Bernstein Jonine L, Concannon Patrick
a Department of Epidemiology and Biostatistics , Memorial Sloan Kettering Cancer Center , New York , NY , U.S.A.
b Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine , University of Florida , Gainesville , FL , U.S.A.
Int J Radiat Biol. 2017 Oct;93(10):1121-1127. doi: 10.1080/09553002.2017.1344363. Epub 2017 Jul 27.
It was first suggested more than 40 years ago that heterozygous carriers for the human autosomal recessive disorder Ataxia-Telangiectasia (A-T) might also be at increased risk for cancer. Subsequent studies have identified the responsible gene, Ataxia-Telangiectasia Mutated (ATM), characterized genetic variation at this locus in A-T and a variety of different cancers, and described the functions of the ATM protein with regard to cellular DNA damage responses. However, an overall model of how ATM contributes to cancer risk, and in particular, the role of DNA damage in this process, remains lacking. This review considers these questions in the context of contralateral breast cancer (CBC).
Heterozygous carriers of loss of function mutations in ATM that are A-T causing, are at increased risk of breast cancer. However, examination of a range of genetic variants, both rare and common, across multiple cancers, suggests that ATM may have additional effects on cancer risk that are allele-dependent. In the case of CBC, selected common alleles at ATM are associated with a reduced incidence of CBC, while other rare and predicted deleterious variants may act jointly with radiation exposure to increase risk. Further studies that characterize germline and somatic ATM mutations in breast cancer and relate the detected genetic changes to functional outcomes, particularly with regard to radiation responses, are needed to gain a complete picture of the complex relationship between ATM, radiation and breast cancer.
40多年前首次有人提出，人类常染色体隐性疾病共济失调毛细血管扩张症（A-T）的杂合子携带者患癌症的风险可能也会增加。随后的研究确定了致病基因——共济失调毛细血管扩张症突变基因（ATM），明确了该基因座在A-T及多种不同癌症中的遗传变异情况，并阐述了ATM蛋白在细胞DNA损伤反应方面的功能。然而，目前仍缺乏关于ATM如何导致癌症风险，尤其是DNA损伤在此过程中的作用的整体模型。本综述在对侧乳腺癌（CBC）的背景下探讨了这些问题。
导致A-T的ATM功能丧失突变的杂合子携带者患乳腺癌的风险增加。然而，对多种癌症中一系列罕见和常见遗传变异的研究表明，ATM可能对癌症风险有额外的等位基因依赖性影响。就CBC而言，ATM上选定的常见等位基因与CBC发病率降低相关，而其他罕见和预测的有害变异可能与辐射暴露共同作用增加风险。需要进一步开展研究，对乳腺癌中的种系和体细胞ATM突变进行特征分析，并将检测到的基因变化与功能结果相关联，特别是在辐射反应方面，以全面了解ATM、辐射与乳腺癌之间的复杂关系。
