Treatment of first primary neoplasms (PN) in childhood with radiotherapy or chemotherapy is an established risk factor for second primary neoplasms (SN). In addition, there is growing evidence for this association from observational studies on ionizing radiation and cancer risk, in particular after radiation exposure in childhood. As only a subgroup of the treated children suffers from SN, other risk modifying factors (e.g. genetics) must be involved. We are conducting a case-control study with 600 anticipated participants to evaluate gene-radiation interactions and risk of SN (leukemia, thyroid or skin cancer) as well as PN (leukemia, lymphoma or CNS) with a new epidemiological design, in which we combine observational with experimental elements by analyzing gene expression in irradiated cultured human fibroblasts from skin biopsies. In a first step, we examine the participation proportions of survivors of childhood cancer with and without a SN and cancer free control patients (CO) from the department of accident surgery and orthopaedics. In addition to a skin biopsy of 3 mm and a saliva sample, we collect detailed questionnaire information on lifetime exposure to medical radiation and chemotherapy, socio-demographic factors, smoking, drinking, physical activity, medical history and family history of cancer and other diseases. Cases and controls will be matched by sex and age (1:1), and additionally among the former childhood cancer patients by type of the PN and year of first diagnosis (1 SN:3 PN). In explorative pilot experiments, we estimate gene expression differences by RNA-Seq in fibroblasts after low (0.05 Gy) and high (2 Gy) radiation doses at different time points (0.25 h, 2 h, 24 h). In the first recruitment drives of the ongoing study, we recruited 77 patients with SN and 95 matched patients with only one PN from 1975 eligible former childhood cancer patients at the German Childhood Cancer Registry, as well as 22 CO patients. Until November 2016, 33% of the contacted 231 SN patients, 20% of the 486 contacted PN patients and 69% of the 32 contacted CO patients participated in our study. Two hours after low and high in vitro radiation doses, the largest number of genes were differentially expressed, some of them only after high doses, some only after low doses and some after both. To our knowledge, the KIKME study is the first epidemiological project analyzing differential gene expression in primary fibroblasts before and after radiation with high and low doses to evaluate the potential genetic basis for emergence of a SN and a PN. However, the biological importance of the suggested differential gene expression after high and low doses of radiation has to be confirmed with the full study population. In addition, the gene expression must be analyzed in detail by group (SN, PN, CO) and will be combined with results from whole genome sequencing in order to obtain a comprehensive view of the role of radiation in the carcinogenesis of childhood cancer. Citation Format: Manuela Marron, Sebastian Zahnreich, Olesja Sinizyn, Heinz Schmidberger, Moritz Hess, Patricia Sadre Dadras, Iris Altebockwinkel, Thomas Hankeln, Steffen Rapp, Anne Ebersberger, Christian Grad, Eva Holzhäuser, Lukas Eckhard, Dirk Proschek, Maria Blettner, Peter Kaatsch, Claudia Spix, Danuta Galetzka, Harald Binder. Cancer in childhood and molecular epidemiology - The KIKME case-control study [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 4261. doi:10.1158/1538-7445.AM2017-4261
Despite the fact that cervical cancer is one of the leading causes of death in women worldwide, research has yet to elucidate why some HPV-infected women develop cancerous lesions while others are able to clear the infection. Previous studies have shown that HPV integration status may be associated with cervical cancer development, and yet, host genetic factors that may be involved in the viral integration process have not yet been identified. The purpose of this study was to examine the association between both HPV 18 viral integration status and single nucleotide polymorphisms (SNPs) in non-homologous end-joining (NHEJ) DNA repair pathway genes on cervical dysplasia. Specifically, we sought to compare women with no dysplasia to those with low-grade or high-grade squamous intraepithelial lesions. METHODS: A total of 765 women were selected from two large trials designed to evaluate optical technologies for cervical cancer. Genotyping was performed using the Illumina Golden Gate platform. HPV 18 integration status was determined using a previously established protocol. Chi-square tests were conducted to determine which SNPs were associated with normal cytology, low-grade, or high-grade lesions. Among participants with cervical dysplasia, polytomous logistic regression models were used to evaluate the effect of each polymorphism on viral integration status. An additive genetic model was used for all tests. P-values were adjusted using the false discovery rate method. RESULTS: Women with high-grade lesions were significantly younger than women with low-grade or no lesions. Tag-SNPs in 13 DNA repair genes, including MRE11A, ATM, and XRCC4, were significantly associated with cervical dysplasia. Most participants had a mix of both episomal and integrated HPV 18. Tag-SNPs in the XRCC4, PRKCH, and MRE11A genes were found to be significantly associated with HPV 18 integration status. CONCLUSION: Our study indicates that host genetic variation in NHEJ DNA repair pathway genes, including MRE11A and XRCC4, are significantly associated with HPV 18 integration, and that these genes may play a key role in determining cervical cancer development and progression. This is the first study to examine host genetic variation in association with the viral integration event. Predictors of Cancer Survivors' Receptivity to Lifestyle Behavior Change InterventionsBasen-Engquist K, Carmack C, Blalock J, Baum G, Rahming W, Demark-Wahnefried W Purpose: To assess cancer survivors' interest in lifestyle behavior change interventions, and to identify predictors of interest.Methods: Mailed surveys were sent to a stratified random sample of breast, colorectal, and prostate cancer survivors ascertained from the MD Anderson tumor registry and departmental databases. Surveys queried survivors about their diet, exercise, and smoking behaviors; symptoms; and their interest in interventions.Results: Surveys were received from 1053 cancer survivors. Roughly half of the sample were very/extremely interested in programs to help them get in shape (45%), e...
Treatment of the primary neoplasm with radiotherapy or chemotherapy is an established risk factor for second neoplasms (SNs) after childhood cancer. As only a small percentage of the treated children suffer from SN, other shared risk factors must be involved. A predisposition for the occurrence of a SN might be a pre-existing somatic genetic defect associated with DNA repair. We investigated the association between gene expression involved in DNA-repair and the development of SNs after childhood cancer. Designed as a feasibility study this project addressed the possibility of obtaining samples for genetic analyses from former patients through the German Childhood Cancer Registry. We recruited 20 patients with two neoplasms (the first occurring in childhood) and 20 matched patients with one neoplasm in childhood. Matching was by first neoplasm, age and year of first diagnosis. Registered SN were confirmed to be no relapses or alternative manifestations of the primary neoplasm. Participants were not given financial rewards (except travel expense compensation). Genetic counselling was offered independently of consent to skin biopsy. We compared the DNA repair gene expression in cultivated untreated primary fibroblasts of both patients groups using customized cDNA microarrays (800 genes). For each sample of each subject, trimmed means of the log-ratios were calculated for comparison between the matched samples with paired sample t-tests, regarding the normalized gene expression values (print-tip loess with variance stabilization normalization and quantile normalization with the R package Arraymagic). We used false discovery rate control by explorative Simes procedure to account for multiple testing. Additionally, we used hierarchical cluster analysis (complete linkage and two way clustering) to analyse whether subjects group into the two groups using the 40 sequences with lowest p-values in the paired-sample t-tests. We validated the results for five selected genes by real-time PCR. Overall, 46% of the 52 contacted SN and 18 % of the 132 single neoplasm patients participated in the study. The DNA-repair gene results showed small differences in the basal gene expression of FTH1 and CDKN1A. As the study subjects were very heterogeneous regarding their first and second neoplasms, we performed two subgroup analyses in the most common groups: Subjects with lymphoid leukaemia as a fist neoplasm (n=10) and subjects with thyroid carcinoma as second neoplasm (n=6). FTH1 displayed a small p-value in both subgroups, CDKN1A in the lymphoid leukaemia sample only. To our knowledge, this is the first study using gene expression arrays in untreated primary fibroblasts regarding second neoplasms after a childhood neoplasm. We were able to recruit childhood cancer patients for genetic analyses long after diagnosis. The biological importance of the differences in the DNA-repair gene expression has to be elucidated yet. 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 5504. doi:1538-7445.AM2012-5504
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