bluuebunny/crossref_metadata_2025 huggingface dataset:
Mammographic Density in Relation to Daidzein-Metabolizing Phenotypes in Overweight, Postmenopausal Women
Authors: Frankenfeld Cara L. , McTiernan Anne , Aiello Erin J. , Thomas Wendy K. , LaCroix Kristin , Schramm Judy , Schwartz Stephen M. , Holt Victoria L. , Lampe Johanna W.
Published: June 2022

Circulating hormones are associated with mammographic density, an intermediate marker of breast cancer risk. Differences in circulating hormones, including estrone and testosterone, have been observed in premenopausal women based on their capacity to metabolize daidzein, an isoflavone found predominantly in soybeans. Equol and O-desmethylangolensin (O-DMA) are products of intestinal bacterial metabolism of daidzein. There is interindividual variability in the capacity to produce daidzein metabolites; individuals can be equol producers or non-producers and O-DMA producers or non-producers. We tested the hypothesis that daidzein-metabolizing phenotypes are associated with mammographic density. Participants were recruited from among 92 sedentary, postmenopausal women, ages 50 to 75 years, who participated in a 1-year physical activity intervention. Pre-intervention mammographic density was determined using a computer-assisted, gray-scale thresholding technique. Fifty-five of these women consumed supplemental soy protein (>10 mg daidzein/d) for 3 days and collected a first-void urine sample on the fourth day to determine daidzein-metabolizing phenotypes. Equol and O-DMA concentrations were measured using gas chromatography-mass spectrometry. Associations between daidzein-metabolizing phenotypes and percent mammographic density were adjusted for age, maximum adult weight, gravidity, family history of breast cancer, and serum follicle-stimulating hormone and free testosterone concentrations. Mammographic density was 39% lower in equol producers compared with non-producers (P = 0.04). O-DMA producers had mammographic density 69% greater than non-producers (P = 0.05). These results suggest that particular intestinal bacterial profiles are associated with postmenopausal mammographic density, and these associations are not entirely explained by differences in reproductive or anthropometric characteristics or circulating hormones.
Preliminary Evaluation of DNA Damage Related with the Smoking Habit Measured by the Comet Assay in Whole Blood Cells
Authors: Ellahueñe Manuel F. , Pérez-Alzola Luz Patricia , Farfán-Urzua Mauricio , González-Hormazabal Patricio , Garay Marta , Olmedo Maria Isabel , Last Jerold A.
Published: June 2022

The alkaline single-cell gel electrophoresis (SCGE) assay, also called the comet assay, is a rapid and simple method for the detection of DNA damage in individual cells. The objective of this study was to establish if the alkaline SCGE assay in whole blood cells gives similar results as the same method in isolated lymphocytes, because whole blood cells are simpler and more economical to use, specifically in human genotoxic biomonitoring. To validate the method, we first used mouse blood cells, because mouse is one of the most commonly used animals in genetic toxicology testing. Groups of seven CF1 male mice were given i.p. injections of relatively low doses of methyl methanesulfonate (25 mg/kg body weight), a direct acting genotoxic agent, or cyclophosphamide (50 mg/kg body weight), which requires metabolic activation. Three, 6, 8, 12, 16, 20, and 65 hours after treatment, 5 μL of blood were collected from each animal and were processed for the alkaline SCGE assay. On the basis of an analysis of tail moment, the results showed that this assay can detect DNA damage induced by both kinds of alkylating mutagens. We then did a preliminary study to assess the status of DNA damage in a young (19 to 23 years old) healthy population of male smokers (n = 6) and nonsmokers (n = 6) using the comet assay in whole blood cells. A significant difference was observed between the two groups, showing that the method is able to detect DNA damage in the smoking group despite the short time that the volunteers had actually been smoking.
Parental Exposure to Medications and Hydrocarbons and ras Mutations in Children with Acute Lymphoblastic Leukemia: A Report from the Children's Oncology Group
Authors: Shu Xiao Ou , Perentesis John P. , Wen Wanqing , Buckley Jonathan D. , Boyle Evelyn , Ross Julie A. , Robison Leslie L.
Published: June 2022

Ras proto-oncogene mutations have been implicated in the pathogenesis of many malignancies, including leukemia. While both human and animal studies have linked several chemical carcinogens to specific ras mutations, little data exist regarding the association of ras mutations with parental exposures and risk of childhood leukemia. Using data from a large case-control study of childhood acute lymphoblastic leukemia (ALL; age <15 years) conducted by the Children's Cancer Group, we used a case-case comparison approach to examine whether reported parental exposure to hydrocarbons at work or use of specific medications are related to ras gene mutations in the leukemia cells of children with ALL. DNA was extracted from archived bone marrow slides or cryopreserved marrow samples for 837 ALL cases. We examined mutations in K-ras and N-ras genes at codons 12, 13, and 61 by PCR and allele-specific oligonucleotide hybridization and confirmed them by DNA sequencing. We interviewed mothers and, if available, fathers by telephone to collect exposure information. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived from logistic regression to examine the association of parental exposures with ras mutations. A total of 127 (15.2%) cases had ras mutations (K-ras 4.7% and N-ras 10.68%). Both maternal (OR 3.2, 95% CI 1.7-6.1) and paternal (OR 2.0, 95% CI 1.1-3.7) reported use of mind-altering drugs were associated with N-ras mutations. Paternal use of amphetamines or diet pills was associated with N-ras mutations (OR 4.1, 95% CI 1.1-15.0); no association was observed with maternal use. Maternal exposure to solvents (OR 3.1, 95% CI 1.0-9.7) and plastic materials (OR 6.9, 95% CI 1.2-39.7) during pregnancy and plastic materials after pregnancy (OR 8.3, 95% CI 1.4-48.8) were related to K-ras mutation. Maternal ever exposure to oil and coal products before case diagnosis (OR 2.3, 95% CI 1.1-4.8) and during the postnatal period (OR 2.2, 95% CI 1.0-5.5) and paternal exposure to plastic materials before index pregnancy (OR 2.4, 95% CI 1.1-5.1) and other hydrocarbons during the postnatal period (OR 1.8, 95% CI 1.0-1.3) were associated with N-ras mutations. This study suggests that parental exposure to specific chemicals may be associated with distinct ras mutations in children who develop ALL.
Familial Risk for Colorectal Cancers Are Mainly Due to Heritable Causes
Authors: Hemminki Kari , Chen Bowang
Published: June 2022

A family history is an identified risk factor for colorectal cancer (CRC). However, it is not known to what extent the risk is due to environmental or heritable genetic factors. We wanted to examine this question for familial CRC adenocarcinoma based on the nationwide Swedish Family-Cancer Database on 10.3 million individuals whose invasive cancers were followed up to year 2000. Standardized incidence ratios (SIRs) for offspring, siblings, and spouses were calculated based on 5-year age, sex, period (10-year bands), area (county), and socioeconomic status standardized rates. A significant risk was observed in the parent-offspring comparison among different subsites (left-sided and right-sided colon, rectum, and all CRC), the SIRs ranging from 1.74 to 1.84. When husbands were probands, the SIR in wives was 0.92 for colon cancer (left-sided 0.67 and right-sided 1.07), 0.98 for rectal cancer, and 0.96 for CRC. The risks for husbands when wives were probands were quite similar. None of the SIRs between spouses were significant, indicating lack of concordance between spouses that resided together for a minimum of 30 years. The risks between siblings were also increased particularly for cancer in the right-sided colon (SIR 6.89). The effect of shared childhood environmental effects were probed by analyzing the risks by age difference between the siblings. However, the risks were independent of the age difference. Data among spouses and siblings consistently point to the importance of heritable factors in familial CRC.
Serum Carotenoids and α-Tocopherol and Risk of Nonmelanoma Skin Cancer
Authors: Dorgan Joanne F. , Boakye Naana A. , Fears Thomas R. , Schleicher Rosemary L. , Helsel William , Anderson Christa , Robinson June , Guin Jere D. , Lessin Stuart , Ratnasinghe Luke D. , Tangrea Joseph A.
Published: June 2022

Background: Carotenoids and tocopherols have been hypothesized to protect against cancer. Methods: We prospectively evaluated associations of several carotenoids and α-tocopherol with risk of nonmelanoma skin cancer using serum collected at baseline from 302 subjects in the Isotretinoin-Basal Cell Carcinoma Prevention Trial. All subjects had at least two BCCs in the 5 years prior to randomization. During 5 years of follow-up, 70 subjects did not develop a nonmelanoma skin cancer, 221 developed a BCC, and 85 developed a squamous cell carcinoma (SCC). Cox proportional hazards models were used to estimate risk ratios. Models were stratified by clinical center and gender and adjusted for age, solar damage, skin type, number of prior BCCs and/or SCCs, treatment group, body mass index, and serum low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol. Results: Risk of developing a subsequent BCC was not related to serum levels of any of the carotenoids measured or to α-tocopherol. Serum levels of α-carotene, β-carotene, lycopene, and α-tocopherol also were not independently related to risk of a subsequent SCC. However, serum lutein, zeaxanthin, and β-cryptoxanthin were positively related to SCC risk; risk ratios for subjects in the highest versus lowest tertiles of these micronutrients were 1.63 [95% confidence interval (95% CI) 0.88-3.01; P for trend = 0.01], 2.40 (95% CI 1.30-4.42; P for trend = 0.01), and 2.15 (95% CI 1.21-3.83; P for trend = 0.09), respectively. Conclusion: Additional research is needed on the relationship of carotenoids to SCC risk in the general population and in subsets of the population who are at increased risk.
Oral Contraceptive Use and Breast Cancer Risk: Modification by NAD(P)H:Quinone Oxoreductase (NQO1) Genetic Polymorphisms
Authors: Fowke Jay H. , Shu Xiao-Ou , Dai Qi , Jin Fan , Cai Qiuyin , Gao Yu-Tang , Zheng Wei
Published: June 2022

Despite intensive study, the relationship between oral contraception (OC) and breast cancer remains unclear. OCs contain a potent synthetic estrogen (ethinyl estradiol) but lower endogenous estradiol levels, and ethinyl estradiol is a weak progenitor of semiquinones, catechol estrogens capable of damaging DNA. NAD(P)H:quinone oxoreductase (NQO1) stabilizes semiquinones, thus potentially preventing genetic damage from catechol estrogens, and the NQO1 C609T polymorphism seems functionally relevant. Using data from the Shanghai Breast Cancer Study, a population-based case-control study, we investigated the relationships between OC use (20% ever using), breast cancer, and NQO1 (C/C 31% and C/T + T/T 69%) among 1,039 cases and 1,121 controls. Breast cancer was not significantly associated with NQO1 genotype. There was a significant protective association between OC after age 30 years and premenopausal breast cancer [odds ratio (OR) 0.51, 95% confidence interval (95% CI) 0.29-0.89] primarily with the NQO1 T allele (C/C OR 0.76, 95% CI 0.31-1.82; C/T + T/T OR 0.38, 95% CI 0.18-0.80; P for interaction = 0.19). The association between premenopausal breast cancer and OCs significantly differed with NQO1 genotype when using OCs for >18 months (C/C OR 2.34, 95% CI 0.92-5.99; C/T + T/T OR 0.69, 95% CI 0.38-1.25; P for interaction = 0.02). Among women with the C/C genotype, postmenopausal breast cancer was significantly associated with ever-using OCs (C/C OR 2.01, 95% CI 1.08-3.74; C/T + T/T OR 0.72, 95% CI 0.49-1.05; P for interaction < 0.01). This crossover was stronger with OC use prior to age 30 years (C/C OR 3.00, 95% CI 1.43-6.25; C/T or T/T OR 0.49, 95% CI 0.29-0.81; P for interaction < 0.01). Our results require confirmation but suggest that the OC and breast cancer association depends on the ability to invoke protection from catechol estrogens.
Risk of Early-Onset Prostate Cancer in Relation to Germ Line Polymorphisms of the Vitamin D Receptor
Authors: Oakley-Girvan Ingrid , Feldman David , Eccleshall T. Ross , Gallagher Richard P. , Wu Anna H. , Kolonel Laurence N. , Halpern Jerry , Balise Raymond R. , West Dee W. , Paffenbarger Ralph S. , Whittemore Alice S.
Published: June 2022

Vitamin D inhibits prostate cancer cell growth, angiogenesis, and metastasis. These actions are mediated by the vitamin D receptor. We examined associations between prostate cancer risk and five polymorphisms in the VDR gene: four single nucleotide polymorphisms (FokI, BsmI, ApaI, and TaqI restriction sites) and the polyadenylic acid microsatellite. Specifically, we genotyped population-based samples of young African Americans (113 cases and 121 controls) and Whites (232 cases and 171 controls) and members of 98 predominantly White families with multiple cases of prostate cancer. Among Whites, there was no evidence for association between prostate cancer risk and alleles at any of the five polymorphic sites regardless of how the men were ascertained. Moreover, estimated five-locus haplotype frequencies were similar in White cases and controls. Among African Americans, prostate cancer risk was associated with homozygosity for the F allele at the FokI site (odds ratio 1.9, 95% confidence interval 1.0-3.3). In addition, estimated haplotype frequencies differed significantly (P < 0.01) between African American cases and controls. These findings need replication in other studies of African Americans. Homozygosity for the F allele at the FokI site is more prevalent in the African American population than in U.S. Whites. If the FokI association noted here were causal, this difference could account for some of the disease burden among African Americans and some of the excess risk in African Americans compared with Whites.
Racial Differences in Enrolment in a Cancer Genetics Registry
Authors: Moorman Patricia G. , Skinner Celette Sugg , Evans James P. , Newman Beth , Sorenson James R. , Calingaert Brian , Susswein Lisa , Crankshaw T. Sydnee , Hoyo Cathrine , Schildkraut Joellen M.
Published: June 2022

Background: Lower enrolment of minorities into research studies has been reported frequently. Most studies have little information about nonparticipants, making it difficult to identify characteristics associated with enrolment and how they might vary by race. Methods: Women who had previously participated in a population-based, case-control study of breast cancer in North Carolina were invited to enrol in a cancer genetics registry. Detailed questionnaire data on sociodemographic characteristics and cancer risk factors were available for all women. We compared characteristics of women who agreed to be in the registry with those who were deceased, were unlocatable, or declined enrolment. Unconditional logistic regression analyses were done to identify predictors of enrolment. Results: Enrolment rates were markedly lower among African Americans than Whites (15% and 36%, respectively) due to both lower contact rates (41% versus 63%) and lower enrolment rates among those contacted (37% versus 58%). Logistic regression models suggested that racial differences in enrolment were not due to socioeconomic characteristics or other cancer risk factors; race was the only significant predictor of enrolment in multivariable models (odds ratio 0.41, 95% confidence interval 0.23-0.72). Conclusions: Although all women had previously taken part in a research study, African American women were less likely to enrol in the cancer genetics registry than White women. A possible explanation of these findings is that studies of genetics may present particular concerns for African Americans. Further research is needed to identify attitudes and issues that present barriers to participation among minorities.
Germ Line BAX Alterations Are Infrequent in Li-Fraumeni Syndrome
Authors: Barlow Jason W. , Mous Marieke , Wiley Joe C. , Varley Jennifer M. , Lozano Guillermina , Strong Louise C. , Malkin David
Published: June 2022

Multiple early-onset tumors, frequently associated with germ line TP53 mutations characterize the Li-Fraumeni familial cancer syndrome (LFS). LFS-like (LFS-L) families have lower rates of germ line TP53 alteration and do not meet the strict definition of LFS. This study examined 7 LFS cell lines and 30 LFS and 36 LFS-L primary leukocyte samples for mutations in the proapoptotic p53-regulated gene BAX. No germ line BAX mutations were found. A known BAX polymorphism was observed, yet there was no correlation between polymorphism frequency and TP53 status in either LFS or LFS-L. In summary, alterations of BAX are not responsible for cancers in TP53 wild-type LFS or LFS-L families.
Associations between Two Common Variants C677T and A1298C in the Methylenetetrahydrofolate Reductase Gene and Measures of Folate Metabolism and DNA Stability (Strand Breaks, Misincorporated Uracil, and DNA Methylation Status) in Human Lymphocytes In vivo
Authors: Narayanan Sabrina , McConnell Josie , Little Julian , Sharp Linda , Piyathilake Chandrika J. , Powers Hilary , Basten Graham , Duthie Susan J.
Published: June 2022

Objective: Homozygosity for variants of the methylenetetrahydrofolate reductase (MTHFR) gene is associated with decreased risk for colorectal cancer. We have investigated the relationships between two variants of the MTHFR gene (C677T and A1298C) and blood folate, homocysteine, and genomic stability (strand breakage, misincorporated uracil, and global cytosine methylation in lymphocytes) in a study of 199 subjects. Results: The frequencies of homozygosity for the C677T and A1298C variants of the MTHFR gene were 12.6% and 14.6%, respectively. Plasma homocysteine, folate, vitamin B12, 5-methyltetrahydrofolate, and RBC folate were determined in the C677T genotypes. Plasma folate was significantly lower (P < 0.001) in the homozygous variants (6.7 ± 0.6 ng/mL) compared with wild-types (8.8 ± 0.4 ng/mL) and heterozygotes (9.1 ± 0.5 ng/mL). Homocysteine was significantly higher (P < 0.05) in homozygous variants (13.2 ± 1.1 μmol/L) compared with homozygous subjects (10.9 ± 0.4 μmol/L). Homozygous variants had significantly lower (P < 0.05) RBC folate (84.7 ± 6.3 ng/mL) compared with wild-types (112.2 ± 5.2 ng/mL) and heterozygous individuals (125.1 ± 6.6 ng/mL). No significant difference in RBC folate was observed between wild-types and heterozygotes. The A1298C variant did not influence plasma homocysteine, folate, 5-methyltetrahydrofolate, vitamin B12, or RBC folate. Lymphocyte DNA stability biomarkers (strand breaks, misincorporated uracil, and global DNA methylation) were similar for all MTHFR C677T or A1298C variants. Conclusion: Data from this study do not support the hypothesis that polymorphisms in the MTHFR gene increase DNA stability by sequestering 5,10-methylenetetrahydrofolate for thymidine synthesis and reducing uracil misincorporation into DNA.
A Case-Control Study of Diet and the Risk of Ovarian Cancer
Authors: Pan Sai Yi , Ugnat Anne-Marie , Mao Yang , Wen Shi Wu , Johnson Kenneth C. ,   The Canadian Cancer Registries Epidemiology Research Group
Published: June 2022

Epidemiologic studies have suggested that some dietary factors may play a role in the etiology of ovarian cancer, but the findings have been inconsistent. We assessed the association of ovarian cancer with dietary factors in a population-based case-control study in Canada. Diet information was collected on 442 incident cases of ovarian cancer diagnosed in 1994 to 1997 and 2,135 population controls via a self-administered questionnaire. Compared with women in the lowest quartile of cholesterol intake, those in the second, third, and fourth quartiles had a multivariate adjusted odds ratio [OR; 95% confidence interval (95% CI)] of 1.12 (0.81–1.56), 1.20 (0.85–1.68), and 1.42 (1.03–1.97), respectively (P for trend = 0.031). Higher egg consumption was also associated with a nonsignificant increase in ovarian cancer risk. The ORs (95% CIs) for ovarian cancer were 0.77 (0.60–1.04) and 0.76 (0.56–0.99) among women in the highest quartile of total vegetable and cruciferous vegetable intake as compared with women in the lowest quartile. Women who took supplements of vitamin E, β-carotene, and B-complex vitamins for ≥10 years had ORs (95% CIs) of 0.49 (0.30–0.81), 0.31 (0.11–0.91), and 0.61 (0.36–1.05), respectively. However, we did not observe an association of ovarian cancer risk with dietary fat intake, including saturated, monounsaturated, and polyunsaturated fatty acids, protein, carbohydrate, dietary fiber, fruit, dairy products, meat products, fish, chicken, grain products, nut products, baked desserts, margarine, butter, mayonnaise, and supplement of multiple vitamins, vitamin A, vitamin C, calcium, iron, zinc, and selenium. Our findings suggested that ovarian cancer risk was positively associated with higher consumption of dietary cholesterol and eggs and inversely associated with higher intake of total vegetables and cruciferous vegetables and supplementation of vitamin E, β-carotene, and B-complex vitamins.
Maternal Smoking and Childhood Leukemia and Lymphoma Risk among 1,440,542 Swedish Children
Authors: Mucci Lorelei A. , Granath Frederik , Cnattingius Sven
Published: June 2022

Possible in utero effects of maternal smoking on hemopoietic cancer in the offspring have been addressed previously, although the results are inconclusive. In this investigation, we take advantage of population-based registers in Sweden to examine maternal smoking during pregnancy and childhood risk of leukemia and lymphoma. Prospective data were available from 1,440,542 Swedish children born between 1983 and 1997. Proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) controlling for potential confounders. In the study base, 750 hemopoietic cancers occurred across 11 million person-years. Incidence rates per 100,000 person-years were 4.7 for acute lymphocytic leukemia (ALL), 0.45 for acute myelogenous leukemia, and 0.76 for non-Hodgkin's lymphoma. Maternal smoking was associated with a lower risk of ALL (HR, 0.73; 95% CI, 0.58–0.91). On the other hand, there was a higher risk of acute myelogenous leukemia (HR, 1.41; 95% CI, 0.74–2.67) particularly among heavy (≥10 cigarettes per day) smokers (HR, 2.28; 95% CI, 1.05–4.94). The data also suggested a small excess risk of non-Hodgkin's lymphoma (HR, 1.25; 95% CI, 0.76–2.04). Evidence from this large cohort suggests that maternal smoking affects the risk of childhood leukemia and lymphoma in the offspring. The Swedish registries provide unique opportunities to examine this research question, with a design inherently free of selection and recall biases. The apparent protective effect with ALL needs to be explored further and in no way supports maternal smoking as beneficial, given its adverse association with common pregnancy outcomes.
Association of Nut and Seed Intake with Colorectal Cancer Risk in the European Prospective Investigation into Cancer and Nutrition
Authors: Jenab Mazda , Ferrari Pietro , Slimani Nadia , Norat Teresa , Casagrande Corinne , Overad Kim , Olsen Anja , Stripp Connie , Tjønneland Anne , Boutron-Ruault Marie-Christine , Clavel-Chapelon Françoise , Kesse Emmanuelle , Nieters Alexandra , Bergmann Manuela , Boeing Heiner , Naska Androniki , Trichopoulou Antonia , Palli Domenico , Krogh Vittorio , Celentano Egidio , Tumino Rosario , Sacerdote Carlotta , Bueno-de-Mesquita Hendrik B. , Ocké Marga C. , Peeters Petra H.M. , Engeset Dagrun , Quirós José R. , González Carlos A. , Martínez Carmen , Chirlaque Maria D. , Ardanaz Eva , Dorronsoro Miren , Wallström Peter , Palmqvist Richard , Van Guelpen Bethany , Bingham Sheila , San Joaquin Miguel A. , Saracci Rodolfo , Kaaks Rudolf , Riboli Elio
Published: June 2022

A link between unsaturated fatty acids or phytonutrients and reduced risk of colorectal cancer has been suggested. However, the effects of higher intake of dietary sources of these nutrients, such as the nuts and seeds food group, are less clear. The objective of this study was to determine the effects of nut and seed intake on colorectal cancer risk within the European Prospective Investigation into Cancer and Nutrition study, a large prospective cohort study involving 10 European countries. Total nut and seed intake was determined from country-specific dietary questionnaires. The data set included 478,040 subjects (141,988 men, 336,052 women) with a total of 855 (327 men, 528 women) colon and 474 (215 men, 259 women) rectal cancer cases. A multivariate Cox proportional hazards model, stratified by center and controlled for fruit intake, dietary fiber, energy, height, weight, sex, age, physical activity, and smoking, was used. The data show no association between higher intake of nuts and seeds and risk of colorectal, colon, and rectal cancers in men and women combined, but a significant inverse association was observed in subgroup analyses for colon cancer in women at the highest (>6.2 g/d) versus the lowest (nonconsumers; hazard ratio, 0.69; 95% confidence interval, 0.50-0.95) category of intake and for the linear effect of log-transformed intake (hazard ratio, 0.89; 95% confidence interval, 0.80-0.98), with no associations in men. It is not evident from this data why there may be a stronger association in women or why it may be limited to the colon, suggesting that much further research is necessary.
Chlamydia pneumoniae Infection and Risk of Lung Cancer
Authors: Littman Alyson J. , White Emily , Jackson Lisa A. , Thornquist Mark D. , Gaydos Charlotte A. , Goodman Gary E. , Vaughan Thomas L.
Published: June 2022

Infection with Chlamydia pneumoniae may be associated with an increased risk of lung cancer. We conducted a matched case-control study (508 pairs) nested within a large prospective study to investigate whether IgA antibody titers to C. pneumoniae measured by the microimmunofluorescence test are associated with lung cancer risk after controlling for confounders. Individuals with antibody titers ≥16 had 1.2 times the risk of lung cancer (95% confidence interval, 0.9-1.6) compared to those with lower titers. There was a significant trend (P = 0.007) of increasing odds ratios with increasing IgA titers primarily due to an odds ratio of 2.8 (95% confidence interval, 1.1-6.7) associated with titers ≥256. Lung cancer risk associated with IgA titers ≥16 was stronger among former smokers. To better understand predictors of IgA seropositivity, we also examined demographic, lifestyle, dietary, and medical correlates of IgA titers ≥16 among controls. Those with race not classified as White or Black were more likely to have IgA titers ≥16; there were no significant differences in seropositivity by smoking behaviors. In summary, the adjusted odds ratio for lung cancer associated with IgA titers ≥16 was compatible with a weakly positive association, although nondifferential measurement error of antibody titers may have resulted in a conservative bias. Future studies using precise measures of chronic C. pneumoniae status are needed to better determine the role of this organism in the etiology of lung cancer.
Risk Factors for Breast Cancer Associated with Mammographic Features in Singaporean Chinese Women
Authors: Heng Derrick , Gao Fei , Jong Roberta , Fishell Eve , Yaffe Martin , Martin Lisa , Li Tong , Stone Jennifer , Sun Limei , Hopper John , Boyd Norman F.
Published: June 2022

Background: Mammographic density has been found to be a strong risk factor for breast cancer and to be associated with age, body weight, parity, and menopausal status. Most studies to date have been carried out in Western populations. The purpose of the study described here was to determine in a cross-sectional study in a Singaporean Chinese population the demographic, menstrual, reproductive, and anthropometric factors that are associated with quantitative variations in age-adjusted percentage mammographic densities and to examine the association of these factors with the dense and nondense areas of the mammogram.

Method: We used mammograms and questionnaire data collected from subjects in the Singapore Breast Screening Project. Women ages 45 to 69 years participated and 84% of those screened were Chinese. Mammograms were digitized and percentage density was measured and analyzed in relation to the questionnaire data.

Results: Percentage mammographic density was associated with several risk factors for breast cancer, most of them also associated, in opposite directions, with the dense and nondense components of the image. Percentage density was associated with age and weight (both negatively), height and age at first birth (both positively), and number of births and postmenopausal status (both negatively). Percentage density was weakly associated with a previous breast biopsy but was not associated with age at menarche or menopause, with use of hormones, or with a family history of breast cancer.

Conclusion: Percentage mammographic density in Singaporean Chinese women has similar associations with risk factors for breast cancer to those seen in Caucasians.
How Strong Is the Association Between CAG and GGN Repeat Length Polymorphisms in the Androgen Receptor Gene and Prostate Cancer Risk?
Authors: Zeegers Maurice P. , Kiemeney Lambertus A.L.M. , Nieder Alan M. , Ostrer Harry
Published: June 2022

Objective: Although narrative reviews have suggested an association between (CAG)n and (GGN)n polymorphisms in the AR gene and prostate cancer, it has never been quantified systematically. The purpose of this meta-analysis was to provide relative and absolute quantitative summary estimates with sufficient power.

Method: Publications were identified through database searches for epidemiologic studies published until February 2004. For each study, mean differences in repeat length between cases and controls were calculated as well as continuous odds ratios (OR) per one CAG or GGN repeat decrement and discrete ORs to compare prostate cancer risk in men with short CAG repeats (≤21 repeats) versus long CAG repeats (>21 repeats) and short GGN repeats (≤16 repeats) versus long GGN repeats (>16 repeats). The study-specific estimates were combined by random effects metaregression analyses.

Results: Nineteen case-control studies were included in this review comprising a total of 4,274 cases and 5,275 controls. Prostate cancer cases had on average 0.26 fewer CAG repeats and 0.09 fewer GGN repeats than controls. The continuous ORs of prostate cancer per one repeat decrement were 1.02 and 1.01 for CAG and GGN repeats, respectively. The summary discrete OR (95% confidence interval) were 1.19 (1.07-1.31) and 1.31 (1.06-1.61) for CAG and GGN repeat polymorphisms, respectively.

Conclusion: Although the presence of shorter repeats seemed to be modestly associated with prostate cancer risk, the absolute difference in number of repeats between cases and controls is <1 repeat. We question whether such a small difference is enough to yield measurable biological impact in prostate carcinogenesis.
Utilization of Screening and Preventive Surgery Among Unaffected Carriers of aBRCA1orBRCA2Gene Mutation
Authors: Wainberg Sara , Husted Janice
Published: June 2022

Objective: Women who are carriers of BRCA gene mutations have an elevated lifetime risk of developing breast or ovarian cancer. Although a number of risk-reducing options are currently available to mutation carriers, uncertainty exists in terms of their efficacy. A systematic review of the literature was conducted to describe the utilization of screening and preventive surgery among unaffected mutation carriers in the face of uncertainty.

Methods: MEDLINE, PubMed, and CANCERLIT, English-only computerized literature searches were done to identify articles pertaining to decisions made by unaffected BRCA mutation carriers to reduce risk of breast and ovarian cancer. Studies were required to include information on choices taken by at-risk women following disclosure of a positive BRCA test.

Results: Only seven studies (5 American and 2 Dutch studies) were identified. The proportion of mutation carriers who chose preventive surgery over screening varied widely across the studies, ranging from 0% to 54% for prophylactic mastectomy and from 13% to 53% for prophylactic oophorectomy. Furthermore, a significant minority of women who chose surveillance failed to comply with the recommended schedule.

Conclusion: There is considerable variability within and between countries in risk reduction strategies utilized by healthy mutation carriers. This variability may relate to differences in (1) population characteristics; (2) recommendations for follow-up care of unaffected carriers; (3) prevailing values towards body integrity, femininity, and preventive surgery; and (4) health care funding systems. Future research needs to provide further insight into factors influencing women's decisions to adopt various risk reduction strategies.
UV Dose Determines Key Characteristics of Nonmelanoma Skin Cancer
Authors: Ramos Juan , Villa Jaime , Ruiz Abigail , Armstrong Roy , Matta Jaime
Published: June 2022

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), known as nonmelanoma skin cancer (NMSC), are the most common cancers worldwide. Although many factors are involved in the pathogenesis of NMSC, UV radiation is an important risk factor. A fundamental question in skin cancer research is whether varying doses of total UV radiation influence key characteristics of NMSC. The hypothesis that differences in UV doses influence the BCC/SCC ratio, number of tumors, and anatomic location of the tumor was investigated in 311 participants having 326 tumors and with exposure to a broad range of UV doses. An epidemiologic questionnaire was given to each participant soliciting detailed information on exposure to solar radiation. Environmental UVA and UVB doses were measured continually for 6 years at a permanent UV monitoring station. The total ratio of BCC/SCC was 3.5. Participants who received low and high UV doses had a BCC/SCC ratio of 4.2. Those who received very high UV doses had a ratio of 2.1. A very high UV dose was also associated with the doubling of the total number of tumors per person and a significantly increased risk of having SCC, a more aggressive malignancy. Tumors in sun-exposed areas (on the body) were more common in participants who received high and very high UV doses. The tumors in sun-protected areas were associated with exposure to lower levels of UV. This large-scale population study provides evidence that varying doses of UV radiation have a profound influence on key characteristics of NMSC.
Identifying and Characterizing Adolescent Smoking Trajectories
Authors: Audrain-McGovern Janet , Rodriguez Daniel , Tercyak Kenneth P. , Cuevas Jocelyn , Rodgers Kelli , Patterson Freda
Published: June 2022

Our understanding of longitudinal patterns of adolescent smoking development and the determinants of these patterns is limited. The present study evaluated adolescent smoking trajectories and characterized these trajectories with social, psychological, and behavioral factors in a cohort of adolescents assessed annually from grades 9 to 12. Complete data (smoking practices, novelty seeking, academic performance, substance use, peer smoking, physical activity and sports participation, and tobacco ad receptivity) were available on 968 participants; data were analyzed using latent class growth modeling. Four adolescent smoking trajectories emerged: never smokers, experimenters, earlier/faster smoking adopters, and later/slower smoking adopters. Early adopters were characterized by their high novelty seeking personality, depressive symptoms, poorer academic performance, and receptivity to tobacco advertising, as well as their exposure to other smokers, and use of other substances. Later adopters were characterized quite similarly to the early adopters, although they tended to perform better in school and to be more involved in sports. Experimenters also shared many of these same risk characteristics but to a lesser degree. Overall, never smokers were the most conventional in their profile. These data suggest that there is significant heterogeneity in the timing, rate, and intensity of smoking progression. Adolescent smoking prevention and intervention programs will need to consider this heterogeneity and tailor or enhance attention to risk and protective factors depending on the subpopulation.
ERCC2 Genotypes and a Corresponding Haplotype Are Linked with Breast Cancer Risk in a German Population
Authors: Justenhoven Christina , Hamann Ute , Pesch Beate , Harth Volker , Rabstein Sylvia , Baisch Christian , Vollmert Caren , Illig Thomas , Ko Yon-Dschun , Brüning Thomas , Brauch Hiltrud ,   for the Interdisciplinary Study Group on Gene Environment Interactions and Breast Cancer in Germany Network
Published: June 2022

The polygenic concept of breast cancer susceptibility calls for the identification of genetic variants that contribute to breast cancer risk. Reduced DNA repair proficiencies in women with breast cancer pointed to a possible role of DNA repair enzymes in the risk to develop the disease. The nucleotide excision repair enzyme encoded by the excision repair cross-complementing group 2 gene ERCC2 (formerly XPD) known to cause skin cancer by germ line mutations has multiple regulatory cellular functions, including nucleotide excision repair, basal transcription, cell cycle control, and apoptosis. ERCC2 polymorphisms ERCC2_6540_G>A (Asp312Asn) and ERCC2_18880_A>C (Lys751Gln) within the coding region of this evolutionarily highly conserved gene have been of functional relevance and therefore are potential candidates to confer breast cancer susceptibility. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, we analyzed genotype frequencies in constitutional DNA of study participants of a German case-control study that included 688 cases of incident breast cancer and 724 population-based, age-matched controls. We identified ERCC2_6540_GG (Asp312Asp) as an at-risk genotype [odds ratio (OR), 2.06; 95% confidence interval (95% CI), 1.39-3.07]. The ERCC2_6540_GG-associated breast cancer risk was even higher in women who were also carriers of the ERCC2_18880_CC (Gln751Gln) genotype (OR, 3.69; 95% CI, 1.76-7.74). We identified ERCC2_6540_G/ERCC2_18880_C (Asp312/Gln751) as the most potent risk-conferring haplotype (OR, 3.49; 95% CI, 2.30-5.28). To our knowledge, this is the first study assigning breast cancer risk to both the ERCC2 genotype encoding Asp312Asp and the haplotype encoding Asp312/Gln751.
Synergistic Effects of STK15 Gene Polymorphisms and Endogenous Estrogen Exposure in the Risk of Breast Cancer
Authors: Dai Qi , Cai Qiu-Yin , Shu Xiao-Ou , Ewart-Toland Amanda , Wen Wan-Qing , Balmain Allan , Gao Yu-Tang , Zheng Wei
Published: June 2022

STK15 is a member of a family of serine/threonine kinases that act as key regulators of chromosome segregation and cytokinesis. Over expression of the STK15 gene leads to centrosome amplification, chromosomal instability, aneuploidy, and transformation. It has been reported that the 91T → A (Phe → Ile at codon 31) polymorphism in the STK15 gene affects the function of this gene. We hypothesized that this polymorphism may interact with endogenous estrogen exposure in the risk of breast cancer and evaluated this hypothesis in a population-based, case-control study conducted among Chinese women in Shanghai. Genotyping assays were completed for 1,102 incident cases and 1,186 community controls. Participation and blood donation rates were over 90% and 80%, respectively. Elevated risks of breast cancer were found to be associated with the Phe/Ile [odds ratio (OR), 1.3; 95% confidence interval (CI), 1.0-1.7] and Ile/Ile (OR, 1.2; 95% CI, 0.9-1.6) genotypes at codon 31 of the STK15 gene, although the ORs were not statistically significant. The risk associated with this polymorphism was modified by factors related to endogenous estrogen exposure, such as high body mass index (BMI), high waist-to-hip ratio, long duration of lifetime menstruation, or long duration of menstruation before first live birth. In particular, a statistically significant interaction was found between BMI and the STK15 Phe31Ile polymorphism (P = 0.02) and a positive association with breast cancer risk for the Ile allele was found only among overweight (BMI ≥ 25 kg/m2) women with adjusted ORs (95% CIs) of 3.3 (1.4-7.7) and 4.1 (1.7-9.8) associated with the Phe/Ile and Ile/Ile genotypes (Pfor trend <0.01), respectively. The findings from this study are consistent with the evidence from invitro and in vivo experiments, implicating an etiologic role of the STK15 gene in human breast cancer, and provide evidence for the modifying effects of genetic background on human cancer risk.
The Economic Impact of False-Positive Cancer Screens
Authors: Lafata Jennifer Elston , Simpkins Janine , Lamerato Lois , Poisson Laila , Divine George , Johnson Christine Cole
Published: June 2022

Objective: Despite the promotion and widespread use of routine cancer screening, little is known about the economic consequences of false-positive screening results. We evaluated the medical and nonmedical costs associated with false-positive prostate, lung, colorectal, and ovarian cancer screens.

Method: We identified 1,087 Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial participants enrolled in a large managed care organization. Medical care use and costs were compiled from automated sources and trial data. Nonmedical care costs to patients with a false-positive lung cancer screen were obtained by telephone interview (n = 98).

Results: Forty-three percent of the study sample incurred at least one false-positive cancer screen. The majority of these patients (83%) received follow-up care. Prior to and after controlling for participant characteristics, significantly higher medical care expenditures in the year following screening were found among those with a false-positive screen. The adjusted mean difference was $1,024 for women and $1,171 for men. Among lung cancer screening patients, few nonmedical care costs were identified beyond the time (mean, 1.5 hours) spent receiving care.

Conclusion: The results here indicate that false-positive results among some available cancer screening tests are relatively common, that patients incurring a false-positive screen tend to receive follow-up testing, and that such follow-up is not without associated medical costs. Along with trials evaluating the health benefits of available cancer screening modalities, investigations into potential undesirable consequences of cancer screening are also warranted.
Short Tandem Repeat Polymorphism and Cancer Risk: Influence of Laboratory Analysis on Epidemiologic Findings
Authors: Tran Nguyet , Bharaj Bupinder S. , Diamandis Eleftherios P. , Smith Mylinh , Li Benjamin D. L. , Yu Herbert
Published: June 2022

Short tandem repeats (STR) are common polymorphisms in the genome. The length of STR may influence gene transcription, exhibiting diverse phenotypes. Two STRs, one trinucleotide repeats in the androgen receptor (AR) gene and one dinucleotide repeats in the insulin-like growth factor-I (IGF-I) gene, have been studied for their role in cancer, and the results are conflicting. Although there are many reasons for inconsistent findings, laboratory issues are often overlooked. DNA sizing analysis is regularly used to determine the length of STR, but its analytic validity has not been evaluated in epidemiologic studies. To examine if sizing analysis can reliably determine dinucleotide STR, we compared the method with direct DNA sequencing in analyzing CA repeats in the IGF-I gene in a small case-control study. The study enrolled 75 breast cancer cases and 75 age- and race-matched controls. DNA was extracted from buffy coats and was analyzed for CA repeats by both DNA sizing and direct sequencing. Our comparison indicated that these methods detected the same number of repeats in the short allele but not in the long allele. There was a substantial discrepancy between the methods in determining homozygous alleles. Although the two methods showed <10% of samples having an exact match on the number of repeats in both alleles, both techniques were able to detect a genotype-phenotype correlation and a racial disparity in the genotype. An association between breast cancer risk and IGF-I genotype was found in sequencing analysis but not in sizing analysis. Overall, the comparison suggests that laboratory analysis of dinucleotide STR may not be as reliable as originally thought. This unreliability in STR analysis may result in inconsistent study findings.
Colorectal Cancer and the Methylenetetrahydrofolate Reductase 677C → T and Methionine Synthase 2756A → G Polymorphisms: A Study of 2,168 Case-Control Pairs from the JANUS Cohort
Authors: Ulvik Arve , Vollset Stein Emil , Hansen Svein , Gislefoss Randi , Jellum Egil , Ueland Per Magne
Published: June 2022

Polymorphisms in genes involved in the metabolism of folate and methyl groups have been implicated with risk of colorectal cancer. We evaluated the relation between the polymorphisms 677C → T of the methylenetetrahydrofolate reductase (MTHFR) and 2756A → G of the methionine synthase (MTR) genes and risk of colorectal cancer. From the Norwegian JANUS cohort of 309,000 subjects, 2,179 cases were identified and a similar number of controls were selected. The controls were matched for age, gender, time, and place of serum donation. Genotypes were obtained from 2,168 case-control pairs by real-time PCR of serum samples. Risk of colorectal cancer was estimated with conditional and unconditional logistic regression. Median age at diagnosis was 60 years and mean follow-up 13 years. The odds ratio for MTHFR TT versus CC was 0.73 [95% confidence interval (95% CI), 0.58-0.92] and for MTR GG versus AA was 0.65 (95% CI, 0.47-0.90). No interaction between the polymorphisms was found. Relative risk estimates were similar for men and women, and for young and old age at diagnosis. For the MTR GG genotype, risk reduction was observed at the two most distal sites (sigmoideum and rectum) only (P = 0.003). The folate marker, serum total homocysteine (tHcy), was measured in 1,837 subjects. Odds ratio for the upper versus the lower tertile of tHcy was 1.32 (95% CI, 1.04-1.68). No significant effect modification by tHcy levels was detected for either polymorphism. In summary, we found significantly reduced risk of colorectal cancer in subjects with the MTHFR 677 TT and MTR 2756 GG genotypes. No interaction between the polymorphisms, or of either polymorphism with tHcy, was detected.