Risk Of Cancer In Subjects Research Articles

Role of Beta-Carotene in Lung Cancer Primary Chemoprevention: A Systematic Review with Meta-Analysis and Meta-Regression.

Lung cancer is one of the most common neoplasms globally, with about 2.2 million new cases and 1.8 million deaths annually. Although the most important factor in reducing lung cancer risk is lifestyle change, most patients favour the use of supplements, for example, rather than quitting smoking or following a healthy diet. To better understand the efficacy of such interventions, a systematic review was performed of data from randomized controlled trials concerning the influence of beta-carotene supplementation on lung cancer risk in subjects with no lung cancer before the intervention. The search corpus comprised a number of databases and eight studies involving 167,141 participants, published by November 2021. The findings indicate that beta-carotene supplementation was associated with an increased risk of lung cancer (RR = 1.16, 95% CI = 1.06–1.26). This effect was even more noticeable among smokers and asbestos workers (RR = 1.21, 95% CI = 1.08–1.35) and non-medics (RR = 1.18, 95% CI = 1.07–1.29). A meta-regression found no relationship between the beta-carotene supplementation dose and the size of the negative effect associated with lung cancer risk. Our findings indicate that beta-carotene supplementation has no effect on lung cancer risk. Moreover, when used as the primary chemoprevention, beta-carotene may, in fact, increase the risk of lung cancer.

Associations of Subtype and Isomeric Plasma Carotenoids with Prostate Cancer Risk in Low-Income African and European Americans.

Various carotenoids in circulation, including isomers, may have different influences on cancer risk. We conducted a nested case-control study including 343 incident prostate cancer cases and 640 controls individually matched on age, race, study site, and time of blood collection. Carotenoids investigated were carotene, cryptoxanthin, lycopene, dihydrolycopene, lutein, anhydrolutein, and zeaxanthin, including α versus β configurations and cis versus trans isomers. General linear model and conditional logistic regression were applied to evaluate associations for prostate cancer risk, with adjustment for potential confounders. We conducted additional analyses with further stratification by race, multivitamin use, and smoking status. Case-control differences were found in carotenoid subtype levels, although not all reached the multiple comparison adjusted threshold for significance. Plasma lycopene [ORT1 vs. T3 = 0.51; 95% confidence interval (CI), 0.29-0.87; P trend = 0.014], dihydrolycopene (ORT1 vs. T3 = 0.37; 95% CI, 0.18-0.74; P trend = 0.006), and cis-anhydrolutein (ORT1 vs. T3 = 0.57; 95% CI, 0.33-0.96; P trend = 0.037) were inversely, while β-trans-carotene (ORT1 vs. T3 = 2.13; 95% CI, 1.32-3.43; P trend = 0.002) and trans-lutein (ORT1 vs. T3, 1.86; 95% CI, 1.20-2.88; P trend = 0.006) were positively associated with prostate cancer risk. Stratified analyses showed inverse associations of lycopene, dihydrolycopene, and cis-anhydrolutein with prostate cancer risk in subjects without multivitamin use; lycopene and dihydrolycopene in African-Americans and current smokers; and dihydrolycopene in nonsmokers. Positive associations of β-trans-carotene and trans-lutein were observed in African-Americans, nonsmokers, and multivitamin users. The associations of carotenoids with risk of prostate cancer differed by carotenoid subtypes. Public health recommendations on carotenoid intakes for prostate cancer prevention should take subtypes and isomers into consideration.

Lifestyle and cancer incidence and mortality risk depending on family history of cancer in two prospective cohorts.

The extent to which a favorable lifestyle may lower cancer risk in subjects with a family history of cancer is unknown. We conducted a prospective study in two Swedish cohorts, the Malmö Diet and Cancer Study (MDCS; n = 25,604) and the Malmö Preventive Project (MPP; n = 16,216). The association between a favorable lifestyle (based on nonsmoking, normal weight, absence of excessive drinking, regular physical activity and healthy diet) and cancer incidence and mortality risk was assessed using Cox regression stratified by family history of cancer (all types). A favorable lifestyle was associated with a 22% (95% confidence interval [CI]: 18-26%) and 40% (95% CI: 36-44%) lower risk of cancer incidence and mortality, respectively, compared to an unfavorable lifestyle. No significant effect modification by family history was observed but there was a null association between lifestyle and cancer incidence among subjects with two or more affected first-degree relatives. The observed relative risk estimates comparing an unfavorable with a favorable lifestyle corresponded to standardized 10-year cancer incidence rates of 11.2 vs. 9.5% in the MDCS, and 4.4 vs. 3.2% in the MPP, and a reduction in 20-year cancer mortality rate from 11.7% to 7.4% in the MDCS and 6.7% to 3.9% in the MPP. Improved adherence to cancer prevention recommendations may reduce cancer incidence and mortality risk in the general population, however, further studies are needed to assess the impact of lifestyle on cancer incidence among subjects with strong familial or polygenic risk for specific cancers.

Association between ATM rs1801516 polymorphism and cancer susceptibility: a meta-analysis involving 12,879 cases and 18,054 controls

BackgroundAtaxia telangiectasia mutated (ATM) gene plays a key role in response to DNA lesions and is related to the invasion and metastasis of malignancy. Epidemiological studies have indicated associations between ATM rs1801516 polymorphism and different types of cancer, but their results are inconsistent. To further evaluate the effect of ATM rs1801516 polymorphism on cancer risk, we conducted this meta-analysis.MethodsStudies were identified according to specific inclusion criteria by searching PubMed, Web of Science, and Embase databases. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) under recessive, dominant, codominant, and overdominant models of inheritance were calculated to estimate the association between rs1801516 polymorphism and cancer risk.ResultsA total of 37 studies with 12,879 cases and 18,054 controls were included in our study. No significant association was found between rs1801516 polymorphism and cancer risk in overall comparisons (AA vs GG + GA: OR = 0.91, 95% CI, 0.78–1.07; AA+GA vs GG: OR = 1.00, 95% CI, 0.90–1.11; AA vs GG: OR = 0.89, 95% CI, 0.75–1.06; GA vs GG: OR = 1.01, 95% CI, 0.91–1.13; GG + AA vs GA: OR = 1.00, 95% CI, 0.88–1.10). However, after subgroup analyses by region-specified population, significant associations were found in European (AA vs GG + GA: OR = 0.79, 95% CI, 0.65–0.96, P = 0.017; AA vs GG: OR = 0.79, 95% CI, 0.65–0.96, P = 0.017), South American (AA+GA vs GG: OR = 2.15, 95% CI, 1.37–3.38, P = 0.001; GA vs GG: OR = 2.19, 95% CI, 1.38–3.47, P = 0.001; GG + AA vs GA: OR = 0.46, 95% CI, 0.29–0.72, P = 0.001), and Asian (AA vs GG + GA: OR = 7.45, 95% CI, 1.31–42.46, P = 0.024; AA vs GG: OR = 7.40, 95% CI, 1.30–42.19, P = 0.024). Subgroup analyses also revealed that compared with subjects carrying a GG genotype, those carrying a homozygote AA had a decreased risk for breast cancer (AA vs GG: OR = 0.76, 95% CI, 0.59–0.98, P = 0.035), and the homozygote AA was associated with decreased cancer risk in subjects with family history (AA vs GG: OR = 0.68, 95% CI, 0.47–0.98, P = 0.039).ConclusionsATM rs1801516 polymorphism is not associated with overall cancer risk in total population. However, for subgroup analyses, this polymorphism is especially associated with breast cancer risk; in addition, it is associated with overall cancer risk in Europeans, South Americans, Asians, and those with family history.

Aging and aging-associated diseases: a microRNA-based endocrine regulation hypothesis.

Although there are numerous hypotheses explaining the nature of aging and associated processes, two concepts are dominant: (i) aging is a result of cell-autonomous processes, such as the accumulation of DNA mutations, aberrant methylations, protein defects, and shortening of telomeres, leading to either inhibition of cellular proliferation and death of non-dividing terminally differentiated cells or tumor development; (ii) aging is a result of a central program that is switched on at a specific stage of organismic development. The microRNA-based endocrine regulation hypothesis combines the two above concepts by proposing central regulation of cell death occurrences via hypothalamus-pituitary gland (PG)-secreted miRNA hormones, the expression and/or secretion of which are regulated by sex hormones. This hypothesis explains such well-known phenomena as inverse comorbidity of either cancer or Alzheimer’s (AD) and other neurodegenerative diseases; higher AD morbidity and lower frequency of many common types of cancer in women vs. men; higher risk of early AD and lower risk of cancer in subjects with Down syndrome; longer life expectancy in women vs. men and much lower sex-dependent differences, if any, in other mammals; increased lifespans due to hypophysectomy or PG hypofunction; and parabiotic effects of blood or plasma transfusions between young and old animals.

Increased risk of bone tumors after growth hormone treatment in childhood: A population-based cohort study in France.

The association between growth hormone (GH) treatment and cancer risk has not been thoroughly evaluated and there are questions about any increased risk of bone tumors. We examined cancer risk and especially bone tumor risk in a population‐based cohort study of 6874 patients treated with recombinant GH in France for isolated GH deficiency, short stature associated with low birth weight or length or idiopathic short stature. Adult mortality and morbidity data obtained from national databases and from questionnaires. Case ascertainment completeness was estimated with capture‐recapture methods. Standardized mortality and incidence ratios were calculated using national reference data. 111 875 person‐years of observation were analyzed and patients were followed for an average of 17.4 ± 5.3 years to a mean age of 28.4 ± 6.2 years. For cancer overall, mortality and incidence were not different from expected figures. Five patients developed bone tumors (chondrosarcoma, 1, Ewing sarcoma, 1, osteosarcoma, 3) of whom 3 died (Ewing sarcoma, 1, osteosarcoma, 2), whereas only 1.4 case and 0.6 deaths were expected: standardized mortality ratio, 5.0 and standardized incidence ratio from 3.5 to 3.8 accounting or not accounting for missed cases. Most patients received conventional doses of GH, although one patient with osteosarcoma had received high dose GH (60 μg/kg/d). This study confirms an increased risk of bone tumors but not overall cancer risk in subjects treated with GH in childhood for isolated GH deficiency or childhood short stature. Further work is needed to elucidate the mechanisms involved.

Perceived stress level and risk of cancer incidence in a Japanese population: the Japan Public Health Center (JPHC)-based Prospective Study

Evidence regarding stress as a risk factor for cancer onset is inconsistent. In this study, based on the Japan Public Health Center-based Prospective Study, we enrolled 101,708 participants aged 40–69 years from 1990–1994. The self-reported perceived stress level was collected at baseline and updated through 5-year follow-up. The association between perceived stress and cancer risk was measured by Cox proportional hazards regression model, adjusted for all known confounders. During follow-up (mean = 17.8 years), we identified 17,161 cancer cases. We found no association between baseline perceived stress level and cancer incidence. However, by taking account of the dynamic changes in perceived stress, time-varying analyses revealed a slightly (4–6%) increased overall cancer risk for subjects under elevated perceived stress levels compared to the ‘low stress level’ group. Analyses concerning long-term perceived stress level showed that individuals with constantly high perceived stress level had an 11% (95% confidence interval 1–22%) excess risk for cancer compared to subjects with persistently low stress levels. This association was confined to men (20% excess risk), and was particularly strong among smokers, alcohol drinkers, obese subjects, and subjects without family history of cancer. Therefore, we concluded high perceived stress level might contribute to excess overall cancer incidence among men.

Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry

We evaluated the overall and site-specific incidence of cancer in subjects with primary immunodeficiency diseases (PIDD) enrolled in the United States Immune Deficiency Network (USIDNET) registry compared with age-adjusted cancer incidence in the Surveillance, Epidemiology and End Results Program (SEER) database. We hypothesized that subjects with PIDD would have an increased incidence of cancer due to impaired immune function. Overall and site-specific cancer incidence rates were evaluated in subjects with PIDD (n=3658) enrolled in the USIDNET registry from 2003 to 2015 and compared with age-adjusted incidence rates in the SEER database. We observed a 1.42-fold excess relative risk of cancer in subjects with PIDD compared with the age-adjusted SEER population (P<.001). Men with PIDD had a 1.91-fold excess relative risk of cancer compared with the age-adjusted male population (P<.001), while women with PIDD had similar overall cancer rates compared with the age-adjusted female population. Of the 4 most common malignancies in men and women in SEER (lung, colon, breast, and prostate cancers), we found no significant increase in these diagnoses in subjects with PIDD. Significant increases in lymphoma in both men (10-fold increase, P<.001) and women (8.34-fold increase, P<.001) with PIDD were observed. Excess incidence of cancer occurred in subjects with PIDD. An excess of lymphoma in specific PIDD populations principally drove this increased incidence, while no increased risk of the most common solid tumor malignancies was observed. These data point to a restricted role of the immune system in protecting from specific cancers.

Progranulin, a New Adipokine at the Crossroads of Metabolic Syndrome, Diabetes, Dyslipidemia and Hypertension.

Progranulin is a multifunctional regulatory protein with growth-promoting, neuroprotective and antiinflammatory activities. Recent studies indicate that progranulin is one of the adipose tissue hormones (adipokines). Progranulin expression in visceral adipose tissue and circulating progranulin concentration are increased in obesity and hyperprogranulinemia is involved in the pathogenesis of obesity-associated insulin resistance. Progranulin impairs insulin signaling and reduces insulin-induced glucose uptake both in vitro and in vivo whereas progranulin deficiency protects from high fat diet-induced insulin resistance. Several studies, including some prospective ones, have demonstrated the association between high progranulin and type 2 diabetes and its complications such as nephro- and retinopathy as well as non-alcoholic fatty liver disease. It is quite well established that progranulin contributes to insulin resistance and resulting deterioration of carbohydrate metabolism. In addition, progranulin may be associated with the development of diabetic microangiopathy, fatty liver disease and possibly with the increased risk of cancer in subjects with the metabolic syndrome. On the other hand, progranulin augments vasorelaxation, inhibits inflammatory reaction, is neuroprotective and reduces ischemiareperfusion injury. Progranulin has both detrimental and beneficial effects. More clinical studies including prospective ones are needed to clarify the role of progranulin in obesity-associated pathologies such as diabetes, hyperlipidemia, hypertension and atherosclerosis.

The Effect of Combined Aspirin and Clopidogrel Treatment on Cancer Incidence

BackgroundMultiple studies have shown an association between aspirin treatment and a reduction in newly diagnosed cancer. Conversely, there are conflicting clinical and laboratory data on the effect of combined clopidogrel and aspirin therapy on cancer incidence, including analyses suggesting an increased cancer risk. No large-scale cohort study has been performed to address this issue in a heterogeneous real-world scenario. We investigated the effect of clopidogrel and aspirin on cancer incidence compared with aspirin alone and no antiplatelet therapy. MethodsA population-based historical cohort study of subjects aged ≥50 years covered by Clalit Health Services, an Israeli health maintenance organization, was performed. Patients treated with the newer antiplatelet drugs, prasugrel or ticagrelor, which, like clopidogrel, inhibit adenosine diphosphate receptors, and those with prior cancer were excluded. Prescription records of antiplatelet medication were retrieved. ResultsThe cohort included 183,912 subjects diagnosed with 21,974 cancer cases based upon the International Classification of Diseases, Ninth Revision. Dual aspirin and clopidogrel was prescribed in 9.6%, while 49% received aspirin alone and 41% used neither. Compared with nonusers, there was a lower risk of cancer in subjects exposed to aspirin with (hazard ratio [HR] 0.46; 95% confidence interval [CI], 0.44-0.49) or without clopidogrel (HR 0.54; 95% CI, 0.52-0.56), on long-term follow-up. Combined treatment was associated with a lower cancer risk than the aspirin-only group (HR 0.92; 95% CI, 0.86-0.97). ConclusionsDual clopidogrel and aspirin treatment is safe regarding the cancer risk. This study generates the hypothesis that clopidogrel may reduce cancer incidence.

Epidemiological research on radiation-induced cancer in atomic bomb survivors.

The late effects of exposure to atomic bomb radiation on cancer occurrence have been evaluated by epidemiological studies on three cohorts: a cohort of atomic bomb survivors (Life Span Study; LSS), survivors exposed in utero, and children of atomic bomb survivors (F1). The risk of leukemia among the survivors increased remarkably in the early period after the bombings, especially among children. Increased risks of solid cancers have been evident since around 10 years after the bombings and are still present today. The LSS has clarified the dose–response relationships of radiation exposure and risk of various cancers, taking into account important risk modifiers such as sex, age at exposure, and attained age. Confounding by conventional risk factors including lifestyle differences is not considered substantial because people were non-selectively exposed to the atomic bomb radiation. Uncertainty in risk estimates at low-dose levels is thought to be derived from various sources, including different estimates of risk at background levels, uncertainty in dose estimates, residual confounding and interaction, strong risk factors, and exposure to residual radiation and/or medical radiation. The risk of cancer in subjects exposed in utero is similar to that in LSS subjects who were exposed in childhood. Regarding hereditary effects of radiation exposure, no increased risk of cancers associated with parental exposure to radiation have been observed in the F1 cohort to date. In addition to biological and pathogenetic interpretations of the present results, epidemiological investigations using advanced technology should be used to further analyze these cohorts.

Serum betaine but not choline is inversely associated with breast cancer risk: a case-control study in China.

Choline and betaine are important for DNA methylation and synthesis, and may affect tumor carcinogenesis. To our knowledge, no previous study has examined the association between serum choline and betaine and breast cancer risk. This study aimed to examine whether serum choline and betaine were inversely associated with breast cancer risk among Chinese women. This hospital-based case-control study consecutively recruited 510 breast cancer cases and 518 frequency-matched (age and residence) controls, and blood samples were available for 500 cases and 500 controls. Serum choline and betaine were assayed by high-performance liquid chromatography-tandem mass spectrometry. Multiple unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). An inverse association with breast cancer risk was observed for serum betaine (fourth vs first quartile adjusted OR 0.68, 95% CI 0.47-0.97) and for the ratio of serum betaine to choline (fourth vs first quartile adjusted OR 0.70, 95% CI 0.48-1.00), but not for serum choline (fourth vs first quartile adjusted OR 0.80, 95% CI 0.56-1.15). Serum betaine was inversely associated with breast cancer risk in subjects with below-median dietary folate intake (fourth vs first quartile adjusted OR 0.48, 95% CI 0.30-0.77). This study suggested that serum betaine but not choline was inversely associated with breast cancer risk. This result needed to be further confirmed by the prospective studies.

Polymorphisms in GSTM1, GSTT1, GSTP1, and GSTM3 genes and breast cancer risk in northeastern Mexico.

Glutathione S-transferases (GSTs) are a family of phase II metabolizing enzymes involved in carcinogen detoxification and the metabolism of various bioactive compounds. Several genes that code for these enzymes are polymorphic in an ethnicity-dependent manner, with particular genotypes previously associated with an increased risk of breast cancer. The purpose of this study was to determine the frequencies of polymorphisms in the genes GSTM1, GSTT1, GSTP1, and GSTM3 and to investigate whether an association exists between these genes and breast cancer risk in subjects from northeastern Mexico. Genotypes were determined for 243 women with histologically confirmed breast cancer and 118 control subjects. Gene polymorphisms were analyzed using a DNA microarray. We found an increased breast cancer risk associated with the GSTM1 gene deletion polymorphism (OR = 2.19; 95%CI = 1.50-3.21; P = 0.001). No associations between the GSTT1, GSTP1, and GSTM3 genotypes and neoplasia risk were observed. In conclusion, we determined the genotype distribution of GST polymorphisms in control subjects and breast cancer patients from northeastern Mexico. The GSTM1 null genotype was associated with breast cancer risk. Our findings may be used to individualize breast cancer screening and therapeutic intervention in our population, which displays ethnic characteristics that differentiate it from other populations in Mexico.

Conventional hypoglycaemic agents and the risk of lung cancer in patients with diabetes: a meta-analysis.

BackgroundAccumulating evidence suggests that hypoglycaemic agents influence lung cancer risk in patients with diabetes. It remains to be fully elucidated whether conventional hypoglycaemic agents (metformin, sulfonylureas, thiazolidinediones [TZDs] or insulin) affect lung cancer incidence in patients with diabetes.MethodsWe performed a meta-analysis using EMBASE, MEDLINE and Web of Science to search randomised controlled trials (RCTs), cohort studies, and case-control studies published up to October 2013 that assessed the effects of metformin, sulfonylurea, TZDs or insulin on lung cancer risk in subjects with diabetes. Fixed and random effects meta-analysis models were used, and the effect size was expressed as a summary odds ratio (OR) with 95% confidence intervals (CI). The Grades of Research, Assessment, Development and Evaluation (GRADE) approach was applied to define the quality of the evidence.ResultsAnalysis of 15 studies (11 cohort studies, 2 case-control studies, and 2 RCTs) showed that metformin use was associated with a 15% reduction in risk of lung cancer (OR 0.85, 95% CI 0.77 to 0.92), but this finding was not supported by sub-analysis of smoking-adjusted studies (OR 0.84, 95% CI 0.61 to 1.06). Moreover, sulfonylurea or TZDs use was not associated with increased or decreased lung cancer risk, respectively (OR 1.10, 95% CI 0.93 to 1.26), (OR 0.86, 95% CI 0.70 to 1.02). Higher lung cancer risk was related to insulin (OR 1.23, 95% CI 1.10 to 1.35). However, all data from RCTs failed to demonstrate a statistically significant effect.ConclusionsThis analysis demonstrated that metformin use may reduce lung cancer risk in patients with diabetes but not in a smoking-adjusted subgroup and that insulin use may be associated with an increased lung cancer risk in subjects with diabetes.

Mood Disorders and Risk of Lung Cancer in the EAGLE Case-Control Study and in the U.S. Veterans Affairs Inpatient Cohort

BackgroundMood disorders may affect lung cancer risk. We evaluated this hypothesis in two large studies.Methodology/Principal FindingsWe examined 1,939 lung cancer cases and 2,102 controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) case-control study conducted in Italy (2002–2005), and 82,945 inpatients with a lung cancer diagnosis and 3,586,299 person-years without a lung cancer diagnosis in the U.S. Veterans Affairs Inpatient Cohort (VA study), composed of veterans with a VA hospital admission (1969–1996). In EAGLE, we calculated odds ratios (ORs) and 95% confidence intervals (CI), with extensive adjustment for tobacco smoking and multiple lifestyle factors. In the VA study, we estimated lung cancer relative risks (RRs) and 95% CIs with time-dependent Poisson regression, adjusting for attained age, calendar year, hospital visits, time within the study, and related previous medical diagnoses. In EAGLE, we found decreased lung cancer risk in subjects with a personal history of mood disorders (OR: 0.59, 95% CI: 0.44–0.79, based on 121 lung cancer incident cases and 192 controls) and family history of mood disorders (OR: 0.62, 95% CI: 0.50–0.77, based on 223 lung cancer cases and 345 controls). The VA study analyses yielded similar results (RR: 0.74, 95% CI: 0.71–0.77, based on 2,304 incident lung cancer cases and 177,267 non-cancer person-years) in men with discharge diagnoses for mood disorders. History of mood disorders was associated with nicotine dependence, alcohol and substance use and psychometric scales of depressive and anxiety symptoms in controls for these studies.Conclusions/SignificanceThe consistent finding of a relationship between mood disorders and lung cancer risk across two large studies calls for further research into the complex interplay of risk factors associated with these two widespread and debilitating diseases. Although we adjusted for smoking effects in EAGLE, residual confounding of the results by smoking cannot be ruled out.

Influence of the OGG1 Ser326Cys polymorphism on oxidatively damaged DNA and repair activity

Oxidatively damaged DNA base lesions are considered to be mainly repaired by 8-oxoguanine DNA glycosylase (OGG1) mediated pathways. We investigated the effect of the OGG1 Ser326Cys polymorphism on the level and repair of oxidatively damaged DNA in mononuclear blood cells (MNBC) by means of the comet assay. We collected blood samples from 1,019 healthy subjects and genotyped for the OGG1 Ser326Cys polymorphism. We found 49 subjects homozygous for the variant genotype (Cys/Cys) and selected same numbers of age-matched subjects with the heterozygous (Ser/Cys) and homozygous wild-type genotype (Ser/Ser). Carriers of the Cys/Cys genotype had higher levels of formamidopyrimidine DNA glycosylase (FPG) sensitive sites in MNBC (0.31 ± 0.03 lesions/106bp) compared to Ser/Ser (0.19 ± 0.02 lesions/106bp, P<0.01). The level of hOGG1 sensitive sites in MNBC from the Ser326Cys carriers (0.19 ± 0.16 lesions/106bp) was also higher compared to the Ser/Ser genotype (0.11 ± 0.09 lesions/106bp, P<0.05). Still, there was no genotype-related difference in DNA repair incision activity of MNBC extracts on nucleoids with oxidatively damaged DNA induced by Ro19-8022/white light (P=0.20). In addition, there were no differences in the expression of OGG1 (P=0.69), ERCC1 (P=0.62), MUTYH (P=0.85), NEIL1 (P=0.17) or NUDT1 (P=0.48) in whole blood. Our results indicate that the OGG1 Ser326Cys polymorphism has limited influence on the DNA repair incisions by extracts of MNBC, whereas the apparent increased risk of cancer in subjects with the Cys/Cys genotype may be because of higher levels of oxidatively damaged DNA.

The possible risk of cancer in patients with MS: a controversial issue

Sir, With great interest and pleasure, we have read the article by Ragonese et al. [1] and have some comments about the results obtained in this study. In brief, Ragonese and colleagues conducted a populationbased study to investigate the mortality risk in multiple sclerosis (MS) patients with MS. Concerning the Result section, they have claimed that the risk of cancer is significantly increased, nearly doubled, in MS. With all sincerity, we believe that the incidence of cancer amongst patients with MS might be circumstantial, irrelative of a possible interaction between these two diseases. To date, several studies have shown inconsistent results regarding the risk of cancer in MS, making this issue one of the most controversial in the pathophysiology of MS. Whilst some studies have shown no changes in the risk of cancer in patients with MS [2,3], others have declared a reduced risk of cancer in the individuals with MS compared with the normal population [4,5]. In an investigation by Nielsen et al. [6], sex-specific risk of cancer has been also observed: men with MS had a slightly significant risk of cancer, whereas no alteration in the cancer risk was observed in women with MS. To resolve this controversy, Ramagopolan et al. [7] performed a met-analysis on the populations from Norway [3], Sweden [4], France [5], Denmark [6] and UK [2]. By pooling the data derived form these studies, Ramagopolan et al. reported a small but significant reduction in the risk of all cancers amongst patients with MS but were unable to explain the mechanism underlying this reverse association [7]. In addition, by a survey on the individuals with MS registered at Kashani MS Centre in Isfahan province of Iran, we observed a decreased cancer risk in subjects with MS comparing with sexand age-matched controls (data have not been published yet). Regarding the observations by these studies, we therefore reason that the risk of cancer, including all types, is not only increased but also decreased in MS. Both the genetic and environmental factors might be the key players acting in this scenario because these two elements are the main explanations for the aetiology of cancer and MS. However, further studies on the reverse association of MS and cancer are needed to put an end to this controversy.

Alcohol-Folate Interactions in the Risk of Oral Cancer in Women: A Prospective Cohort Study

The aim of this cohort study was to quantify the effect of alcohol on the risk of oral cancer in different strata of folate intake, controlling for known confounders. A cohort of 87,621 women in the Nurses' Health Study was followed up from 1980 to 2006, and 147 incident oral cancer cases were reported and confirmed. Data on alcohol intake and diet were obtained through self-reported food frequency questionnaires every 4 years. Cox proportional regression analysis was conducted to estimate the adjusted risk ratios (RR) and 95% confidence intervals (95% CI). When compared with nondrinkers, the adjusted RRs (95% CIs) for alcohol intake were 0.59 (0.39-0.87) for 0.1-14.9 g/d, 1.15 (0.67-1.97) for 15-29.9 g/d, and 1.92 (1.08-3.40) for ≥30 g/d. We observed a significant interaction between alcohol and folate intakes (P = 0.02). The cancer risk for subjects with high alcohol (≥30 g/d) and low folate (<350 μg/d) intakes was significantly elevated (RR, 3.36; 95% CI, 1.57-7.20) as compared with nondrinkers with low folate intake. The risk associated with high alcohol intake (≥30 g/d) was reduced to 0.98 (0.35-2.70) in the high-folate (≥350 μg/d) group as compared with nondrinkers with high folate intake. High alcohol intake is associated with significantly increased oral cancer risk, especially in women with low folate intake. A significant interaction between alcohol and folate intakes seems to affect oral cancer risk in women, a finding with potential public health utility.

Quality of Life in GERD and Barrett's Esophagus Is Related to Gender and Manifestation of Disease

Gastroesophageal reflux disease (GERD) is a common condition that affects patients' health-related quality of life (HRQoL). The HRQoL of Barrett's esophagus (BE) has been less well studied. Furthermore, it is unknown to what extent BE patients suffer from psychological distress as a result of carrying a diagnosis of a premalignant condition. We sought to compare BE and GERD (stratified by erosive reflux disease (ERD) and non-erosive reflux disease (NERD)) with regard to HRQoL and psychological impact. In this single-center study of subjects presenting for elective upper endoscopy, consecutive patients with BE and GERD were enrolled. Participants completed questionnaires assessing generic HRQoL (medical outcomes study short form-36 (SF-36)), disease-specific HRQoL (gastrointestinal quality of life index (GIQLI)), a measure of psychological distress (the Revised Hopkins Symptom Checklist: SCL-90R), and a patient-centered assessment of the impact of disease severity (the GERD health-related quality of life measure (GERD HRQL)). Patients with BE had the lowest symptom severity compared with those suffering from NERD or ERD (GERD HRQL: 13.7 vs. 18 and 15.9, respectively, P<0.01). Those with BE also had better disease-specific quality of life compared with NERD or ERD patients (GIQLI: 137.2 vs. 124.3 and 131.0, respectively, P<0.001). After adjusting for potential confounding variables including symptom severity and gender, BE patients continued to demonstrate better disease-specific HRQoL, scoring 12.2 points higher on the GIQLI than NERD patients (95% confidence interval (CI) 5.1-19.3) and 16.3 points higher than ERD patients (95% CI 5.4-27.3), as well as better generic HRQoL, scoring 4.8 points higher on the SF-36 physical component summary than NERD patients (95% CI 0.8-8.8) and 7.1 points higher than ERD patients (95% CI 1.2-13.1). There were no significant differences between groups in psychological distress, as demonstrated by the SCL-90R global severity index, although BE patients scored lower on the somatization domain compared with NERD and ERD patients. When stratified by gender, females with NERD and BE had worse disease-specific HRQoL than males. Patients with BE have better generic and disease-specific HRQoL when compared with patients suffering from NERD and ERD. This difference is only partially attributable to lower symptom severity amongs BE patients. Psychological distress did not differ significantly amongs groups. Female gender was associated with worsened HRQoL regardless of GERD disease manifestation. Though more precise instruments may aid in detecting any HRQoL decrements in BE patients because of perceived cancer risk or fear of developing or dying from cancer, we were unable to demonstrate an additional decrement in HRQoL because of cancer risk in subjects with BE.

Cancer Risk and GSTM1 and GSTT1 Polymorphisms: Hansteen et al. Respond

We thank Cetta et al. for the interesting comments regarding our article (Rossi et al. 2009). In their letter they address two main issues. The first refers to the role of genetic polymorphisms in the causal relationships between exposure to carcinogens and cancer occurrence. The second is more conceptual and criticizes the evolution of association studies, claiming a decreased attention to pathogenetic mechanisms in favor of an indiscriminate increase of the study size, with a consequent lack of biological plausibility. We agree that these are important issues. We have addressed the problem of inherited predisposition for DNA damage from a different angle, namely using the frequency of chromosomal aberration (CA) as a response indicator for occupational and environmental exposure to genotoxic agents. An increase in CA level in exposed individuals compared with controls has been documented since the 1990s (Nordic Study Group 1990). The conceptual basis for using this assay has been the hypothesis that the extent of genetic damage in peripheral lymphocytes reflects critical events for the carcinogenic process in target tissues. The key issue—whether the association with cancer risk is attributable to exposure to carcinogenic agents or reflects inherited susceptibility and accumulated damages—was addressed with a nested case–control study on incident and deceased cancer cases in the Nordic and Italian cohorts (Bonassi et al. 2000). The main findings of that study indicated an increase in cancer risk for subjects with high CA levels compared with those with low levels. This increase was independent of exposure history, as further verified in follow-up studies (Bonassi et al. 2008; Hagmar et al. 2004). In all these studies, cancer has been studied as one entity. This summarization was mostly due to statistical needs, although the very early occurrence of chromosome damage in the carcinogenic pathway of most solid cancers provided a valuable rationale (Mitelman et al. 2004). A further reason for summarizing data by cancer type was that damages were measured in surrogate tissues and not in the target, providing only an indirect measure of cancer-related events. However, studying the cancer site in relation to CA frequency was a major interest of our group, because different types of cancers have different pathogenetic models. In our recent article (Rossi et al. 2009), we grouped cancer types into three groups, and we showed for all of these groups that subjects with high levels of CAs are more susceptible to developing cancer than are subjects with low or medium levels of CAs; this indicates that CA is an inherited susceptibility marker for cancer regardless of cancer type. The beginning of Cetta et al.’s letter is misleading. The statement from our article (Rossi et al. 2009) that “GSTM1 [gluta-thione S-transferase M1] and GSTT1 [gluta-thione S-transferase theta 1]polymorphisms [as all individual polymorphisms] . . . are not expected to have a dramatic influence on baseline CA [chromosomal aberration] or overall cancer risk” is not a conclusion of the study, but describes the conclusions of the extensive literature supporting this evidence (Hirschhorn 2009). We agree that it is important to examine the cause of different types of cancer and the role(s) of the different modifying enzymes, including GSTM1 and GSTT1. However, the present study was designed to evaluate a possible modifying effect of GSTM1 and GSTT1 on the cancer predictivity of CA (indicating individual susceptibility to developing cancer). Our main concern was identify individuals more susceptible to damage from known genotoxic exposure. Because only GSTM1 and GSTT1 polymorphisms have been extensively evaluated in human surveillance studies, we tested only these genotypes. Within the consortium of studies included in this project (Bonassi et al. 2008), further follow-up studies to differentiate cancer types or include other genotypes are possible, providing adequate financial support. The issue raised by Cetta et al. of decreased attention to pathogenetic mechanisms in favor of larger studies, with a consequent lack of biological plausibility, is only partially correct. Actually, in association studies that link a genetic polymorphism to the effect of exposure or to the risk of cancer, the lack of specificity is the main reason for failure. Another reason for their failure is small study size, which generates meaningless and often contrasting results. The conflict noted by Cetta et al. is apparent because, as demonstrated by the success of genome-wide association studies, the need of reaching a proper statistical power is as important as studying a genetic polymorphism in a specific pathway.