INCREASED RISK OF PANCREATIC-CANCER IN MELANOMA-PRONE KINDREDS WITH P16(INK4) MUTATIONS
INCREASED RISK OF PANCREATIC-CANCER IN MELANOMA-PRONE KINDREDS WITH P16(INK4) MUTATIONS
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DOI：
10.1056/nejm199510123331504
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发表时间：
1995-10-12
影响因子：
158.5
通讯作者：
TUCKER, MA
中科院分区：
文献类型：
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作者：
GOLDSTEIN, AM;FRASER, MC;TUCKER, MA
背景在19个黑色素瘤易感家族中，染色体9p上的基因p16（INK4）与皮肤恶性黑色素瘤的发病有关。在10个损害p16（INK4）蛋白功能的激酶突变（p16M等位基因）中，与疾病共分离。相比之下，在其他9种激酶中，突变并没有改变p16（INK4）（p16W等位基因）的功能。我们在这两组家庭中寻找临床和遗传流行病学特征的差异。我们比较了诊断黑色素瘤时的中位年龄、黑色素瘤的数量、肿瘤的厚度和皮肤中痣的数量。我们通过比较观察到的癌症病例数和预期的癌症病例数，前瞻性地估计了随访6~18年的家族中黑色素瘤或其他癌症的风险，以及自1925年以来（整个时期）其他癌症的风险。侵袭性黑色素瘤的风险在p16W等位基因的kindergarten中增加了75倍，在p16W等位基因的kindergarten中增加了38倍。虽然这种差异不显著（P = 0.14），但在其他肿瘤的风险方面存在显著差异。在p16M等位基因的激酶中，胰腺癌的风险在前瞻性时期增加了13倍。（观察到2例，预期为0.15;标准化发病率比为13.1; 95%置信区间为1.5 - 47.4），在整个期间增加了22倍（观察到7例，预期为0.32;标准化发病率为21.8; 95%置信区间为8.7~44.8）。与此相反，我们没有发现胰腺癌的病例与p16W等位基因的kinetics。在容易患黑色素瘤的家族中，胰腺癌的发生可能需要p16 M突变。遗传因素，如p16（INK4）中发现的突变类型，可以解释这些激酶中其他癌症的不一致发生。
Background. A gene on chromosome 9p, p16(INK4), has been implicated in the pathogenesis of cutaneous malignant melanoma in 19 melanoma-prone families. In 10 of these kindreds mutations that impaired the function of the p16(INK4) protein (p16M alleles) cosegregated with the disease. By contrast, in the other nine kindreds the mutation did not alter the function of p16(INK4) (p16W alleles). We looked for differences in clinical and genetic epidemiologic features in these two groups of families.Methods. We compared the median ages at diagnosis of melanoma, number of melanomas, thickness of the tumors, and number of nevi in the kindreds. We estimated prospectively the risks of melanoma or other cancers in families followed for 6 to 18 years and the risks of other cancers since 1925 (the entire period) by comparing the number of cancer cases observed with the number expected.Results. The risk of invasive melanoma was increased by a factor of 75 in kindreds with p16W alleles and a factor of 38 in kindreds with p16W alleles. Although this difference was not significant (P=0.14), there was a striking difference in the risk of other tumors. In kindreds with p16M alleles, the risk of pancreatic cancer was increased by a factor of 13 in the prospective period (2 cases observed, 0.15 expected; standardized incidence ratio, 13.1; 95 percent confidence interval, 1.5 to 47.4) and by a factor of 22 in the entire period (7 cases observed, 0.32 expected; standardized incidence ratio, 21.8; 95 percent confidence interval, 8.7 to 44.8). In contrast, we found no cases of pancreatic cancer in kindreds with p16W alleles.Conclusions. The development of pancreatic cancer in kindreds prone to melanoma may require a p16M mutation. Genetic factors, such as the kind of mutation found in p16(INK4), may explain the inconsistent occurrence of other cancers in these kindreds.