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Analyses for Genes Controlling Susceptibility to Radiation-Induced Tumorigenesis

控制辐射诱发肿瘤发生易感性的基因分析

基本信息

批准号：
14580571
负责人：
MORI Nobuko
金额：
$ 1.92万
依托单位：
Osaka Prefecture University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

(1)Genome-wide screening for tumor susceptibility in [(BALB/c x STS)F1 x STS] mice subjected to 4 x 1.7 Gy X-irradiation detected no chromosomal segment carrying homozygous STS allele, which could achieve tumor resistance equivalent to that of STS mice. This indicates that resistance to lymphomagenesis in STS mice is not under a single gene control. Suggestive (not significant) linkage was detected in the segment close to Pten on chromosome 19 and at a marker D1Mit14 near the telomere of chromosome 1.(2)Linkage analysis using [(BALB/c x STS)F1 x BALE/c] mice identified two loci responsible for tumor susceptibility on chromosome 4, where the STS allele conferred resistance to lymphomagenesis (chi square values were more than 15.3). One locus located in the vicinity of D4Mit17 (30 cM distal to the centromere) and nearby D4Mit9, INK4a and b, approximately 10 cM distal to the locus, another locus existed. Analysis of several congenic lines bearing various portions of STS-derived chromosome 4 in the BALB/c background confirmed the presence of a tumor susceptibility gene in a 10 Mb region containing these INK4 family genes. Experiments to confirm the existence of another susceptibility gene for lymphomagenesis are ongoing by using a set of congenic mouse lines.(3)A single exposure to 4 Gy of X-irradiation induced mammary tumors with a frequency less than that of lymphomas in p53 hemizygous mice with the BALE/c background. Furthermore, in the p53 hemizygous mice 4 times irradiation with an X-ray dose less than 1 Gy at a week interval doubled the mammary tumor frequency in compensation for a reduced incidence of lymphomas. Using a genetic cross between (C57BL/6 x p53 hemizygous BALB/c)F1 and BALB/c linkage analysis for mammary tumor susceptibility is presently under way.

(1)对接受4×1.7 Gy X射线照射的[(BALB/c x STS)F1 x STS]小鼠进行全基因组肿瘤易感性筛查，未检测到携带纯合STS等位基因的染色体片段，可达到与STS小鼠相当的抗肿瘤能力。这表明STS小鼠对淋巴瘤发生的抵抗力不受单一基因控制。在 19 号染色体上靠近 Pten 的片段和靠近 1 号染色体端粒的标记 D1Mit14 处检测到提示性（不显着）连锁。(2)使用 [(BALB/c x STS)F1 x BALE/c] 小鼠进行连锁分析，鉴定了 4 号染色体上负责肿瘤易感性的两个位点，其中 STS 等位基因赋予对淋巴瘤发生的抗性（卡方值更大）高于 15.3）。一个基因座位于D4Mit17附近(距着丝粒远端30cM)和D4Mit9、INK4a和b附近，距离该基因座大约10cM，存在另一个基因座。对 BALB/c 背景中带有 STS 衍生的 4 号染色体不同部分的几个同系系的分析证实，在包含这些 INK4 家族基因的 10 Mb 区域中存在肿瘤易感基因。通过使用一组同源小鼠系，正在进行证实另一种淋巴瘤发生易感基因的存在的实验。(3)单次暴露于4Gy的X射线照射诱发乳腺肿瘤的频率低于具有BALE/c背景的p53半合子小鼠中淋巴瘤的频率。此外，在 p53 半合子小鼠中，每周间隔 4 次低于 1 Gy 的 X 射线照射，乳腺肿瘤发生率增加了一倍，以补偿淋巴瘤发病率的降低。目前正在使用 (C57BL/6 x p53 半合子 BALB/c)F1 和 BALB/c 连锁分析之间的遗传杂交来分析乳腺肿瘤易感性。