343S [Ser(T)343Ser(C)], and K656N (Lys656Asn), of reported physiologic significance during a controlled intervention. Fifty-three participants rotated through three 8-week treatment periods and consumed 0, 15 (equivalent to one drink), or 30 g (equivalent to two drinks) of alcohol (95% ethanol in 12 ounces of orange juice) per day, in random order. During the controlled feeding periods, all food and beverages including alcoholic beverages were prepared and supplied by the staff of the Beltsville Human Nutrition Research Center's Human Study Facility (Beltsville, MD), and energy intake was adjusted to maintain a constant weight. Blood was collected after an overnight fast on 3 separate days during the last week of each controlled feeding period and pooled for hormone analysis. Circulating serum leptin concentration was measured in duplicate by RIA and genotype analysis was done on DNA extracted from WBC using real-time PCR analysis amplification (TaqMan). Linear mixed models with a single random intercept reflecting a participant effect were used to estimate changes in serum leptin levels at 15 and 30 g of alcohol per day relative to 0 g of alcohol per day. No significant effects were found between common leptin receptor polymorphisms and serum leptin levels (P ≥ 0.26).