Risk Of Cancer In Offspring Research Articles

Maternal diabetes and risk of childhood cancer in the offspring.

An association between maternal diabetes, its medication and childhood cancer has not been previously explored in a registry-based setting. With a case-control design, we aimed to explore whether maternal diabetes is associated with an increased risk of childhood cancer in the offspring. Combining data from population-based registries, we analyzed a total of 2,029 cases, that is, persons with childhood cancer diagnosed under the age of 20 years between years 1996-2014 and a total of 10,103 matched population controls. The mothers of the cases/controls and their diagnoses of diabetes (DM) before/during pregnancy as well as their insulin/metformin prescriptions during pregnancy were identified. Conditional logistic regression modeling was used to analyze the risk of childhood cancer. The OR for childhood cancer among those exposed to any maternal diabetes was 1.32 (95% CI 1.14-1.54) compared to the offspring of the nondiabetic mothers. The effect of maternal diabetes on the risk of childhood cancer remained elevated even after adjusting for maternal age, parity and smoking. Our data suggest that maternal diabetes medication may reduce the risk for childhood cancer (adjusted OR 0.83, 95% CI 0.36-1.94), especially in gestational diabetes (adjusted OR 0.26, 95% CI 0.05-1.25), compared to the diabetic mothers without medication. The risk of childhood leukemia was significantly higher among children exposed to any maternal diabetes (OR 1.36, CI 1.04-1.77) compared to the unexposed. Maternal diabetes appears to be associated with an increased risk of childhood cancer in the offspring. The possible risk-reducing effect of an exposure to diabetes medication on offspring cancer risk warrants further investigation.

Abstract 646: Pre conception paternal DDT exposure and programming of metabolic dysfunction and breast cancer risk in offspring

Abstract Background: Breast cancer is the most common cancer in American women, being the second leading cause of cancer-related death in this group. Exposure to environmental chemicals, such as the pesticide DDT (dichlorodiphenyltrichloroethane), has been long suspected to be a contributing factor in the development of metabolic disease and breast cancer. For instance, early life (in utero and early childhood) exposure to DDT has been associated with increased breast cancer risk in women, and these findings are supported by animal studies. While maternal DDT exposure in pregnancy has been linked to metabolic syndrome and breast cancer risk in offspring, the effects of paternal DDT exposure in male germ-line reprogramming and phenotypes in their progeny has not been investigated. Here, we evaluated the effects of pre-conception paternal exposure to DDT on offspring’s metabolism and susceptibility of breast cancer, using a mouse model. Methods: Male mice were exposed to DDT (1.7mg/kg body weight) by oral gavage for two weeks. At the end of this period, DDT and control-vehicle (CO) were housed with female mice, with free access to a standard chow diet, for three days. Pregnancy onset was assessed by the presence of a vaginal plug. The weight and number of pups per litter were determined two days after birth. Pups were weaned from mothers at 21 days of age, fed a standard chow diet for the extent of the study and weighed weekly. Mammary tumors were induced by subcutaneous administration of 15mg of medroxyprogesterone to six-week-old female offspring, followed by oral administration of 1mg 7,12-dimethylbenz[a]anthracene once-a-week for 3 weeks. Results: Paternal DDT exposure reprogramed the sperm small non-coding RNA content. In line with that, DDT offspring had decreased birthweight (p=0.04) and weaning weight (p=0.01) compared to CO. Further, ancestral DDT exposure caused metabolic dysfunction in offspring (p<0.05) at 7 and 22 weeks of age. Further, female offspring of DDT exposed fathers showed alterations in mammary gland development with a non-significant increase in numbers of terminal end buds and lower rates of apoptosis. In line with that, our preliminary data suggest that ancestral paternal exposures to DDT increases breast cancer risk in offspring: Compared to CO, the DDT offspring presented a non-significant increase in mammary tumor incidence and shorter latency to first-tumor onset. In addition, tumor growth (volume) was significantly increased in DDT offspring compared to CO (p<0.01). In conclusion, our findings support a role for DDT exposure from the paternal lineage in metabolic dysfunction and increased breast cancer risk in their offspring. Citation Format: Raquel Santana Da Cruz, Hong Cao, Camille Castilho Fontelles, Apsra Nasir, M Idalia Cruz, Sonia de Assis. Pre conception paternal DDT exposure and programming of metabolic dysfunction and breast cancer risk in offspring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 646.

Paternal malnutrition programs breast cancer risk and tumor metabolism in offspring

BackgroundWhile many studies have shown that maternal factors in pregnancy affect the cancer risk for offspring, few studies have investigated the impact of paternal exposures on their progeny’s risk of this disease. Population studies generally show a U-shaped association between birthweight and breast cancer risk, with both high and low birthweight increasing the risk compared with average birthweight. Here, we investigated whether paternal malnutrition would modulate the birthweight and later breast cancer risk of daughters.MethodsMale mice were fed AIN93G-based diets containing either 17.7% (control) or 8.9% (low-protein (LP)) energy from protein from 3 to 10 weeks of age. Males on either group were mated to females raised on a control diet. Female offspring from control and LP fathers were treated with 7,12-dimethylbenz[a]anthracene (DMBA) to initiate mammary carcinogenesis. Mature sperm from fathers and mammary tissue and tumors from female offspring were used for epigenetic and other molecular analyses.ResultsWe found that paternal malnutrition reduces the birthweight of daughters and leads to epigenetic and metabolic reprogramming of their mammary tissue and tumors. Daughters of LP fathers have higher rates of mammary cancer, with tumors arising earlier and growing faster than in controls. The energy sensor, the AMP-activated protein kinase (AMPK) pathway, is suppressed in both mammary glands and tumors of LP daughters, with consequent activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, LP mammary tumors show altered amino-acid metabolism with increased glutamine utilization. These changes are linked to alterations in noncoding RNAs regulating those pathways in mammary glands and tumors. Importantly, we detect alterations in some of the same microRNAs/target genes found in our animal model in breast tumors of women from populations where low birthweight is prevalent.ConclusionsOur study suggests that ancestral paternal malnutrition plays a role in programming offspring cancer risk and phenotype by likely providing a metabolic advantage to cancer cells.

Abstract 2404: Paternal intake of an obesity-inducing diet before conception modulates the risk of pancreatic cancer in offspring in a mouse model

Abstract Pancreatic cancer is a mostly untreatable malignancy, with 5-year survival rates of about 5%. Life-style and dietary factors have been associated with pancreatic cancer risk. Particularly, the consumption of high-fat diets and obesity (and underlying metabolic dysfunction) have been linked to increased susceptibility to this cancer. Recent studies have shown that the paternal diet and life-style can have a significant influence on offspring’s health via epigenetic information transmitted in the germ-line. Paternal overweight before conception has been shown to increase offspring’s susceptibility of developing metabolic diseases and some types of cancer. Here, we evaluated the effects of paternal overweight in the susceptibility of pancreatic cancer in offspring using the P48Cre/+ /KrasG120/+ mouse model of pancreatic cancer. LSL-KrasG120/+ and P48Cre/+ male mice were fed either an obesity-inducing (OID) or control (CO) diet for 8 weeks from weaning to sexual maturity. After this period, OID-fed and CO-fed male mice were housed together with 7 week-old female mice, with free access to CO diet, for 3 days. Pregnant dams were kept on the CO diet during pregnancy and after giving birth. Pups were weaned from mothers at 21 days of age, fed a standard chow diet for the extent of the study and weighed weekly. The offspring of CO or OID fathers were used to study body weight, metabolic parameters and pancreatic cancer development. Fathers fed an OID gained significantly more weight (CO 15.7±1.0g; OID 19.7±1.3g, p=0.02) and had higher leptin levels (p=0.04), compare to CO group fathers. Body weight analyses of OID and CO offspring, showed gender-specific effects. While the OID female offspring had higher weight at birth (p=0.005) and at weaning (p=0.02), compare to CO group, no significant differences were observed between the CO and OID male offspring. Those gender-specific differences were also observed in metabolic parameters such GTT with the OID male, but not female, offspring showing impaired glucose tolerance (p=0.0004) compared to CO. While the monitoring period is still ongoing, 8-week old OID offspring present gender-specific differences in susceptibility to pancreatic cancer: Males OID offspring have higher number/area (481±25; 2.6±0.3) of pancreatic intraepithelial neoplasia (PanIn), compared to CO (359±61; 2.0±0.5). On the other hand, female OID offspring have similar levels of PanIn, but have higher incidence of PDACs compare to CO. In conclusion, an ancestral history of overweight through the paternal lineage may be associated with an increased susceptibility to pancreatic cancer development in adulthood. The mechanisms mediating this effect remain to be elucidated. Citation Format: Raquel Santana Da Cruz, Johan Clarke, Ali Baird, Hong Cao, Carlos Benitez, M. Idalia Cruz, Sonia De Assis. Paternal intake of an obesity-inducing diet before conception modulates the risk of pancreatic cancer in offspring in a mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2404. doi:10.1158/1538-7445.AM2017-2404

Gestational high-fat diet and bisphenol A exposure heightens mammary cancer risk.

In utero exposure to bisphenol A (BPA) increases mammary cancer susceptibility in offspring. High-fat diet is widely believed to be a risk factor of breast cancer. The objective of this study was to determine whether maternal exposure to BPA in addition to high-butterfat (HBF) intake during pregnancy further influences carcinogen-induced mammary cancer risk in offspring, and its dose–response curve. In this study, we found that gestational HBF intake in addition to a low-dose BPA (25 µg/kg BW/day) exposure increased mammary tumor incidence in a 50-day-of-age chemical carcinogen administration model and altered mammary gland morphology in offspring in a non-monotonic manner, while shortening tumor-free survival time compared with the HBF-alone group. In utero HBF and BPA exposure elicited differential effects at the gene level in PND21 mammary glands through DNA methylation, compared with HBF intake in the absence of BPA. Top HBF + BPA-dysregulated genes (ALDH1B1, ASTL, CA7, CPLX4, KCNV2, MAGEE2 and TUBA3E) are associated with poor overall survival in The Cancer Genomic Atlas (TCGA) human breast cancer cohort (n = 1082). Furthermore, the prognostic power of the identified genes was further enhanced in the survival analysis of Caucasian patients with estrogen receptor-positive tumors. In conclusion, concurrent HBF dietary and a low-dose BPA exposure during pregnancy increases mammary tumor incidence in offspring, accompanied by alterations in mammary gland development and gene expression, and possibly through epigenetic reprogramming.

Maternal pre-pregnancy and gestational diabetes, obesity, gestational weight gain, and risk of cancer in young children: a population-based study in California.

We aimed to examine the influence of pre-pregnancy diabetes, pre-pregnancy body mass index (BMI), gestational diabetes, and gestational weight gain on childhood cancer risk in offspring. We identified cancer cases (n=11,149) younger than age 6years at diagnosis from the California Cancer Registry registered between 1988 and 2013. Controls (n=270,147) were randomly sampled from California birth records, and frequency matched by year of birth to all childhood cancers during the study period. Exposure and covariate information were extracted from birth records. Unconditional logistic regression models were generated to assess the importance of pre-pregnancy diabetes, pre-pregnancy BMI, gestational diabetes, and gestational weight gain on childhood cancer risk. We observed increased risks of acute lymphoblastic leukemia and Wilms' tumor in children of mothers with pre-pregnancy diabetes [odds ratio (OR) 95% confidence interval (CI) 1.37 (1.11, 1.69); OR (95% CI) 1.45 (0.97, 2.18), respectively]. When born to mothers who were overweight prior to pregnancy (BMI 25-<30), children were at increased risk of leukemia [OR (95% CI) 1.27 (1.01, 1.59)]. Insufficient gestational weight gain increased the risk of acute myeloid leukemia [OR (95% CI) 1.50 (0.92, 2.42)] while excessive gestational weight gain increased the risk of astrocytomas [OR (95% CI) 1.56 (0.97, 2.50)]. No associations were found between gestational diabetes and childhood cancer risk in offspring. We estimated elevated risks of several childhood cancers in the offspring of mothers who had diabetes and were overweight prior to pregnancy, as well as mothers who gained insufficient or excessive weight. Since few studies have focused on these factors in relation to childhood cancer, replication of our findings in future studies is warranted.

Bias Explains Most of the Parent-of-Origin Effect on Breast Cancer Risk in BRCA1/2 Mutation Carriers

Paternal transmission of a BRCA mutation has been reported to increase the risk of breast cancer in offspring more than when the mutation is maternally inherited. As this effect might be caused by referral bias, the aim of this study was to assess the parent-of-origin effect of the BRCA1/2 mutation on the breast cancer lifetime risk, when adjusted for referral bias. A Dutch national cohort including 1,314 proven BRCA1/2 mutation carriers and covering 54,752 person years. Data were collected by family cancer clinics, via questionnaires and from the national Dutch Cancer Registry. The parent-of-origin effect was assessed using Cox regression analyses, both unadjusted and adjusted for referral bias. Referral bias was operationalized by number of relatives with cancer and by personal cancer history. The mutation was of paternal origin in 330 (42%, P < 0.001) BRCA1 and 222 (42%, P < 0.001) BRCA2 carriers. Paternal origin increased the risk of prevalent breast cancer for BRCA1 [HR, 1.54; 95% confidence interval (CI), 1.19-2.00] and BRCA2 carriers (HR, 1.40; 95% CI, 0.95-2.06). Adjusted for referral bias by several family history factors, these HRs ranged from 1.41 to 1.83 in BRCA1 carriers and 1.27 to 1.62 in BRCA2 carriers. Adjusted for referral bias by personal history, these HRs were 0.66 (95% CI, 0.25-1.71) and 1.14 (95% CI, 0.42-3.15), respectively. A parent-of-origin effect is present after correction for referral bias by family history, but correction for the personal cancer history made the effect disappear. There is no conclusive evidence regarding incorporating a BRCA1/2 parent-of-origin effect in breast cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 25(8); 1251-8. ©2016 AACR.

Paternal programming of breast cancer risk in daughters in a rat model: opposing effects of animal- and plant-based high-fat diets.

BackgroundAlthough males contribute half of the embryo’s genome, only recently has interest begun to be directed toward the potential impact of paternal experiences on the health of offspring. While there is evidence that paternal malnutrition may increase offspring susceptibility to metabolic diseases, the influence of paternal factors on a daughter’s breast cancer risk has been examined in few studies.MethodsMale Sprague-Dawley rats were fed, before and during puberty, either a lard-based (high in saturated fats) or a corn oil-based (high in n-6 polyunsaturated fats) high-fat diet (60 % of fat-derived energy). Control animals were fed an AIN-93G control diet (16 % of fat-derived energy). Their 50-day-old female offspring fed only a commercial diet were subjected to the classical model of mammary carcinogenesis based on 7,12-dimethylbenz[a]anthracene initiation, and mammary tumor development was evaluated. Sperm cells and mammary gland tissue were subjected to cellular and molecular analysis.ResultsCompared with female offspring of control diet-fed male rats, offspring of lard-fed male rats did not differ in tumor latency, growth, or multiplicity. However, female offspring of lard-fed male rats had increased elongation of the mammary epithelial tree, number of terminal end buds, and tumor incidence compared with both female offspring of control diet-fed and corn oil-fed male rats. Compared with female offspring of control diet-fed male rats, female offspring of corn oil-fed male rats showed decreased tumor growth but no difference regarding tumor incidence, latency, or multiplicity. Additionally, female offspring of corn oil-fed male rats had longer tumor latency as well as decreased tumor growth and multiplicity compared with female offspring of lard-fed male rats. Paternal consumption of animal- or plant-based high-fat diets elicited opposing effects, with lard rich in saturated fatty acids increasing breast cancer risk in offspring and corn oil rich in n-6 polyunsaturated fatty acids decreasing it. These effects could be linked to alterations in microRNA expression in fathers’ sperm and their daughters’ mammary glands, and to modifications in breast cancer-related protein expression in this tissue.ConclusionsOur findings highlight the importance of paternal nutrition in affecting future generations’ risk of developing breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0729-x) contains supplementary material, which is available to authorized users.

Young adult female cancer survivors’ concerns about genetic cancer risk in offspring.

121 Background: More than 362,000 female cancer survivors under 40 years old live in the US. Research consistently shows no increased cancer risk among offspring of cancer survivors in the absence of a hereditary cancer. Still survivors voice concerns over the health of future children. This analysis explores young adult female cancer survivors’ (YAFCS) perceptions of genetic cancer risk and related reproductive concerns. Methods: Eligible females were aged 18-35, at least one year post-treatment. Participants were recruited using social media posts from 17 young adult cancer advocacy groups and directed to an anonymous web-based survey that included the Reproductive Concerns after Cancer Scale (RCACS), with a 3-item “Concerns about Future Child Health” subscale. Results: 346 YAFCS completed the full survey, and based on logic-based branching, 192 respondents could have completed the RCACS: 177 (92%) completed the entire scale and 187 (97%) completed the child’s health subscale. Mean RCACS score was 58.5 (sd = 11.6; range 22-86); mean child’s health score was 11.3 (sd = 3.3; range 3-15), with a negative skew. At the item-level, 65% of the sample worried about passing along cancer risk to offspring; 71% worried about family health history affecting future children; and 60% were afraid their children would have a high chance of getting cancer. RCACS and child’s health subscale scores did not vary by age, race, education, income, or diagnosis. Further, mean scores did not vary between survivors of family cancer syndromes (breast, ovarian, colorectal) and those with other diagnoses (RCACS: t = 1.4, df = 175, p = .14; child’s health: t = 0.02, df = 185, p = .99). Conclusions: Despite studies showing minimal genetic cancer risk in offspring of survivors, many YAFCS have concerns about the health of future children. This may be related to mistaken beliefs that genetic mutations within tumor cells are transmissible or unawareness of availability of pre-implantation genetic diagnosis for embryo selection in those with transmissible genetic mutations. There is a need to educate patients about these issues to enable them to make family building choices based on accurate information about genetic risk.

Hyperemesis gravidarum and risk of cancer in offspring, a Scandinavian registry-based nested case-control study.

BackgroundHyperemesis gravidarum is a serious condition affecting 0.8–2.3 % of pregnant women and can be regarded as a restricted period of famine. Research concerning potential long-term consequences of the condition for the offspring, is limited, but lack of nutrition in-utero has been associated with chronic disease in adulthood, including some cancers. There is growing evidence that several forms of cancer may originate during fetal life. We conducted a large study linking the high-quality population-based medical birth- and cancer registries in Norway, Sweden and Denmark, to explore whether hyperemesis is associated with increased cancer risk in offspring.MethodsA registry-based nested case–control study. Twelve types of childhood cancer were selected; leukemia, lymphoma, cancer of the central nervous system, testis, bone, ovary, breast, adrenal and thyroid gland, nephroblastoma, hepatoblastoma and retinoblastoma. Conditional logistic regression models were applied to study associations between hyperemesis and risk of childhood cancer, both all types combined and separately. Cancer types with five or more exposed cases were stratified by age at diagnosis. All analysis were adjusted for maternal age, ethnicity and smoking, in addition to the offspring’s Apgar score, placental weight and birth weight. Relative risks with 95 % confidence intervals were calculated.ResultsIn total 14,805 cases and approximately ten controls matched on time, country of birth, sex and year of birth per case (147,709) were identified. None of the cancer types, analyzed combined or separately, revealed significant association with hyperemesis. When stratified according to age at diagnosis, we observed a RR 2.13 for lymphoma among adolescents aged 11–20 years ((95 % CI 1.14–3.99), after adjustment for maternal ethnicity and maternal age, RR 2.08 (95 % CI 1.11–3.90)). The finding was not apparent when a stricter level of statistical significance was applied.ConclusionsThe main finding of this paper is that hyperemesis does not seem to increase cancer risk in offspring. The positive association to lymphoma may be by chance and needs confirmation.

Abstract P6-07-02: Amplified DERE-mediated epigenetic repression in ERα-mediated breast tumorigenesis

Abstract Epidemiological studies reveal that maternal exposure to estrogenic chemicals during pregnancy results in higher risk of breast cancer in offspring. One of possible causal mechanisms is epigenetic reprogramming, but how estrogen/ERα signaling contributes to tumorigenesis through epigenetic machinery remains unclear. In this study, we demonstrate that the epigenetic modulation mediated by estrogen-driven amplification of distant-acting regulatory elements, or enhancers, may be an explanation addressing to this question. Enhancers contain transcription factor binding sites known to remotely regulate transcription through chromatin looping or transvection. Using our in vitro model to mimic maternal estrogen exposure and a "Seq-to-Seek" strategy integrating three next-generation sequencing approaches, we comprehensively mapped distant estrogen response elements (DEREs) that remotely control transcription of target genes through chromatin proximity. Surprisingly, a densely mapped DERE region located on chromosome 20q13 frequently amplifies in ERα-positive breast cancer with poor prognosis. Progressive accumulation of DERE copies was observed in normal breast progenitor and cancer cells chronically exposed to estrogen. Upon estrogen stimulation, these aberrantly amplified DEREs are clustered as a potential transcriptional depot for suppressing target gene expression through altering chromatin interactions, leading to accumulation of repressive histone marks (e.g. trimethylated H3K27 and H3K9), polycomb repressive complex 2, the presence of heterochromatin protein 1 (HP1) and DNA methylation, following prevention of RNA polymerase II and active histone mark- H3K4me3 binding. Furthermore, neutralization of HP1 function can significantly attenuate estrogen-driven DERE clustering and DERE-mediated repressive chromatin interactions, resulting in inhibition of cell proliferation. Deletion of the interested DERE regions using CRISPR/Cas9 genomic editing system further demonstrated that DERE-driven remote transcriptional control play a crucial role in tumor cell growth. Our data support a model in which amplified DEREs preferentially induce repressive epigenetic modulation of target genes. These findings indicate that 20q13 DERE region is a potential transcriptionally repressive domain whose aberrant amplification can result in suppressing expression of tumor suppressor genes, leading to tumorigenesis. In summary, our findings suggest that amplification of DNA regulatory elements can profoundly alter target transcriptome during tumorigenesis and amplified DEREs can be used as potential prognostic markers for endocrine resistance and predicative for progeny at risk of breast cancer. Citation Format: Pei-Yin Hsu, Hang-Kai Hsu, Yi-dong Chen, Victor X Jin, Zelton D Sharp, Tim H-M Huang. Amplified DERE-mediated epigenetic repression in ERα-mediated breast tumorigenesis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-07-02.

Protection of the gametes embryo/fetus from prenatal radiation exposure.

There is no convincing evidence of germline mutation manifest as heritable disease in the offspring of humans attributable to ionizing radiation, yet radiation clearly induces mutations in microbes and somatic cells of rodents and humans. Doses to the embryo estimated to be in the range of 0.15-0.2 Gy during the pre-implantation and pre-somite stages may increase the risk of embryonic loss. However, an increased risk of congenital malformations or growth retardation has not been observed in the surviving embryos. These results are primarily derived from mammalian animal studies and are referred to as the "all-or-none phenomenon." The tissue reaction effects of ionizing radiation (previously referred to as deterministic effects) are congenital malformations, mental retardation, decreased intelligence quotient, microcephaly, neurobehavioral effects, convulsive disorders, growth retardation (height and weight), and embryonic and fetal death (miscarriage, stillbirth). All these effects are consistent with having a threshold dose below which there is no increased risk. The risk of cancer in offspring that have been exposed to diagnostic x-ray procedures while in utero has been debated for 55 y. High doses to the embryo or fetus (e.g., >0.5 Gy) increase the risk of cancer. Most pregnant women exposed to x-ray procedures and other forms of ionizing radiation today received doses to the embryo or fetus <0.1 Gy. The risk of cancer in offspring exposed in utero at exposures <0.1 Gy is controversial and has not been fully resolved. Diagnostic imaging procedures using ionizing radiation that are clinically indicated for the pregnant patient and her fetus should be performed because the clinical benefits outweigh the potential oncogenic risks.

Environmental Contributions to Childhood Cancers

Recent increases in incidence of childhood cancers cannot be explained by genetic factors. Identifying the environmental risk factors that may explain increases in cancer incidence is an important step to reduce the overall burden of disease. The risk factors for which the most evidence exists include ionising radiation, ultraviolet radiation and chemicals such as benzene and pesticides, biological agents as well as parental smoking and parental substance use. Regarding the link between exposure to non-ionising radiation and development of cancer, the evidence was limited. Maternal vitamin supplementation may reduce the risk of cancer in offspring. Environmental exposures encountered during development and early childhood may be even more important contributors to the risk of cancer than exposures in adulthood and the early developmental period presents an important opportunity for cancer prevention.

Perinatal characteristics and bone cancer risk in offspring – a Scandinavian population-based study

Background. We investigated perinatal factors in relation to bone cancer subtypes, osteosarcoma (OS), Ewing Sarcoma (ES) and chondrosarcoma (CS).Materials and methods. All cases in Norway (1970–2009), Sweden (1974–2009) and Denmark (1980–2010) < 43 years were included (n = 914); 10 controls per case were selected from birth registries (which provided information on pregnancies) matched on birth country, sex and birth year (n = 9140). Unconditional logistic regression models including sex and birth year were used to compute relative risk (RR) and 95% confidence intervals (CI).Results. Higher maternal education was associated with a 40% increase in OS risk (95% CI 1–93%). The RR for OS was 3.22 (95% CI 1.37–7.59) comparing offspring of hypertensive mothers with those of mothers with a normotensive pregnancy, and Cesarean section was associated with a 29% risk reduction (95% CI 0–50%). When gestational age, birth weight and birth length were assessed simultaneously, there were no associations with any of the bone tumor subtypes.Conclusion. These results provided little evidence of an important role of pregnancy factors in the etiology of bone cancers. Higher maternal education may be associated with factors, possibly early nutrition or other correlates of socioeconomic status, that increase OS risk in offspring. The elevated OS risk associated with gestational hypertension and reduced risk associated with Cesarean section warrant replication.

Differential modulation of dibenzo[def,p]chrysene transplacental carcinogenesis: Maternal diets rich in indole-3-carbinol versus sulforaphane

Cruciferous vegetable components have been documented to exhibit anticancer properties. Targets of action span multiple mechanisms deregulated during cancer progression, ranging from altered carcinogen metabolism to the restoration of epigenetic machinery. Furthermore, the developing fetus is highly susceptible to changes in nutritional status and to environmental toxicants. Thus, we have exploited a mouse model of transplacental carcinogenesis to assess the impact of maternal dietary supplementation on cancer risk in offspring. In this study, transplacental and lactational exposure to a maternal dose of 15mg/Kg B.W. of dibenzo[def,p]chrysene (DBC) resulted in significant morbidity of offspring due to an aggressive T-cell lymphoblastic lymphoma. As in previous studies, indole-3-carbinol (I3C, feed to the dam at 100, 500 or 1000ppm), derived from cruciferous vegetables, dose-dependently reduced lung tumor multiplicity and also increased offspring survival. Brussels sprout and broccoli sprout powders, selected for their relative abundance of I3C and the bioactive component sulforaphane (SFN), respectively, surprisingly enhanced DBC-induced morbidity and tumorigenesis when incorporated into the maternal diet at 10% wt/wt. Purified SFN, incorporated in the maternal diet at 400ppm, also decreased the latency of DBC-dependent morbidity. Interestingly, I3C abrogated the effect of SFN when the two purified compounds were administered in equimolar combination (500ppm I3C and 600ppm SFN). SFN metabolites measured in the plasma of neonates positively correlated with exposure levels via the maternal diet but not with offspring mortality. These findings provide justification for further study of the safety and bioactivity of cruciferous vegetable phytochemicals at supplemental concentrations during the perinatal period.

Familial risk of early and late onset cancer: nationwide prospective cohort study

Objective To determine whether familial risk of cancer is limited to early onset cases.Design Nationwide prospective cohort study.Setting Nationwide Swedish Family-Cancer Database.Participants All Swedes born after 1931 and their biological...

Abstract 629: Childhood cancer incidence trends in association with folic acid fortification in the United States (1986-2008)

Abstract Folic acid plays a critical role in embryonic development and sufficient maternal prenatal folic acid consumption significantly reduces the incidence of congenital abnormalities in offspring. Epidemiological evidence supports the hypothesis that maternal prenatal folic acid supplementation lowers the risk of childhood cancer in offspring; however a systematic evaluation of population-based childhood cancer incidence trends following fortification of enriched grain products with folic acid in the U.S. in 1996-1998 has not been previously reported. Here we describe temporal trends in childhood cancer incidence in association with U.S. folic acid fortification. Using Surveillance, Epidemiology, and End Results program data (1986-2008) we calculated incidence rate ratios (IRRs) and 95% confidence intervals (CIs) to compare pre- and post-fortification incidence rates in children aged 0-4 years. Using joinpoint and loess regression models, we looked for inflection points during this period where the incidence trend changed in magnitude and/or direction. From 1986-2008, 8,829 children aged 0-4 years were diagnosed with malignancies, including 3,790 and 3,299 in utero during the pre- and post-fortification periods, respectively. Pre- and post-fortification incidence rates were similar for all cancers combined (IRR=1.01, 95% CI: 0.96-1.06) and for most specific cancer types examined. Rates of ependymomas (IRR=0.70, 95% CI: 0.51-0.97), primitive neuroectodermal tumors (PNETs) (IRR=0.56, 95% CI: 0.37-0.84) and Wilms tumor (WT) (IRR=0.80, 95% CI: 0.68-0.95) were significantly lower post-fortification. Notably, a greater reduction in post-fortification incidence was observed for the latter two subtypes upon restricting the analysis to infants, in whom any true effect of folic acid is expected to be greater. Joinpoint regression models detected increasing PNET incidence from 1986-1993 (annual percent change, APC=11.5, 95% CI: -5.0-31.0) followed by a sharp decrease from 1993-2008 (APC=−7.4%, 95% CI: -12.1- -2.4), and increasing WT incidence from 1986-1997 (APC=2.2, 95% CI: -1.2-5.8) followed by a sizable decline from 1997-2008 (APC=−4.0%, 95% CI: -7.3- -0.6). Loess curves indicated similar patterns. These results provide support for decreases in PNET and WT incidence, but not other childhood cancers, following U.S. folic acid fortification. Ten years of data are now available post-fortification and any substantial changes in childhood cancer rates attributable to fortification should be evident. Drawing firm conclusions regarding the isolated effects of folic acid is difficult, however, as other temporal trends occurred during the time period examined. Alternative study designs are required to rule out other explanations and confirm causal relationships. Supported by NIH Grants T32 CA099936 and K05 CA157439, and Children's Cancer Research Fund, Minneapolis, MN. A.M. Linabery and K.J. Johnson contributed equally to this work. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 629. doi:1538-7445.AM2012-629

Abstract 2625: Is familial risk of cancer limited to relatively early onset cases

Abstract Purpose: It is widely believed that familial cancers are of early onset. We aimed to find out whether familial risk of cancer is limited to relatively early onset cases. Methods and material: Standardized incidence ratios (SIR) were calculated for familial risk in offspring by parental age at diagnosis in the nation-wide Swedish Family-Cancer Database including all Swedes born after 1931 with their biological parents, totaling &amp;gt;12.2 million individuals and including &amp;gt;1.1 million first primary cancer cases. Results: Median parental age at diagnosis in those whose offspring were affected with a concordant cancer was somewhat over 70 years. Some 56-86% of familial cancers in parents occurred at age over 69 years. Even when parents were diagnosed at advanced age (90+), the risk of concordant cancer in offspring was significantly increased for skin (SIR=2.1), colorectal (1.7), breast (1.6), and prostate cancer (1.5). In offspring aged 60 to 76 years whose parents were affected with a concordant cancer, almost none of the cases had a parent affected at &amp;lt;40 years. Conclusion: Despite the common believe that familial cancers are of early onset, the majority of familial cancers occur at advanced ages. Familial cancers may not be early onset in those whose probands were affected at advanced ages, which may suggest concordance of age of onset in familial cancers. We identified reliable familial risks for skin, colorectal, breast, and prostate cancer even when parents were diagnosed at age 90+. The present study provides novel information, important for clinical counseling, cancer genetics and screening guidance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2625. doi:1538-7445.AM2012-2625

Maternal one-carbon nutrient intake and cancer risk in offspring

Dietary intake of one-carbon nutrients, particularly folate, vitamin B(2) (riboflavin), vitamin B(6) , vitamin B(12) , and choline have been linked to the risk of cancers of the colon and breast in both human and animal studies. More recently, experimental and epidemiological data have emerged to suggest that maternal intake of these nutrients during gestation may also have an impact on the risk of cancer in offspring later in life. Given the plasticity of DNA methylation in the developing embryo and the established role of one-carbon metabolism in supporting biological methylation reactions, it is plausible that alterations in maternal one-carbon nutrient availability might induce subtle epigenetic changes in the developing embryo and fetus that persist into later life, altering the risk of tumorigenesis throughout the lifespan. This review summarizes the current literature on maternal one-carbon nutrient intake and offspring cancer risk, with an emphasis on cancers of the colon and breast, and discusses specific epigenetic modifications that may play a role in their pathogenesis.

Mothers’ pre-pregnancy BMI and weight gain during pregnancy and risk of breast cancer in daughters

Previous studies have established that higher birthweight is associated with increased risk of breast cancer. However, the mechanisms underlying this association remain unclear. We explored whether maternal pregnancy weight gain and pre-pregnancy body mass index (BMI), which influence birthweight, are associated with risk of breast cancer in offspring. The Nurses' Mothers case-control study of breast cancer was nested in the Nurses' Health Study I and II cohorts. Mothers of 814 nurses with and 1,809 nurses without breast cancer completed questionnaires with information on pre-pregnancy height and weight, pregnancy weight gain, and other aspects of their pregnancies with the nurse daughters. We calculated odds ratios for breast cancer using conditional logistic regression. Mean pregnancy weight gain was 23 lb, and average pre-pregnancy BMI was 21 kg/m². Mothers' weight gain during pregnancy was not associated with the daughters' risk of breast cancer. Compared to women whose mothers gained 20-29 lb, women whose mothers gained less than 10 lb had a relative risk of 0.92 (95% confidence interval [CI]: 0.62-1.36), adjusting for the age of the nurses. Women whose mothers gained 40 or more pounds had a relative risk of 0.82 (95% CI: 0.55-1.23). Mothers' pre-pregnancy BMI was not associated with the daughters' risk of breast cancer. Women whose mothers had a pre-pregnancy BMI of 30 or more had a relative risk of 0.77 (95% CI: 0.34-1.74) compared to those with BMI less than 20. Additional adjustment for prenatal factors or for nurses' characteristics later in life had no effect on the results. The association between birthweight and breast cancer risk is likely due to factors independent of mothers' weight gain during pregnancy or pre-pregnancy BMI. Because BMIs and pregnancy weight gains were lower in this population than today, we cannot rule out associations for very high pre-pregnancy BMIs or pregnancy weight gains.