Centre for Cancer Research, Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, 2145, Australia.
Melanoma Institute Australia, The University of Sydney, North Sydney, NSW, 2065, Australia.
Fam Cancer. 2021 Jul;20(3):231-239. doi: 10.1007/s10689-020-00209-x. Epub 2020 Sep 29.
Germline mutations in CDKN2A greatly increase risk of developing cutaneous melanoma. We have constructed a risk prediction model, Familial Risk Assessment of Melanoma (FRAMe), for estimating the likelihood of carrying a heritable CDKN2A mutation among Australian families, where the prevalence of these mutations is low. Using logistic regression, we analysed characteristics of 299 Australian families recruited through the Sydney site of GenoMEL (international melanoma genetics consortium) with at least three cases of cutaneous melanoma (in situ and invasive) among first-degree blood relatives, for predictors of the presence of a pathogenic CDKN2A mutation. The final multivariable prediction model was externally validated in an independent cohort of 61 melanoma kindreds recruited through GenoMEL Queensland. Family variables independently associated with the presence of a CDKN2A mutation in a multivariable model were number of individuals diagnosed with melanoma under 40 years of age, number of individuals diagnosed with more than one primary melanoma, and number of individuals blood related to a melanoma case in the first degree diagnosed with any cancer excluding melanoma and non-melanoma skin cancer. The number of individuals diagnosed with pancreatic cancer was not independently associated with mutation status. The risk prediction model had an area under the receiver operating characteristic curve (AUC) of 0.851 (95% CI 0.793, 0.909) in the training dataset, and 0.745 (95%CI 0.612, 0.877) in the validation dataset. This model is the first to be developed and validated using only Australian data, which is important given the higher rate of melanoma in the population. This model will help to effectively identify families suitable for genetic counselling and testing in areas of high ambient ultraviolet radiation. A user-friendly electronic nomogram is available at www.melanomarisk.org.au .
CDKN2A 种系突变大大增加了发生皮肤黑色素瘤的风险。我们构建了一个风险预测模型，即家族性黑色素瘤风险评估（FRAMe），用于估计澳大利亚家族中携带可遗传 CDKN2A 突变的可能性，因为这些突变在这些家族中的发生率较低。我们使用逻辑回归分析了通过 GenoMEL（国际黑色素瘤遗传学联合会）悉尼站招募的 299 个澳大利亚家族的特征，这些家族中有至少 3 例一级亲属的皮肤黑色素瘤（原位和侵袭性），分析了预测存在致病性 CDKN2A 突变的因素。最终的多变量预测模型在通过 GenoMEL 昆士兰站招募的 61 个黑色素瘤家族的独立队列中进行了外部验证。多变量模型中与 CDKN2A 突变存在相关的家族变量是：40 岁以下诊断为黑色素瘤的人数、诊断为多个原发性黑色素瘤的人数、以及与一级黑色素瘤病例有血缘关系的人被诊断出除黑色素瘤和非黑色素瘤皮肤癌以外的任何癌症的人数。被诊断为胰腺癌的人数与突变状态无独立相关性。在训练数据集和验证数据集中，该风险预测模型的受试者工作特征曲线（ROC）下面积（AUC）分别为 0.851（95%CI 0.793，0.909）和 0.745（95%CI 0.612，0.877）。该模型是第一个仅使用澳大利亚数据开发和验证的模型，这在黑色素瘤发病率较高的人群中非常重要。该模型将有助于有效识别适合在高环境紫外线辐射地区进行遗传咨询和检测的家族。一个用户友好的电子诺模图可在 www.melanomarisk.org.au 上获得。
