Cancer risks and mortality in heterozygous ATM mutation carriers
Cancer risks and mortality in heterozygous ATM mutation carriers
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DOI：
10.1093/jnci/dji141
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发表时间：
2005-06-01
影响因子：
10.3
通讯作者：
Easton, DF
中科院分区：
文献类型：
--
作者：
Thompson, D;Duedal, S;Easton, DF
背景：ATM基因纯合或复合杂合突变是共济失调毛细血管扩张症（A-T）的主要病因。一些研究表明，ATM突变的杂合子携带者患乳腺癌和其他癌症的风险增加，但确切的风险尚不确定。研究方法：通过国家卫生服务中心登记处获得了169名英国A-T患者（包括247名专性携带者）的1160名亲属的癌症发病率和死亡率信息。考虑到基因型的不确定性，采用EM算法的最大m-似然法估计携带者患癌症的相对风险（RR）。使用系谱分析程序MENDEL计算与三组突变相关的癌症风险的最大似然估计。所有统计检验均为双侧检验。结果如下：与一般人群相比，携带者患乳腺癌的总体相对风险为2.23（95%置信区间[CI] = 1.16至4.28），但在50岁以下人群中为4.94（95% CI = 1.90至12.9）。女性携带者患除乳腺癌以外所有癌症的相对危险度为2.05（95%CI = 1.09 ~ 3.84），男性携带者为1.23（95%CI = 0.76 ~ 2.00）。乳腺癌是唯一一个风险明显增加的部位，尽管有一些证据表明结直肠癌（RR = 2.54，95%CI = 1.06至6.09）和胃癌（RR = 3.39，95%CI = 0.86至13.4）的风险过高。预测编码全长ATM蛋白质的突变携带者与携带截短突变的人具有相似的癌症风险。结论：这些结果证实A-T杂合子患乳腺癌的风险为中等，并提供了患其他癌症风险过高的一些证据，但没有为风险的巨大突变特异性差异提供支持。
Background: Homozygous or compound heterozygous mutations in the ATM gene are the principal cause of ataxia telangiectasia (A-T). Several studies have suggested that heterozygous carriers of ATM mutations are at increased risk of breast cancer and perhaps of other cancers, but the precise risk is uncertain. Methods: Cancer incidence and mortality information for 1160 relatives of 169 UK A-T patients (including 247 obligate carriers) was obtained through the National Health Service Central Registry. Relative risks (RRs) of cancer in carriers, allowing for genotype uncertainty, were estimated with a maxima m-likelihood approach that used the EM algorithm. Maximum-likelihood estimates of cancer risks associated with three groups of mutations were calculated using the pedigree analysis program MENDEL. All statistical tests were two-sided. Results: The overall relative risk of breast cancer in carriers was 2.23 (95% confidence interval [CI] = 1.16 to 4.28) compared with the general population but was 4.94 (95% CI = 1.90 to 12.9) in those younger than age 50 years. The relative risk for all cancers other than breast cancer was 2.05 (95% CI = 1.09 to 3.84) in female carriers and 1.23 (95% CI = 0.76 to 2.00) in male carriers. Breast cancer was the only site for which a clear risk increase was seen, although there was some evidence of excess risks of colorectal cancer (RR = 2.54, 95% CI = 1.06 to 6.09) and stomach cancer (RR = 3.39, 95% CI = 0.86 to 13.4). Carriers of mutations predicted to encode a full-length ATM protein had cancer risks similar to those of people carrying truncating mutations. Conclusion: These results confirm a moderate risk of breast cancer in A-T heterozygotes and give some evidence of an excess risk of other cancers but provide no support for large mutation-specific differences in risk.