Thompson Deborah, Duedal Silvia, Kirner Jennifer, McGuffog Lesley, Last James, Reiman Anne, Byrd Philip, Taylor Malcolm, Easton Douglas F
CR-UK Genetic Epidemiology Unit, University of Cambridge, Cambridge, UK.
J Natl Cancer Inst. 2005 Jun 1;97(11):813-22. doi: 10.1093/jnci/dji141.
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.
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 maximum-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.
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.
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.
ATM基因的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。多项研究表明，ATM突变的杂合携带者患乳腺癌以及其他癌症的风险增加，但确切风险尚不确定。
通过英国国家医疗服务体系中央登记处获取了169名英国A-T患者的1160名亲属（包括247名必然携带者）的癌症发病率和死亡率信息。采用使用期望最大化（EM）算法的最大似然法，在考虑基因型不确定性的情况下，估计携带者患癌的相对风险（RRs）。使用谱系分析程序MENDEL计算与三组突变相关的癌症风险的最大似然估计值。所有统计检验均为双侧检验。
与普通人群相比，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风险为2.05（95%CI=1.09至3.84），男性携带者为1.23（95%CI=0.76至2.00）。乳腺癌是唯一明显风险增加的部位，不过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）风险过高。预测编码全长ATM蛋白的突变携带者的癌症风险与携带截短突变者相似。
这些结果证实了A-T杂合子患乳腺癌的中度风险，并提供了一些其他癌症风险过高的证据，但没有支持风险存在巨大突变特异性差异的证据。
