Linkage disequilibrium pattern of the ATM gene in breast cancer patients and controls; association of SNPs and haplotypes to radio-sensitivity and post-lumpectomy local recurrence.
Linkage disequilibrium pattern of the ATM gene in breast cancer patients and controls; association of SNPs and haplotypes to radio-sensitivity and post-lumpectomy local recurrence.
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DOI：
10.1186/1748-717x-2-25
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发表时间：
2007-07-10
影响因子：
3.6
通讯作者：
Borresen-Dale, Anne-Lise
中科院分区：
文献类型：
--
作者：
Edvardsen, Hege;Tefre, Toril;Jansen, Laila;Vu, Phuong;Haffty, Bruce G.;Fossa, Sophie D.;Kristensen, Vessela N.;Borresen-Dale, Anne-Lise
ATM蛋白质因电离辐射而被激活，因此ATM基因的遗传变异可能影响辐射引起的损伤程度。据报道，ATM突变杂合子个体患恶性肿瘤的风险增加，尤其是乳腺癌。接受放射治疗的挪威乳腺癌患者（272例）（其中252人进行了放射性不良副作用的评估），95名没有已知癌症史的挪威妇女和95名接受放射治疗的美国乳腺癌患者（其中44例发生同侧乳腺肿瘤复发，通过变性高效液相色谱法（dHPLC），然后测序以确定变体的性质，筛选ATM基因的所有外显子中的序列变异以及已知的内含子变体。在合并的三种材料中共鉴定出56种变体。在挪威对照组和乳腺癌患者之间，发现外显子11的1229 T>C（瓦尔>Ala）取代与乳腺癌风险存在边缘显著相关（P值0.055），单倍型分布也存在边缘显著差异（P值0.06）。在挪威患者中评价了不良副作用，如：肋骨骨折和毛细血管扩张、皮下和肺纤维化、胸膜增厚和萎缩。发现了几种鉴定的变体的显著关联，例如rs1800058（Leu > Phe），其中发现次要等位基因频率的降低与临床终点胸膜增厚和肺纤维化的不良副作用水平的增加有关，从而产生保护作用。总的来说，我们的研究结果表明，ATM基因的变异对乳腺癌的发病风险和辐射引起的不良副作用都有作用。在美国患者资料中发现的同侧乳腺肿瘤复发风险与任何序列变异之间均无关联。
The ATM protein is activated as a result of ionizing radiation, and genetic variants of the ATM gene may therefore affect the level of radiation-induced damage. Individuals heterozygous for ATM mutations have been reported to have an increased risk of malignancy, especially breast cancer. Norwegian breast cancer patients (272) treated with radiation (252 of which were evaluated for radiation-induced adverse side effects), 95 Norwegian women with no known history of cancer and 95 American breast cancer patients treated with radiation (44 of which developed ipsilateral breast tumour recurrence, IBTR) were screened for sequence variations in all exons of the ATM gene as well as known intronic variants by denaturating high performance liquid chromatography (dHPLC) followed by sequencing to determine the nature of the variant. A total of 56 variants were identified in the three materials combined. A borderline significant association with breast cancer risk was found for the 1229 T>C (Val>Ala) substitution in exon 11 (P-value 0.055) between the Norwegian controls and breast cancer patients as well as a borderline significant difference in haplotype distribution (P-value 0.06). Adverse side effects, such as: development of costal fractures and telangiectasias, subcutaneous and lung fibrosis, pleural thickening and atrophy were evaluated in the Norwegian patients. Significant associations were found for several of the identified variants such as rs1800058 (Leu > Phe) where a decrease in minor allele frequency was found with increasing level of adverse side effects for the clinical end-points pleural thickening and lung fibrosis, thus giving a protective effect. Overall our results indicate a role for variation in the ATM gene both for risk of developing breast cancer, and in radiation induced adverse side effects. No association could be found between risk of developing ipsilateral breast tumour recurrence and any of the sequence variants found in the American patient material.