CCDC26, CDKN2BAS, RTEL1 and TERT Polymorphisms in pediatric brain tumor susceptibility

The role of genetic polymorphisms in pediatric brain tumor (PBT) etiology is poorly understood. In this study, we tested the hypothesis that single nucleotide polymorphisms identified by genome-wide association studies on adult glioma are also associated with PBT ris

CCDC26, CDKN2BAS, RTEL1 and TERT Polymorphisms in pediatric brain tumor susceptibility

The role of genetic polymorphisms in pediatric brain tumor (PBT) etiology is poorly understood. In this study, we tested the hypothesis that single nucleotide polymorphisms identified by genome-wide association studies on adult glioma are also associated with PBT ris

Role of Tobacco Use in the Etiology of Acoustic Neuroma

Two previous studies suggest that cigarette smoking reduces acoustic neuroma risk; however, an association between use of snuff tobacco and acoustic neuroma has not been investigated previously. The authors conducted a case-control study in Sweden from 2002 to 2007, in which 451 cases and 710 population-based controls completed questionnaires. Cases and controls were matched on gender, region, and age within 5 years. The authors estimated odds ratios using conditional logistic regression analyses, adjusted for education and tobacco use (snuff use in the smoking analysis and smoking in the snuff analysis). The risk of acoustic neuroma was greatly reduced in male current smokers (odds ratio (OR) = 0.41, 95% confidence interval (CI): 0.23, 0.74) and moderately reduced in female current smokers (OR = 0.70, 95% CI: 0.40, 1.23). In contrast, current snuff use among males was not associated with risk of acoustic neuroma (OR = 0.94, 95% CI: 0.57, 1.55). The authors’ findings are consistent with previous reports of lower acoustic neuroma risk among current cigarette smokers than among never smokers. The absence of an association between snuff use and acoustic neuroma suggests that some constituent of tobacco smoke other than nicotine may confer protection against acoustic neuroma

Mobile Phone Use and Brain Tumors in Children and Adolescents: A Multicenter Case-Control Study

Background It has been hypothesized that children and adolescents might be more vulnerable to possible health effects from mobile phone exposure than adults. We investigated whether mobile phone use is associated with brain tumor risk among children and adolescents. Methods CEFALO is a multicenter case-control study conducted in Denmark, Sweden, Norway, and Switzerland that includes all children and adolescents aged 7-19 years who were diagnosed with a brain tumor between 2004 and 2008. We conducted interviews, in person, with 352 case patients (participation rate: 83%) and 646 control subjects (participation rate: 71%) and their parents. Control subjects were randomly selected from population registries and matched by age, sex, and geographical region. We asked about mobile phone use and included mobile phone operator records when available. Odds ratios (ORs) for brain tumor risk and 95% confidence intervals (CIs) were calculated using conditional logistic regression models. Results Regular users of mobile phones were not statistically significantly more likely to have been diagnosed with brain tumors compared with nonusers (OR = 1.36; 95% CI = 0.92 to 2.02). Children who started to use mobile phones at least 5 years ago were not at increased risk compared with those who had never regularly used mobile phones (OR = 1.26, 95% CI = 0.70 to 2.28). In a subset of study participants for whom operator recorded data were available, brain tumor risk was related to the time elapsed since the mobile phone subscription was started but not to amount of use. No increased risk of brain tumors was observed for brain areas receiving the highest amount of exposure. Conclusion The absence of an exposure-response relationship either in terms of the amount of mobile phone use or by localization of the brain tumor argues against a causal associatio

Structural and functional basis of mammalian microRNA biogenesis by Dicer

MicroRNA (miRNA) and RNA interference (RNAi) pathways rely on small RNAs produced by Dicer endonucleases. Mammalian Dicer primarily supports the essential gene-regulating miRNA pathway, but how it is specifically adapted to miRNA biogenesis is unknown. We show that the adaptation entails a unique structural role of Dicer’s DExD/H helicase domain. Although mice tolerate loss of its putative ATPase function, the complete absence of the domain is lethal because it assures high-fidelity miRNA biogenesis. Structures of murine Dicer⋅miRNA precursor complexes revealed that the DExD/H domain has a helicase-unrelated structural function. It locks Dicer in a closed state, which facilitates miRNA precursor selection. Transition to a cleavage-competent open state is stimulated by Dicer-binding protein TARBP2. Absence of the DExD/H domain or its mutations unlocks the closed state, reduces substrate selectivity, and activates RNAi. Thus, the DExD/H domain structurally contributes to mammalian miRNA biogenesis and underlies mechanistical partitioning of miRNA and RNAi pathways

Common genetic variations in cell cycle and DNA repair pathways associated with pediatric brain tumor susceptibility.

Knowledge on the role of genetic polymorphisms in the etiology of pediatric brain tumors (PBTs) is limited. Therefore, we investigated the association between single nucleotide polymorphisms (SNPs), identified by candidate gene-association studies on adult brain tumors, and PBT risk.The study is based on the largest series of PBT cases to date. Saliva DNA from 245 cases and 489 controls, aged 7-19 years at diagnosis/reference date, was genotyped for 68 SNPs. Data were analyzed using unconditional logistic regression.The results showed EGFRrs730437 and EGFRrs11506105 may decrease susceptibility to PBTs, whereas ERCC1rs3212986 may increase risk of these tumors. Moreover, stratified analyses indicated CHAF1Ars243341, CHAF1Ars2992, and XRCC1rs25487 were associated with a decreased risk of astrocytoma subtype. Furthermore, an increased risk of non-astrocytoma subtype associated with EGFRrs9642393, EME1rs12450550, ATMrs170548, and GLTSCRrs1035938 as well as a decreased risk of this subtype associated with XRCC4rs7721416 and XRCC4rs2662242 were detected.This study indicates SNPs in EGFR, ERCC1, CHAF1A, XRCC1, EME1, ATM, GLTSCR1, and XRCC4 may be associated with the risk of PBTs. Therefore, cell cycle and DNA repair pathways variations associated with susceptibility to adult brain tumors also seem to be associated with PBT risk, suggesting pediatric and adult brain tumors might share similar etiological pathways

The risk of second primary lung carcinoma in breast cancer patients

The overall aim of this thesis was to investigate the risk of second primary malignancies - with a special focus on lung cancer - in a cohort of approximately 152,000 Swedish women diagnosed with breast cancer between 1958 and 2000. With recent advances in early diagnosis and treatment, breast cancer is becoming an increasingly survivable disease. Women with breast cancer normally receive post surgical adjuvant therapy, either as radio-, chemo-, or hormonal therapy, or as a combination of any of those modalities. Adjuvant radiotherapy reduces the risk of local recurrence, and its use is increasing as more women today choose partial mastectomies as their surgical choice. However one of the growing concerns is the chronic or late-occurring complications to the normal tissue from treatment of primary malignancies, among them therapy-related second primary cancer. We found a statistically significant increased risk of second primary lung cancers more than 5 years after breast cancer diagnosis. The highest risk of a second primary lung cancer was observed among women <50 years of age at the time of breast cancer diagnosis. The risk of lung cancer increased with time between breast cancer diagnosis and the diagnosis of second primary lung cancer, independently of the age at breast cancer diagnosis. In addition, the risk of lung cancer increased with birth year cohort, which mirrors the increasing smoking prevalence seen among women in Sweden. The completeness and quality of the information on tobacco use is most important when studying the risk of lung cancer. We contacted next-of-kin and living patients by mailed questionnaire to validate the quality of smoking information of the studied patients given in patient records. The total response rates were 89% and 93% for next-of-kin and living patients respectively. When information about overall smoking history from patient records and next-ofkin was compared, an almost perfect agreement was found (kappa=0.83), and similar result was found for living patients (kappa=0.86). Our results demonstrated that next-of-kin data are reliable and that the time between patient death and contact with next-of-kin did riot affect the response rate nor the agreement. Patient records and radiotherapy charts were abstracted for detailed information about treatment for 182 cases. Information about smoking history was identified in patient records or retrieved from nextof-kin. Our results demonstrated that in women treated with radiotherapy the risk of lung cancer increased after a follow-up time of more (ban 15 years. This risk was mostly confined to squamous cell carcinomas. In addition, the increased risk was restricted to women who smoked at the time of radiotherapy. Notably, non smoking women who received radiotherapy were not found to have an increased risk of lung cancer. The estimated excess relative risk for women with follow-up time >10 years after radiotherapy for breast cancer was 0.11 per gray. Women previously diagnosed with breast cancer have a 20% increased risk of a second primary malignancy except breast cancer. The overall risk for second primary malignancy did not vary by follow-up period, but large differences were noted between individual cancer sites, probably reflecting different etiologies. Women with a breast cancer diagnosis before the age of 50 years and women with a family history of breast cancer had elevated risks of developing a number of second primary cancers indicating a genetic predisposition to develop multiple tumours and/or susceptibility to the carcinogenic effect of breast cancer therapy. In conclusion, we have been able to establish an association between radiotherapy, smoking and risk of second primary lung cancer. We have shown that next-of-kin can provide reliable information on lifetime smoking status and should be considered as a valuable resource in studies where information on tobacco use is missing. We confirmed that women diagnosed with breast cancer have increased risks of most second primary malignancies. Finally, we showed that family history of breast cancer as well as young age at the time of breast cancer diagnosis increases these risks

Bones, Glands, Ears and More: The Multiple Roles of FGF10 in Craniofacial Development.

Members of the fibroblast growth factor (FGF) family have myriad functions during development of both non-vertebrate and vertebrate organisms. One of these family members, FGF10, is largely expressed in mesenchymal tissues and is essential for postnatal life because of its critical role in development of the craniofacial complex, as well as in lung branching. Here, we review the function of FGF10 in morphogenesis of craniofacial organs. Genetic mouse models have demonstrated that the dysregulation or absence of FGF10 function affects the process of palate closure, and FGF10 is also required for development of salivary and lacrimal glands, the inner ear, eye lids, tongue taste papillae, teeth, and skull bones. Importantly, mutations within the FGF10 locus have been described in connection with craniofacial malformations in humans. A detailed understanding of craniofacial defects caused by dysregulation of FGF10 and the precise mechanisms that underlie them offers new opportunities for development of medical treatments for patients with birth defects and for regenerative approaches for cancer patients with damaged gland tissues

Expression of FGFs during early mouse tongue development

The fibroblast growth factors (FGFs) constitute one of the largest growth factor families, and several ligands and receptors in this family are known to play critical roles during tongue development. In order to provide a comprehensive foundation for research into the role of FGFs during the process of tongue formation, we measured the transcript levels by quantitative PCR and mapped the expression patterns by in situ hybridization of all 22 Fgfs during mouse tongue development between embryonic days (E) 11.5 and E14.5. During this period, Fgf5, Fgf6, Fgf7, Fgf9, Fgf10, Fgf13, Fgf15, Fgf16 and Fgf18 could all be detected with various intensities in the mesenchyme, whereas Fgf1 and Fgf2 were expressed in both the epithelium and the mesenchyme. Our results indicate that FGF signaling regulates tongue development at multiple stages