Geographical variation in the penetrance of CDKN2A mutations for melanoma
Geographical variation in the penetrance of CDKN2A mutations for melanoma
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DOI：
10.1093/jnci/94.12.894
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发表时间：
2002-06-19
期刊：
影响因子：
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通讯作者：
Tucker, MA
中科院分区：
文献类型：
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作者：
Bishop, DT;Demenais, F;Tucker, MA
背景：编码两种蛋白（p16INK4A和p14ARF）的CDKN2A基因的种系突变是黑色素瘤遗传易感性的最常见原因。我们使用来自欧洲、澳大利亚和美国的8个群体的数据检查了这些突变的外显率，这些群体是黑色素瘤遗传学联盟的一部分。我们分析了80个有CDKN2A突变记录的家庭和多个皮肤黑色素瘤病例。我们使用包含生存分析的逻辑回归模型来模拟黑色素瘤的外显率。假设检验基于似然比检验。协变量包括性别、p14APF蛋白的改变和人群黑色素瘤发病率。所有统计检验均为双侧检验。结果：80个被分析的家庭包含402名黑色素瘤患者，其中320人进行了突变检测，291人是突变携带者。我们还对713名未受影响的家庭成员进行了突变检测，其中194名是携带者。总体而言，CDKN2A突变外显率在50岁时估计为0.30(95%置信区间(CI) = 0.12至0.62)，在80岁时估计为0.67 （95% CI = 0.31至0.96）。外显率不受性别或CDKN2A突变是否改变p14ARF蛋白的影响。然而，居住在黑色素瘤发病率高的地区有统计学上显著的影响（P = 0.003）。到50岁时，CDKN2A突变外显率在欧洲为0.13，在美国为0.50，在澳大利亚为0.32；到80岁时，欧洲为0.58，美国为0.76，澳大利亚为0.91。结论：这项研究给出了CDKN2A突变外显率的最明智估计，表明外显率随黑色素瘤人群发病率的变化而变化。因此，影响人群黑色素瘤发病率的相同因素也可能介导CDKN2A外显率。
Background: Germline mutations in the CDKN2A gene, which encodes two proteins (p16INK4A and p14ARF), are the most common cause of inherited susceptibility to melanoma. We examined the penetrance of such mutations using data from eight groups from Europe, Australia and the United States that are part of The Melanoma Genetics Consortium Methods: We analyzed 80 families with documented CDKN2A mutations and multiple cases of cutaneous melanoma. We modeled penetrance for melanoma using a logistic regression model incorporating survival analysis. Hypothesis testing was based on likelihood ratio tests. Covariates included gender, alterations in p14APF protein, and population melanoma incidence rates. All statistical tests were two-sided. Results: The 80 analyzed families contained 402 melanoma patients, 320 of whom were tested for mutations and 291 were mutation carriers. We also tested 713 unaffected family members for mutations and 194 were carriers. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval (CI) = 0.12 to 0.62) by age 50 years and 0.67 (95% CI = 0.31 to 0.96) by age 80 years. Penetrance was not statistically significantly modified by gender or by whether the CDKN2A mutation altered p14ARF protein. However, there was a statistically significant effect of residing in a location with a high population incidence rate of melanoma (P = .003). By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia. Conclusions: This study, which gives the most informed estimates of CDKN2A mutation penetrance available, indicates that the penetrance varies with melanoma population incidence rates. Thus, the same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance.