The use of next generation sequencing technology to study the effect of radiation therapy on mitochondrial DNA mutation

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• 作者：Yan Guo^a ; ¹ ; Qiuyin Cai^c ; ¹ ; David C. Samuels^e ; Fei Ye^a ; Jirong Long^c ; Chung-I. Li^a ; Jeanette F. Winther^f ; E. Janet Tawn^g ; Marilyn Stovall^h ; Pä ; ivi Lä ; hteenmä ; kiⁱ ; Nea Malila^j ; Shawn Levy^d ; Christian Shaffer^e ; Yu Shyr^a ; Xiao-ou Shu^c ; John D. Boice Jr.^b ; ^c ; ^{john.boice@gmail.com}
• 关键词：Mitochondrial ; Heteroplasmy mutation ; Cancer ; Radiation
• 刊名：Mutation Research/Genetic Toxicology and Environmental Mutagenesis
• 出版年：2012
• 期刊代码：31_13835718
• 类别：pha
• 出版时间：15 May, 2012
• 卷：744
• 期：2
• 页码：154-160
• 文件大小：462 K

摘要

The human mitochondrial genome has an exclusively maternal mode of inheritance. Mitochondrial DNA (mtDNA) is particularly vulnerable to environmental insults due in part to an underdeveloped DNA repair system, limited to base excision and homologous recombination repair. Radiation exposure to the ovaries may cause mtDNA mutations in oocytes, which may in turn be transmitted to offspring. We hypothesized that the children of female cancer survivors who received radiation therapy may have an increased rate of mtDNA heteroplasmy mutations, which conceivably could increase their risk of developing cancer and other diseases. We evaluated 44 DNA blood samples from 17 Danish and 1 Finnish families (18 mothers and 26 children). All mothers had been treated for cancer as children and radiation doses to their ovaries were determined based on medical records and computational models. DNA samples were sequenced for the entire mitochondrial genome using the Illumina GAII system. Mother's age at sample collection was positively correlated with mtDNA heteroplasmy mutations. There was evidence of heteroplasmy inheritance in that 9 of the 18 families had at least one child who inherited at least one heteroplasmy site from his or her mother. No significant difference in single nucleotide polymorphisms between mother and offspring, however, was observed. Radiation therapy dose to ovaries also was not significantly associated with the heteroplasmy mutation rate among mothers and children. No evidence was found that radiotherapy for pediatric cancer is associated with the mitochondrial genome mutation rate in female cancer survivors and their children.