Molar pregnancy and childhood cancer: a population-based linkage study from Denmark

We observed a relative risk of 1.40 (95% confidence interval; 0.86-2.16) for cancers diagnosed under the age 20 in 6192 offspring of 3431 mothers with a molar pregnancy, indicating it is not a major determinant of childhood cancer.     

Dietary intake of folic acid and colorectal cancer risk in a cohort of women

Folate is crucial for normal DNA methylation, synthesis and repair, and deficiency of this nutrient is hypothesized to lead to cancer through disruption of these processes. There is some evidence to suggest that relatively high dietary folate intake might be associated with reduced colorectal cancer risk, especially among individuals with low methionine intake. A case-cohort analysis was undertaken within the cohort of 56,837 women who were enrolled in the Canadian National Breast Screening Study and who completed a self-administered dietary questionnaire. During follow-up to the end of 1993, a total of 389 women were diagnosed with colorectal cancer, identified by linkage to the Canadian Cancer Database. For comparative purposes, a subcohort of 5,681 women was randomly selected from the full dietary cohort at baseline. After exclusions for various reasons, the analyses were based on 295 cases and 5,334 non-cases. Folate intake was inversely associated with colorectal cancer risk (IRR = 0.6, 95% CI = 0.4-1.1, p for trend = 0.25). The inverse association was essentially similar among individuals with low and high methionine intake, and was similar for colon and rectal cancers when those endpoints were analyzed separately. Among individuals with low methionine intake, folate intake did not appear to lower the risk of rectal cancer, a finding that may be due, in part, to the low number of cases in the subgroup analysis. Overall, our data lend some support to the hypothesis that high folate intake is associated with a reduced risk of colorectal cancer.     

Birthweight, childhood growth and risk of breast cancer in a British cohort

We have examined the relationship between birthweight and risk of breast cancer, taking into account growth in childhood, using data on a total of 2221 women born in 1946 and followed up to 1997. Thirty-seven breast cancers occurred during follow-up. There was evidence of greater risk of breast cancer with greater birthweight (rate ratio = 1.76 (95% CI: 0.92, 3.35) for birthweight >/= 3.5 kg vs birthweight < 3.5 kg), which was more marked at pre-menopausal ages (RR = 2.31, 95% CI: 0.93, 5.74). The relation with birthweight was not substantially confounded by any of the measured adult risk factors. A significant interaction was observed between the effects of birthweight and height at age 7 years. Relative to those born lighter than 3.5 kg, women who were heavy at birth (>/= 3.5 kg) and short or average at 7 years (< 1.22 m) had a 21% increase in breast cancer rates (RR = 1.21; 95% CI = 0.49-2.99), while women who were heavy at birth (>/= 3.5 kg) but tall at 7 years (>/= 1.22 m) had a four-fold increase (RR = 4.01; 95% CI = 1.82-8.83). These results suggest that the effect of birthweight on breast cancer risk may be modulated by childhood growth.     

Effect of folic acid supplementation on cancer risk among adults with hypertension in China: A randomized clinical trial

The relationship of folic acid supplementation with the risk of cancer remains inconclusive. We aimed to evaluate the effects of folic acid supplementation on cancer incidence among adults with hypertension without history of stroke or myocardial infarction (MI) in the China Stroke Primary Prevention Trial (CSPPT). A total of 20,702 hypertensive adults without history of stroke or MI, stratified by MTHFR C677T genotypes(CC, CT and TT), were randomly assigned to receive double‐blind daily treatment with a single pill containing 10 mg enalapril and 0.8 mg folic acid(n = 10,348) or a pill containing 10 mg enalapril alone(n = 10,354). During a median treatment duration of 4.5 years, cancer occurred in 116 participants(1.12%) in the enalapril‐folic acid group versus 116 participants(1.12%) in the enalapril group (HR, 1.00; 95%CI, 0.77–1.29). There was also no significant difference in the HRs for specific types of cancer(esophageal, gastric, breast, lung, colorectal, head and neck, liver and gynecologic cancer or lymphoma) or cancer mortality(HR, 1.05; 95%CI, 0.69–1.58). For participants not receiving folic acid treatment (enalapril only group), MTHFR 677 TT genotype was an independent predictor of total cancer risk compared to CC genotype (HR, 1.86; 95%CI, 1.07–3.22). Consistently, a beneficial effect was observed in participants with MTHFR TT genotype and low folate levels (<9.0 ng/mL; HR, 0.47; 95%CI, 0.24–0.94). There is no evidence that 0.8 mg daily folic acid supplementation can increase the risk of cancer incidence among adults with hypertension without history of stroke or MI in China. Our data suggest a protective effect in participants with MTHFR TT genotype and low folate levels.     

Folic acid supplementation and cancer risk: A meta‐analysis of randomized controlled trials

There are growing data and a continuing controversy over the effect of folic acid supplementation on cancer risk. We conducted a meta‐analysis based on up‐to‐date published relevant randomized trials to further examine this issue. Relative risk (RR) was used to measure the effect of folic acid supplementation on risk of cancer using a random‐effects model. Overall, folic acid supplementation had no significant effect on total cancer incidence (13 trials, n = 49,406, RR = 1.05; 95% CI: 0.99–1.11, p = 0.13), colorectal cancer (seven trials, n = 33,824, 1.01; 0.82–1.23, p = 0.95), other gastrointestinal cancer (two trials, n = 20,228, 1.00; 0.75–1.33, p = 0.99), prostate cancer (five trials, n = 27,065, 1.17; 0.84–1.62, p = 0.35), other genitourinary cancer (two trials, n = 20,228, 0.97; 0.75–1.27, p = 0.84), lung cancer (five trials, n = 31,864, 1.00; 0.84–1.21, p = 0.97), breast cancer (four trials, n = 19,800, 0.82; 0.63–1.07, p = 0.15), hematological malignancy (three trials, n = 25,670, 0.87; 0.64–1.17, p = 0.35) and total cancer mortality (six trials, n = 31,930, 1.02; 0.90–1.15, p = 0.81). However, a significantly reduced risk was observed for melanoma (three trials, n = 19,128, 0.47; 0.23–0.94, p = 0.03). Furthermore, higher total cancer incidence risk was observed among those trials with a higher percent use of lipid‐lowering drugs (>60%, 1.10; 1.00–1.20, p = 0.04), or with lower percent baseline hypertension (≤70%, 1.08; 1.00–1.16, p = 0.057).Consistently, meta‐regression analyses suggested that the similar trend between percent use of lipid‐lowering drugs (p = 0.084) or percent baseline hypertension (p = 0.056) and log‐RR for total cancer incidence associated with folic acid supplementation. Our findings indicate that folic acid supplementation has no significant effect on total cancer incidence, colorectal cancer, prostate cancer, lung cancer, breast cancer or hematological malignancy, but reduces the risk of melanoma.     

Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake

BACKGROUND:

The incidence of unilateral retinoblastoma varies globally, suggesting possible environmental contributors to disease incidence. Maternal intake of naturally occurring folate from vegetables during pregnancy is associated inversely with the risk of retinoblastoma in offspring.

METHODS:

The authors used a case‐control study design to examine the association between retinoblastoma risk and maternal variations in the folate‐metabolizing genes methylenetetrahydrofolate reductase (MTHFR) (a cytosine‐to‐thymine substitution at nucleotide 677 [MTHFR677C→T]; reference single nucleotide polymorphism rs1801133) and dihydrofolate reductase (DHFR) (a 19‐base‐pair deletion of intron 1a [DHFR19bpdel]; rs70991108). In central Mexico, 103 mothers of children with newly diagnosed unilateral retinoblastoma were enrolled in an institutional review board‐approved study along with a control group of 97 mothers who had healthy children. Mothers were interviewed regarding perinatal characteristics, including use of prenatal vitamin supplements, and gave peripheral blood samples, which were used for polymerase chain reaction‐based genotyping of rs1801133 and rs70991108.

RESULTS:

The risk of having a child with unilateral retinoblastoma was associated with maternal homozygosity for DHFR19bpdel (odds ratio, 3.78; 95% confidence interval, 1.89‐7.55; P = .0002), even after controlling for the child's DHFR19bpdel genotype (odds ratio, 2.81; 95% confidence interval, 1.32‐5.99; P = .0073). In a subgroup of 167 mothers with data on prenatal intake of supplements containing folic acid (a synthetic form of folate), DHFR19bpdel‐associated risk was elevated significantly only among those who reported taking folic acid supplements. Maternal MTHFR genotype was unrelated to the risk of having a child with retinoblastoma.

CONCLUSIONS:

Maternal homozygosity for a polymorphism in the DHFR gene necessary for converting synthetic folic acid into biologic folate was associated with an increased risk for retinoblastoma. Prenatal ingestion of synthetic folic acid supplements may be associated with increased risk for early childhood carcinogenesis in a genetically susceptible subset of the population. Cancer 2012. © 2012 American Cancer Society.     

Plasma B-vitamin and one-carbon metabolites and risk of breast cancer before and after folic acid fortification in the United States

Prior epidemiologic findings for plasma folate and B-vitamins and breast cancer risk are inconsistent and have not assessed the influence of folic acid fortification. Therefore, we examined the associations of plasma folate, B₁₂, pyridoxal 5′-phosphate (PLP), homocysteine, cysteine and cysteinylglycine with breast cancer risk, before and after fortification. We conducted a nested case–control study within the prospective Nurses’ Health Study. In 1989–1990 (pre-fortification), 32,826 women donated a blood sample and 18,743 donated an additional blood sample in 2000–2001 (post-fortification). Between the first blood collection and 2006, 1874 incident breast cancer cases with at least one blood sample and 367 with two were 1:1 matched to controls. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) adjusting for breast cancer risk factors. Overall, higher plasma folate, B₁₂, PLP, homocysteine, cysteine and cysteinylglycine levels were not associated with breast cancer risk. Associations did not vary by in situ/invasive, hormone receptor status, or tumor molecular subtype. Additionally, associations were null before and after fortification. For example, the RR (95% CI) for the highest versus lowest tertile of 1990 (pre-fortification) plasma folate with 1990–2000 follow-up was 0.93 (0.75–1.16) and for the 2000 plasma folate (post-fortification) with 2000–2006 follow-up the RR (95% CI) was 1.17 (0.79–1.74). Plasma folate, B₁₂, PLP, homocysteine, cysteine and cysteinylglycine were not significantly associated with breast cancer overall, before and after fortification, or with specific tumor molecular subtypes. However, long term associations (>8 years) after the implementation of fortification could not be examined.     

Gender of offspring and long-term maternal breast cancer risk

Gender of offspring is influenced by maternal hormonal level during pregnancy, which is believed to influence the subsequent maternal breast cancer risk. However, analysing national birth and cancer registrations in a cohort of 998,499 women, we found no association between gender of offspring and subsequent breast cancer risk.     

Factors related to pregnancy and birth and the risk of childhood brain tumours: The ESTELLE and ESCALE studies (SFCE,France)

Little is known of the causes of childhood brain tumors (CBT). The aims of this study were to investigate whether extremes of birth weight were associated with increased risk of CBT and whether maternal preconceptional folic acid supplementation or breastfeeding reduced the risk. In addition, other maternal characteristics and birth related factors were also investigated. We pooled data from two French national population‐based case‐control studies with similar designs conducted in 2003–2004 and 2010–2011. The mothers of 510 CBT cases (directly recruited from the national childhood cancer register) and 3,102 controls aged under 15 years, frequency matched by age and gender did a telephone interview, which focussed on demographic and perinatal characteristics, and maternal life style habits and reproductive history. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusted for age, sex, study of origin and relevant confounders. No association was found between CBT and birth weight or fetal growth. The use of preconceptional folic acid supplementation was rare (5.3% in cases and 7.8% in controls) and the OR was 0.8 (95% CI 0.5, 1.4). There was no association with breastfeeding, even prolonged (six months or more; OR 1.0, 95% CI 0.8, 1.4). Neither was there any association between CBT and other investigated factors (maternal body mass index, gestational weight gain, congenital abnormality, maternal reproductive history or use of fertility treatments. Although large, this study was underpowered for subtype analyses. Pooling data with other population‐based studies may provide further insight into findings by CBT subtypes.     

Sex ratio among offspring of childhood cancer survivors treated with radiotherapy

It has been postulated that paternal gonadal exposure would increase the sex ratio by inducing X-chromosomal dominant lethals but that maternal gonadal exposure would decrease the sex ratio by inducing recessive sex-linked lethals. We therefore evaluated the sex ratio (male-to-female ratio) of children born to survivors of childhood cancers in Denmark. Children with cancer were identified from the Danish Cancer Registry from 1943 to 1996 and their offspring from the Central Population Registry. Radiation treatments were determined from records within the Cancer Registry and gonadal radiation exposures were estimated based on the cancer being treated and the likely proximity of the radiation fields to the gonads. Overall, 1100 survivors of childhood cancer became the parents of 2130 children. The sex ratio for male (0.99) and female (1.00) cancer survivors was similar and did not differ significantly from the Danish population (1.06). Radiotherapy did not influence the sex ratio of the children of either male or female survivors, and there was no evidence for dose-related changes over categories of estimated dose to parental gonads. We saw no consistent association between the sex ratio and the interval between cancer diagnosis of the parent and birth of the child. This nationwide study provides no support for the hypothesis that radiation exposure to the gonads results in an inherited genetic effect that would be manifested by a change in the sex ratio of children born after exposure. It may be, however, that sex ratio alterations are not a good or even a valid indicator of possible genetic effects in humans.     

叶酸及维生素B12与肿瘤治疗的关系及研究进展

叶酸和维生素B12是人体必需的维生素,参与人体细胞的增殖。叶酸和维生素B12因其对细胞增殖和甲基化的影响,在肿瘤发生与治疗的过程中发挥着一定作用。本文概述了其延缓肿瘤发生,作为特异性靶点识别和治疗肿瘤,增强现有化疗效果,改善化疗药物所致毒副反应等方面的研究进展。     

Estimated phytanic acid intake and prostate cancer risk: a prospective cohort study

Phytanic acid is a saturated fatty acid found predominantly in red meat and dairy products and may contribute to increases in prostate cancer risk that are observed with higher intakes of these foods. We constructed a novel summary measure of phytanic acid intake and prospectively examined its association with prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study--a cohort of Finnish male smokers aged 50-69 years. Diet was assessed at baseline in 27,111 participants using a validated 276-item dietary questionnaire. Since phytanic acid is not currently included in food composition tables, we used the published phytanic acid content of 151 major food items to estimate total daily intake. During up to 21 years of follow-up, a total of 1,929 incident prostate cancer cases (including 438 advanced cases) were identified. Higher phytanic acid intake, though unrelated to the risk of localized disease [relative risks (RR) and 95% confidence intervals (CI) for increasing quartiles of intake = 1.00 (ref), 0.83 (0.68-1.01), 0.76 (0.62-0.94) and 0.91 (0.74-1.13); p trend = 0.23], was associated with increased risks of advanced prostate cancer [RR and 95% CI = 1.00 (ref), 1.43 (1.09-1.89), 1.31 (0.99-1.75) and 1.38 (1.02-1.89); p trend = 0.06]. This association appeared to be driven predominantly by phytanic acid obtained from dairy products (particularly butter). Our study indicates that phytanic acid may contribute to previously observed associations between high-fat animal foods (particularly dairy products) and prostate cancer risk, although some caution is warranted as it may be acting as a surrogate marker of dairy fat.     

Phase II study of pemetrexed disodium (Alimta) administered with oral folic acid in patients with advanced gastric cancer.

BACKGROUND: The aim of this study was to assess the activity of pemetrexed in patients with advanced gastric cancer. PATIENTS AND METHODS: Thirty-eight eligible patients (median age 60 years) received pemetrexed 500 mg/m(2) every 3 weeks. Since toxicity was considerable in the first six patients, the protocol was amended to supplement subsequent patients with oral folic acid (5 mg/day on days -2 to +2 of every cycle). RESULTS: Among 36 stage IV patients evaluable for efficacy (six non-supplemented\30 supplemented), there were two complete and six partial responses. The response rate was 21% (95% confidence interval 8% to 32%) according to intention-to-treat analysis. All responding patients were in the supplemented group. The median duration of response was 4.6 months and the median survival was 7.8 months. Five of six non-supplemented patients (83%) developed grade 3/4 neutropenia; two (33%) unsupplemented patients discontinued; two (33%) patients died due to toxicity. In the supplemented group, 12 of 32 patients (37%) had grade 3/4 neutropenia. None of the supplemented patients discontinued treatment due to hematological toxicity. Severe non-hematological toxicities were infrequent. CONCLUSIONS: The activity of pemetrexed is promising in light of the tumor burden in these patients (all patients were stage IV and 39% had three or more organs involved). Toxicities were remarkably decreased with folic acid supplementation. Combination studies are warranted.     

不同剂量叶酸对宫颈癌SiHa细胞自噬小体形成的影响

目的:探讨不同剂量叶酸对宫颈癌SiHa细胞自噬小体形成的影响。方法:选取处于对数生长期的SiHa细胞,将其分为5组,分别应用不同浓度叶酸（0.1 μg/ml、1.0 μg/ml、10 μg/ml、100 μg/ml、1 000 μg/ml）干预72 h,记录干预后各组SiHa细胞自噬小体数量;采用qRT-PCR法测定不同浓度叶酸干预后宫颈癌SiHa细胞自噬蛋白中Beclin1、LC3及p62 mRNA表达情况;采用Western blot法测定不同浓度叶酸干预后宫颈癌SiHa细胞自噬蛋白中Beclin1、LC3和p62蛋白表达情况。结果:不同浓度叶酸干预后自噬小体数量比较,1 000 μg/ml组明显高于其他组（P<0.05）,其中0.1 μg/ml组数量最低,1.0 μg/ml组与10 μg/ml组比较差异无统计学意义（P>0.05）。qRT-PCR法测定结果显示,随干预叶酸浓度升高,宫颈癌SiHa细胞中自噬蛋白Beclin1、LC3的mRNA明显升高（P<0.05）;p62 mRNA表达水平随叶酸浓度升高而降低（P<0.05）。Western blot法测定结果显示,自噬蛋白Beclin1、LC3的蛋白表达水平随叶酸浓度增高而增高（P<0.05）,p62蛋白表达水平随叶酸浓度升高而下降（P<0.05）。结论:不同剂量叶酸对宫颈癌SiHa细胞自噬小体形成的抑制效果不同,剂量越低抑制效果越强,高剂量叶酸还有刺激宫颈癌SiHa细胞自噬小体形成的作用。     

Maternal smoking during pregnancy and risk of brain tumors in the offspring. A prospective study of 1.4 million Swedish births

Objective: Studies of the effect of maternal smoking during pregnancy on development of brain tumors in the offspring generally have found no increase in risk but most have mainly relied on retrospective exposure assessment. We conducted a prospective study on a large birth cohort in Sweden. Methods: Women giving birth during 1983–1997 were classified as smokers or non-smokers based on information ascertained at the first prenatal visit and recorded in the Swedish Birth Register. Follow-up of brain tumor incidence among offspring through 1997 was achieved by linkage with the Swedish Cancer Register. Hazard ratios were estimated using Cox proportional hazard regression, adjusting for demographic characteristics available in the Birth Register. Results: Brain tumors (n = 480) occurred at a rate of 4.5 cases per 100,000 person-years. Children of women who smoked during pregnancy had an increased incidence of brain tumors (hazard ratio = 1.24; 95% confidence interval: 1.01–1.53). The increase in risk was similar for benign and malignant tumors, and was most apparent for astrocytoma. The effect of smoking on the occurrence of brain tumors was seen most strongly among 2–4 year-old children. Conclusions: These results support a role for maternal smoking during pregnancy in the etiology of childhood brain tumors. Our findings should be confirmed in other prospective studies.     

Fetal growth and the risk of childhood CNS tumors and lymphomas in Western Australia

The etiology of childhood cancers is largely unknown, although the early age at diagnosis has led to particular interest in in utero and perinatal factors. Birth weight is the most frequently studied perinatal factor in relation to risk of childhood cancers, and results have been inconsistent. We investigated whether the risk of CNS tumors and lymphomas in children was associated with three measures of the appropriateness of intra-uterine growth: proportion of optimal birth weight (POBW), birth length (POBL) and weight for length (POWFL). A cohort of 576,633 infants born in Western Australia in 1980-2004 were followed from birth to diagnosis of a CNS tumor (n = 183) or lymphoma (n = 84) before age 15, death, or December 31, 2005, and analyzed with Cox regression. Overall, there was little evidence of any association between fetal growth and risk of CNS tumors, although risk of ependymoma/choroid plexus tumors was positively associated with POBL and negatively associated with POWFL. The risk of Hodgkin and Burkitt lymphoma increased with increasing fetal growth among boys only, whereas the increased risk observed with non-Hodgkin lymphoma was only in girls. These associations between fetal growth and disease risk were also observed among children not classified as high birth weight, suggesting that accelerated growth is more important than birth weight per se. Results were similar when cases were compared with their unaffected siblings, suggesting that the increased growth associated with cancer risk was not general to the family. The associations we observed are consistent with causal pathways involving fetal growth factors.