DNA methylation in pre-diagnostic serum samples of breast cancer cases: Results of a nested case–control study

Background: Promoter methylation of tumor suppressor genes is a frequent and early event in breast carcinogenesis. Paired tumor tissue and serum samples from women with breast cancer show that promoter methylation is detectable in both sample types, with good concordance. This suggests the potential for these serum markers to be used for breast cancer detection. Methods: The current study was a case–control study nested within the prospective New York University Women's Health Study cohort aimed to assess the ability of promoter methylation in serum to detect pre-clinical disease. Cases were women with blood samples collected within the 6 months preceding breast cancer diagnosis (n = 50). Each case was matched to 2 healthy cancer-free controls and 1 cancer-free control with a history of benign breast disease (BBD). Results: Promoter methylation analysis of four cancer-related genes: — RASSF1A, GSTP1, APC and RARβ2, — was conducted using quantitative methylation-specific PCR. Results showed that the frequency of methylation was lower than expected among cases and higher than expected among controls. Methylation was detected in the promoter region of: RASSF1A in 22.0%, 22.9% and 17.2% of cases, BBD controls and healthy controls respectively; GSTP1 in 4%, 10.4% and 7.1% respectively; APC in 2.0%, 4.4% and 4.2% respectively and RARβ2 in 6.7%, 2.3% and 1.1% respectively. Conclusion: Methylation status of the four genes included in this study was unable to distinguish between cases and either control group. This study highlights some methodological issues to be addressed in planning prospective studies to evaluate methylation markers as diagnostic biomarkers.     

Family history of cancer and the risk of bladder cancer: A case–control study from Italy

BackgroundA family history of bladder cancer has been associated with the risk of bladder cancer, but quantification of the excess risk in different populations is still a relevant issue. Further, the role of a family history of other cancers on the risk of bladder cancer remains unclear.MethodsWe analyzed data from an Italian case–control study, including 690 bladder cancer cases and 665 hospital controls. Odds ratios (ORs) were estimated through unconditional logistic regression models, adjusted for sex, age, study center, year of interview and further for education, smoking and sibling’s number.ResultsThe OR for family history of bladder cancer was 2.13 (95% confidence intervals (95%CIs) 1.02–4.49) from the model with partial adjustment, and 1.99 (95%CI 0.91–4.32) after additional adjustment for smoking and siblings’ number, based on 23 cases (3.3%) and 11 controls (1.7%) with a family history of bladder cancer. The fully adjusted OR was 3.77 when the relative was diagnosed at age below 65 years. Smokers with a family history of bladder cancer had a four-fold increased risk compared to non-smokers without a family history. Bladder cancer risk was significantly increased among subjects with a family history of hemolymphopoietic cancers (OR = 2.97, 95%CI 1.35–6.55). Family history of cancer at other sites showed no significant association with bladder cancer risk.ConclusionThis study confirms an approximately two-fold increased risk of bladder cancer for family history of bladder cancer, and indicates a possible familial clustering of bladder cancer with cancers of the hemolymphopoietic system.     

Male pattern baldness and prostate cancer risk in a population-based case–control study

Purpose: Male pattern baldness (MPB) and prostate cancer (PCa) share commonality as prevalent, heritable and androgen-related conditions. Studies exploring the relationship between the two conditions have been inconclusive. Using a population-based, case–control study of PCa, we explore the relationship between early-onset MPB and PCa risk. Methods: Cases were men aged 35–74 diagnosed with PCa between 2002 and 2005 in King County, Washington. Controls were frequency matched by age and identified by random digit dialing. Hair pattern at age 30 and at 1 year prior to diagnosis (cases) or reference date (controls) was determined using showcards. PCa risk associated with balding was assessed with logistic regression. Results: Data from 999 cases of PCa and 942 controls were analyzed. Hair loss at age 30 was more common in controls (25.2%) than cases (19.8%, p = 0.005), and those with hair loss at age 30 had a 29% relative risk reduction for PCa (OR 0.71, 95% CI 0.56–0.91). No risk reduction was seen for men only reporting hair loss at referent age (OR 0.90, 95% CI 0.73–1.12). In men aged >60 at referent date, the risk reduction was greater for men with hair loss at age 30 from both the top of head and forehead (OR 0.55, 95% CI 0.33–0.93). Conclusion: Early-onset MPB was associated with a reduced relative risk of PCa in this population-based study. Further research into a possible mechanistic link between these prevalent and androgen-related conditions is warranted.     

Carcinogen DNA adducts and the risk of colon cancer: case–control study

Colorectal cancer represents 8.5% of all tumours at the King Faisal Specialist Hospital & Research Centre. Environmental and dietary carcinogens such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs) have long been suspected to play a prominent role in colon cancer aetiology. We designed a case–control study to test the hypothesis of whether or not the presence of DNA adducts can play a role in the aetiology of colon cancer. DNA adducts were measured in 24 cancerous and 20 non-cancerous tissue samples of newly diagnosed colon cancer patients by ³²P-post-labelling technique. Normal tissue from 19 hospital patients served as controls. The mean levels of adducts per 10¹⁰ nucleotides in cancerous and non-cancerous tissue were 151.75±217.27 and 114.81±186.10, respectively; however, only adducts in cancerous tissue were significantly higher than controls (32.78±57.51 per 10¹⁰ nucleotides) with p-values of 0.017. No BPDE-DNA adducts were found. No relationship was found between urinary cotinine as a marker of tobacco smoke and 1-hydroxypyrene as an indicator of an individual's internal dose of PAHs and DNA adducts. In a logistic regression model, only adducts in cancerous tissue were associated with the subsequent risk of colon cancer, with an odds ratio of 3.587 (95% confidence interval 0.833–15.448) after adjustment for age and the duration of living in the current region, but of a borderline significance (p=0.086). Although it is difficult to arrive at a definite conclusion from a small dataset, our preliminary results suggest the potential role of DNA adducts in the colon carcinogenesis process. Additional studies with larger sample sizes are needed to confirm our preliminary finding. It is also important to identify the structural characterization of these unknown DNA adducts in order to have a better understanding of whether or not environmental carcinogens play a role in the aetiology of colon cancer.     

2q35-rs13387042 variant and the risk of breast cancer: a case–control study

Molecular Biology Reports - Breast Cancer is the most frequent neoplasm diagnosed among women worldwide. Genetic background and lifestyle/environment play a significant role in the disease...     

Tobacco,alcohol and tea drinking as risk factors for esophageal cancer: A case–control study from Mumbai,India

Esophageal cancer is a relatively rare form of cancer, but some world areas have a markedly higher incidence than others: China, Iceland, India, Japan and United Kingdom, appear to have a higher incidence, as well as the region around the Caspian Sea. In India the incidence rates vary across the country. Despite higher incidence rate, there are only few studies from the Indian subcontinent. This study conducted at Tata Memorial hospital, Mumbai, India, included 442 cases of esophageal cancer and 1628 hospital controls. Data was collected on chewing, smoking, alcohol habits and dietary habits. The results indicated a moderate 1.1 times excess risk for chewers of pan (betel-leaf) with tobacco, 1.8-fold excess risk for bidi smokers and 2-fold for cigarette smokers, and 1.8-fold excess risk for alcohol drinkers. There was a clear dose–response relationship in those with the habits. Among the beverages, tea drinking, common in India, showed a 4-fold excess risk for esophageal cancer. However fresh-fish showed a 20% reduction in risk for esophageal cancer. Besides several other risk factors, these may be studied in the Indian set-up which has a heterogeneous population with a varied life-style and dietary habits. This could give indicators for prevention.     

Associations between oral hygiene habits,diet, tobacco and alcohol and risk of oral cancer: A case–control study from India

ObjectiveThis study examines the association between the incidence of oral cancer in India and oral hygiene habits, diet, chewing and smoking tobacco, and drinking alcohol. We also assessed the effects of oral hygiene habits with oral cancer risk among chewers versus never chewers.MethodsA hospital-based case–control study was conducted in Pune, India, based on face-to-face interviews, anthropometry, and intra-oral examinations conducted for 187 oral cancer cases and 240 controls.ResultsPoor oral hygiene score was associated with a significant risk of oral cancer (adjusted OR = 6.98; 95%CI 3.72–13.05). When stratified by tobacco-chewing habit, the poor oral hygiene score was a significant risk factor only among ever tobacco chewers (adjusted OR = 14.74; 95%CI 6.49–33.46) compared with never chewers (adjusted OR = 0.71; 95%CI 0.14–3.63). Dental check-ups only at the time of pain by ever-chewers with poor oral hygiene was associated with an elevated risk (adjusted OR = 4.22; 95%CI 2.44–7.29), while consumption of green, yellow, and cruciferous vegetables and citrus fruits was protective. A linear dose–response association was observed between oral cancer and chewing tobacco in terms of age at initiation, duration, and frequency of chewing per day (P < 0.001). Smoking more than 10 bidis/cigarettes per day (adjusted OR = 2.74; 95%CI 1.28–5.89) and for a duration >25 years (adjusted OR = 2.31; 95%CI 1.14–4.71) elevated the risk of oral cancer.ConclusionGood oral hygiene habits – as characterized by healthy gums, brushing more than once daily, use of toothpaste, annual dental check-ups, and a minimal number of missing teeth – can reduce the risk of oral cancer significantly. In addition to refraining from chewing/smoking tobacco, a diet adequate in fruits and vegetables may protect against the disease.     

Anti-citrullinated peptide autoantibodies,human leukocyte antigen shared epitope and risk of future rheumatoid arthritis: a nested case–control study

Introduction

The aim of this study was to characterize anti-citrullinated peptide antibody (ACPA) serostatus in pre-clinical rheumatoid arthritis (RA) with and without Human Leukocyte Antigen-Shared Epitope (HLA-SE) alleles.

Methods

We identified 192 women in the Nurses’ Health Study cohorts with blood samples obtained 4 months to 17 years prior to medical record-confirmed RA diagnosis. Three controls were selected matched on age, cohort, menopausal status and post-menopausal hormone use. Reactivities to 18 ACPAs were measured using a custom BioPlex platform. We used conditional logistic regression to calculate the relative risk (RR) of RA for any ACPA-positive and peptide-specific ACPA-positive and examined RRs by time between blood draw and RA onset. Measures of multiplicative and additive interaction between any ACPA-positive and HLA-SE were calculated.

Results

All ACPAs by peptide groups were significantly associated with RA risk, RRs ranged from 4.7 to 11.7. The association between ACPA and RA varied over time with the strongest association in those with blood draw less than 5 years before onset (RR 17.0 [95% CI 5.8 to 53.7]) and no association 10 or more years prior to onset (RR 1.4 [95% CI 0.5 to 4.3]). Individuals with both HLA-SE and any ACPA-positive had the highest risk of RA. HLA-SE-positive RA cases showed reactivity to more ACPA types than HLA-SE negative (χ² test for trend, P = 0.01).

Conclusions

There is increasing ACPA reactivity up to 10 years before RA onset with the strongest association within 5 years of RA onset. The magnitude of the response to ACPAs, in combination with the presence of HLA-SE, is most important for identifying those individuals with the highest risk of RA.     

History of gonorrhea and prostate cancer in a population-based case–control study in Mexico

We evaluated the association between a history of sexually transmitted diseases (STDs) and the risk for prostate cancer (PC) among Mexican males.MethodsPC incident cases (n = 402) that were identified at six public hospitals in Mexico City were matched by age (±5 years) with 805 population controls with no history of PC. By face-to-face interview, we obtained information about sexual history, previous STDs, sociodemographic characteristics, and familial history of PC. An unconditional logistic regression model was used to estimate the risk for PC.ResultsA total of 16.6% of men reported having had at least one previous STD, and the most frequently reported STD was gonorrhea (10.5%). After adjusting by PC familial history, the history of STD was associated with a two-fold greater risk of PC: odds ratio (OR) = 2.67; 95% confidence interval (95% CI = 1.91–3.73). When each STD was evaluated separately, only gonorrhea was associated with a significant increase in PC risk (OR = 3.04; 95% CI = 1.99–4.64). These associations were similar when we stratified by low-risk PC (Gleason <7) and high-risk PC (Gleason ≥7).ConclusionThese results confirm that STDs, and particularly gonorrhea, may play an etiological role in PC among Mexican males, which is consistent with a previous report from a multiethnic cohort.     

Association between the XRCC3 T241M polymorphism and risk of cancer: Evidence from 157 case–control studies

The T241M polymorphism in the X-ray cross-complementing group 3 (XRCC3) had been implicated in cancer susceptibility. The previous published data on the association between XRCC3 T241M polymorphism and cancer risk remained controversial. Hence, we performed a meta-analysis to investigate the association between cancer susceptibility and XRCC3 T241M (61,861 cases and 84,584 controls from 157 studies) polymorphism in different inheritance models. We used odds ratios with 95% confidence intervals to assess the strength of the association. Overall, significantly increased cancer risk was observed in any genetic model (dominant model: odds ration [OR] = 1.07, 95% confidence interval [CI] = 1.00–1.13; recessive model: OR = 1.15, 95% CI = 1.08–1.23; additive model: OR = 1.17, 95% CI = 1.08–1.28) when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, the elevated risk remained for subgroups of bladder cancer and breast cancer, especially in Caucasians. In addition, significantly decreased lung cancer risk was also observed. In summary, this meta-analysis suggests the participation of XRCC3 T241M in the susceptibility for bladder cancer and breast cancer, especially in Caucasians, and XRCC3 T241M polymorphism is associated with decreased lung cancer risk. Moreover, our work also points out the importance of new studies for T241M association in some cancer types, such as gastric cancer, colorectal cancer, and melanoma skin cancer, where at least some of the covariates responsible for heterogeneity could be controlled, to obtain a more conclusive understanding about the function of the XRCC3 polymorphism in cancer development.     

Local radiation dose and solid second malignant neoplasms after childhood cancer in Germany: a nested case–control study

Radiotherapy (RT) has been associated with the development of solid second malignant neoplasms (SMNs) in childhood cancer survivors. The aim of this study was to analyse the effect of cumulative doses of previous RT received at the SMN body region, at all other body regions and at body regions adjacent to the SMN, on the risk of developing a solid SMN. A total of 190 cases diagnosed with a solid second malignant neoplasm in 1980–2002 were matched with 368 controls with single neoplasm from the database of the German Childhood Cancer Registry (GCCR) (33,809 patients at cut-off date). The GCCR registers approximately 97 % of all childhood malignancies which occur at an age of less than 15 years in Germany since 1980. It was found that 147 (77.4 %) cases had received RT compared to 208 (56.6 %) controls with cumulative focus doses from 8 to 110 Gy. Fifty per cent of the SMNs and 60 % of RT affected the head region. RT was shown to increase the risk of a solid second tumour within the body region of radiation by 5.3 % per Gy (odds ratio 1.053; 95 % confidence interval 1.036–1.071). With increasing age at diagnosis and with more recent treatment eras, this effect decreased. Cumulative RT doses received at all other body regions or only at body regions adjacent to the SMN did not show an additional effect on the risk of developing an SMN. It is thus concluded that RT is the main risk factor for the development of SMNs within the irradiated body region. Late effects surveillance of former patients should give special attention to the originally irradiated parts of the body.     

Prolonged breastfeeding reduces risk of breast cancer in Sri Lankan women: A case–control study

Goal: To assess the association between duration of breastfeeding and the risk of breast cancer in Sri Lankan women. Methods: We conducted a case–control study in women aged 30–64 years in selected health care facilities in the Western province. A total of 100 recent cases of breast cancer (histologically confirmed) and 203 controls (age and parity matched) were included. Detailed information regarding breastfeeding, menstruation, reproductive factors, passive smoking and other confounders was collected using a structured questionnaire. Adjusted odds ratios and 95% confidence intervals were calculated using multiple logistic regressions. Principle results: Multivariate analysis found that those women who breastfed for ≥24 months during lifetime had significantly lower risk of breast cancer than those who breastfed for less than 24 months (OR = 0.40; 95%CI = 0.22, 0.73). Compared to 0–11 months of lifetime breastfeeding, there was a 66.3% reduction in breast cancer risk in women who breastfed for 12–23 months, 87.4% reduction in 24–35 months and 94% reduction in 36–47 months categories. The mean duration of breastfeeding per child for ≥12 months was also associated with reduced risk of breast cancer (OR = 0.52; 95%CI = 0.28, 0.94). The significant factors associated with increased risk of breast cancer were: post-menopausal women (OR = 1.74; 95%CI = 1.01, 3.01); having an abortion in the past (OR = 3.42; 95%CI = 1.75, 6.66) and exposure to passive smoking (OR = 2.96, 95%CI = 1.53, 5.75). Major conclusions: Prolonged breastfeeding significantly reduces the risk of breast cancer and this protective effect was supported by a dose–response relationship. Risk due to passive smoking should be emphasized in anti-smoking programmes.     

Association between XRCC1 and XRCC3 polymorphisms and colorectal cancer risk: a meta-analysis of 23 case–control studies

Several potential functional polymorphisms in the DNA repair gene X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln (rs25487), Arg194Trp (rs1799782), Arg280His (rs25489) and X-ray repair cross-complementing group 3 (XRCC3) T241M (rs861539) have been implicated in colorectal cancer (CRC) risk, but the results are conflicting. Here, we performed a meta-analysis of 23 published case control datasets and assessed genetic heterogeneity between those datasets. All the case–control studies published from January 2000 to June 2012 on the association between those polymorphisms and CRC risk were identified by searching the electronic literature Medline. Statistical analysis was performed with the software programs Review Manager (version 4.2). For overall CRC, no significant association was observed, the pooled odds ratios for XRCC1 Arg399Gln, Arg194Trp, Arg280His, and XRCC3 T241M were 1.02 (95 % CI: 0.93, 1.12), 1.03 (95 % CI: 0.94, 1.14), 0.98 (95 % CI: 0.85, 1.13) and 1.03 (95 % CI: 0.85, 1.26), respectively. Furthermore, no significant association was observed in subgroup analyses based on ethnicity. The results suggested that these four SNPs evaluated are not associated with risk of CRC.     

DNMT3B polymorphisms and cancer risk: a meta analysis of 24 case–control studies

The association between polymorphism of DNA methyltransferases 3B and cancer risk has been widely studied recently, and no consensus conclusion is available up to now. We perform a comprehensive search using the databases of Medline, ISI Web of Knowledge and Embase. The odds ratio (OR) and its 95% confidence interval (95% CI) are used to investigate the strength of the association. A total of 24 case–control studies with 15,647 individuals are included in this meta-analysis. For −149C > T (17 studies, 5229 cases and 6910 controls), no evidence indicate that individuals carrying the variant genotypes (CC + CT), relative to those carrying the wild homozygote TT genotype, have an increased risk of cancer (OR = 1.03; 95% CI = 0.84–1.26; P = 0.76). Similarly, no cancer risk is found in the subgroup analyses. For −579G > T (11 studies, 3513 cases and 3714 controls), significantly decreased risks of cancer are observed, and the ORs (95% CI) are 0.70 (0.56–0.87) for GT versus TT, 0.70 (0.57–0.85) for GG + GT versus TT and 0.76 (0.63–0.93) for G-allele versus T-allele, respectively. Subgroup analyses stratified by ethnicity and types of cancer are also performed, and results indicated that −579G > C polymorphism is associated with risk of cancer in Asians [0.68 (0.53–0.87) for GT vs. TT] but not in Europeans [0.82 (0.63–1.07) for GT vs. TT]. We also observe that the −579G is associated with decreased risk of colorectal cancer [0.49(0.38–0.62) for GT vs. TT]. More studies with larger sample size were needed to provide more precise evidence.     

The XRCC3 Thr241Met polymorphism and breast cancer risk: a case–control study in a Thai population

The X-ray repair cross-complementing group 3 gene (XRCC3) belongs to a family of genes responsible for repairing DNA double-strand breaks caused by normal metabolic processes and exposure to ionizing radiation. Polymorphisms in DNA repair genes may alter an individual's capacity to repair damaged DNA and may lead to genetic instability and contribute to malignant transformation. We examined the role of a polymorphism in the XRCC3 gene (rs861529; codon 241: threonine to methionine change) in determining breast cancer risk in Thai women. The study population consisted of 507 breast cancer cases and 425 healthy women. The polymorphism was analysed by fluorescence-based melting curve analysis. The XRCC3 241Met allele was found to be uncommon in the Thai population (frequency 0.07 among cases and 0.05 among controls). Odds ratios (OR) adjusted for age, body mass index, age at menarche, family history of breast cancer, menopausal status, reproduction parameters, use of contraceptives, tobacco smoking, involuntary tobacco smoking, alcohol drinking, and education were calculated for the entire population as well as for pre- and postmenopausal women. There was a significant association between 241Met carrier status and breast cancer risk (OR 1.58, 95% confidence interval (CI) 1.02–2.44). Among postmenopausal women, a slightly higher OR (1.82, 95% CI 0.95–3.51) was found than among premenopausal women (OR 1.48, 95% CI 0.82–2.69). Our findings suggest that the XRCC3 Thr241Met polymorphism is likely to play a modifying role in the individual susceptibility to breast cancer among Thai women as already shown for women of European ancestry.     

Occupation and risk of glioma,meningioma and acoustic neuroma: Results from a German case–control study (Interphone Study Group,Germany)

Background: Several epidemiological studies have investigated the association between occupation and brain tumour risk, but results have been inconclusive. We investigated the association between six occupational categories defined a priori: chemical, metal, agricultural, construction, electrical/electronic and transport, and the risk of glioma, meningioma and acoustic neuroma. Methods: In a population-based case–control study involving a total of 844 cases and 1688 controls conducted from 2000 to 2003, detailed information on life-long job histories was collected during personal interviews and used to create job calendars for each participant. Job title, job activity, job number, and the starting and ending dates of the activity were recorded for all activities with duration of at least 1 year. Reported occupational activities were coded according to the International Standard Classification of Occupations 1988 (ISCO 88). For the analyses we focused on six a priori defined occupational sectors, namely chemical, metal, agricultural, construction, electrical/electronic and transport. Multiple conditional logistic regression analysis was used to estimate odds ratios and their 95% confidence intervals. Results: Most of the observed odds ratios were close to 1.0 for ever having worked in the six occupational sectors and risk of glioma, meningioma and acoustic neuroma. Sub-group analyses according to duration of employment resulted in two elevated odds ratios with confidence intervals excluding unity. Conclusions: We did not observe an increased risk of glioma or meningioma for occupations in the agricultural, construction, transport, chemical, electrical/electronic and metal sectors. The number of ‘significant’ odds ratios is consistent with an overall ‘null-effect’.     

Association between the CYP1A1 T3801C polymorphism and risk of cancer: Evidence from 268 case–control studies

T3801C is a common polymorphism in CYP1A1, showing differences in its biological functions. Case–control studies have been performed to elucidate the role of T3801C in cancer, although the results are conflicting and heterogeneous. Hence, we performed a meta-analysis to investigate the association between cancer susceptibility and T3801C (55,963 cases and 76,631 controls from 268 studies) polymorphism in different inheritance models. We used odds ratios with 95% confidence intervals to assess the strength of the association. Overall, significantly increased cancer risk was observed in any genetic model (dominant model: odds ratio [OR] = 1.14, 95% confidence interval [CI] = 1.09–1.19; recessive model: OR = 1.23, 95% CI = 1.12–1.34; CC vs. TT: OR = 1.31, 95% CI = 1.19–1.45; TC vs. TT: OR = 1.12, 95% CI = 1.07–1.18; additive model: OR = 1.14, 95% CI = 1.09–1.19) when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, the elevated risk remained for subgroups of cervical cancer, head and neck cancer, hepatocellular cancer, leukemia, lung cancer, prostate cancer and breast cancer. In addition, significantly decreased colorectal cancer risk was also observed. In summary, this meta-analysis suggests that the participation of CYP1A1 T3801C is a genetic susceptibility for some cancer types. Moreover, our work also points out the importance of new studies for T3801C association in some cancer types, such as gallbladder cancer, Asians of acute myeloid leukemia, and thyroid cancer, where at least some of the covariates responsible for heterogeneity could be controlled, to obtain a more conclusive understanding about the function of the CYP1A1 T3801C polymorphism in cancer development.