Stanford Genome Technology Center, Department of Biochemistry, Stanford University, Stanford, California, USA.
Cancer Res. 2010 Jan 15;70(2):552-9. doi: 10.1158/0008-5472.CAN-09-2653. Epub 2010 Jan 12.
Personalized cancer risk assessment remains an essential imperative in postgenomic cancer medicine. In hereditary melanoma, germline CDKN2A mutations have been reproducibly identified in melanoma-prone kindreds worldwide. However, genetic risk counseling for hereditary melanoma remains clinically challenging. To address this challenge, we developed and validated MelaPRO, an algorithm that provides germline CDKN2A mutation probabilities and melanoma risk to individuals from melanoma-prone families. MelaPRO builds on comprehensive genetic information, and uses Mendelian modeling to provide fine resolution and high accuracy. In an independent validation of 195 individuals from 167 families, MelaPRO exhibited good discrimination with a concordance index (C) of 0.86 [95% confidence intervals (95% CI), 0.75-0.97] and good calibration, with no significant difference between observed and predicted carriers (26; 95% CI, 20-35, as compared with 22 observed). In cross-validation, MelaPRO outperformed the existing predictive model MELPREDICT (C, 0.82; 95% CI, 0.61-0.93), with a difference of 0.05 (95% CI, 0.007-0.17). MelaPRO is a clinically accessible tool that can effectively provide personalized risk counseling for all members of hereditary melanoma families.
个性化癌症风险评估仍然是后基因组癌症医学的重要要求。在遗传性黑色素瘤中，世界各地易患黑色素瘤的家族中已经反复鉴定出种系 CDKN2A 突变。然而，遗传性黑色素瘤的遗传风险咨询在临床上仍然具有挑战性。为了解决这一挑战，我们开发并验证了 MelaPRO，这是一种算法，可为易患黑色素瘤的家族中的个体提供种系 CDKN2A 突变概率和黑色素瘤风险。MelaPRO 建立在全面的遗传信息基础上，并使用孟德尔建模提供精细分辨率和高精度。在对 167 个家族的 195 名个体进行的独立验证中，MelaPRO 表现出良好的区分度，一致性指数（C）为 0.86 [95%置信区间（95%CI），0.75-0.97]，校准良好，观察到的和预测的携带者之间没有显着差异（26；95%CI，20-35，而观察到的为 22）。在交叉验证中，MelaPRO 优于现有的预测模型 MELPREDICT（C，0.82；95%CI，0.61-0.93），差异为 0.05（95%CI，0.007-0.17）。MelaPRO 是一种临床可及的工具，可以有效地为遗传性黑色素瘤家族的所有成员提供个性化的风险咨询。
