对CDKN2A相关的黑色素瘤-星形胶质瘤综合征（MAS）的患病率和肿瘤类型的认识有限，而且提高对该疾病的认知能够改善疾病的识别。本回顾性队列研究分析了美国（2个中心）和欧洲（2个中心）医疗中心以及生物医学人群基因组数据库（英国生物库[英国]，Geisinger MyCode [美国]）中所有可用的MAS病例，并设定时间范围从1976年1月1日至2020年12月31日。包括CDKN2A有丝分裂抑制蛋白（germline）致病变异和1个或更多神经性肿瘤的MAS患者。数据的分析时间为2022年6月1日至2023年1月31日。研究目标为疾病患病率和肿瘤发生频率。在Geisinger MyCode（n＝170,503；平均[标准差]年龄，58.9 [19.1] 岁；女性占60.6% ；白人占96.2% ）中，MAS的患病率范围为170,503例中的1例（95%可信区间，1：30,098-1：965,887）到UK Biobank（n＝469,789；平均[标准差]年龄，70.0[8.0]岁；女性占54.2%；白人占94.8% ）中的39,149例中的1例（95%可信区间，1：22,396-1：68,434）。在使用无偏基因组确认方法在UK Biobank中鉴定的MAS患者（n＝12）中，脑肿瘤（12例中的4例，33%，包括1例胶质母细胞瘤，1例胶质肉瘤，1例星形胶质瘤，1例未指明类型）和神经鞘瘤（12例中的3例，25%）是最常见的恶性和良性神经性肿瘤，而皮肤黑色素瘤（12例中的2例，17%）和头颈部鳞状细胞癌（12例中的2例，17%）是最常见的非神经恶性肿瘤。在一个不同的美国和欧洲14例MAS病例系列中，脑肿瘤（14例中的4例，29%，包括2例胶质母细胞瘤，2例未指明类型）和恶性周围神经鞘瘤（14例中的2例，14%）是最常见的神经癌肿瘤，而皮肤黑色素瘤（14例中的4例，29%）和肉瘤（14例中的2例，14%，包括1例脂肪肉瘤，1例未指明类型）是最常见的非神经性肿瘤。神经纤维瘤（14例中的7例，50%）和神经鞘瘤（14例中的2例，14%）也较常见。在一个美国家庭中，一对父子患有MAS且临床诊断为神经纤维瘤1型（NF1）。对该子结进行基因检测发现存在致病的CDKN2A剪接变异体（c.151-1G>C），并未检测到NF1基因的变异。在英国生物库中，150例临床NF1诊断的个体中，有2例（1.3%）的CDKN2A基因中存在可能致病的变异体，包括1例未检测到NF1基因变异体的个体。本队列研究估计了MAS的患病率并描述了该疾病的肿瘤。还需要在具有遗传多样性的人群中进行进一步的研究，以进一步确定人群患病率和疾病表型。

Knowledge about the prevalence and tumor types of CDKN2A-related melanoma-astrocytoma syndrome (MAS) is limited and could improve disease recognition.To estimate the prevalence and describe the tumor types of MAS.This retrospective cohort study analyzed all available MAS cases from medical centers in the US (2 sites) and Europe (2 sites) and from biomedical population genomic databases (UK Biobank [United Kingdom], Geisinger MyCode [US]) between January 1, 1976, and December 31, 2020. Patients with MAS with CDKN2A germline pathogenic variants and 1 or more neural tumors were included. Data were analyzed from June 1, 2022, to January 31, 2023.Disease prevalence and tumor frequency.Prevalence of MAS ranged from 1 in 170 503 (n = 1 case; 95% CI, 1:30 098-1:965 887) in Geisinger MyCode (n = 170 503; mean [SD] age, 58.9 [19.1] years; 60.6% women; 96.2% White) to 1 in 39 149 (n = 12 cases; 95% CI, 1:22 396-1:68 434) in UK Biobank (n = 469 789; mean [SD] age, 70.0 [8.0] years; 54.2% women; 94.8% White). Among UK Biobank patients with MAS (n = 12) identified using an unbiased genomic ascertainment approach, brain neoplasms (4 of 12, 33%; 1 glioblastoma, 1 gliosarcoma, 1 astrocytoma, 1 unspecified type) and schwannomas (3 of 12, 25%) were the most common malignant and benign neural tumors, while cutaneous melanoma (2 of 12, 17%) and head and neck squamous cell carcinoma (2 of 12, 17%) were the most common nonneural malignant neoplasms. In a separate case series of 14 patients with MAS from the US and Europe, brain neoplasms (4 of 14, 29%; 2 glioblastomas, 2 unspecified type) and malignant peripheral nerve sheath tumor (2 of 14, 14%) were the most common neural cancers, while cutaneous melanoma (4 of 14, 29%) and sarcomas (2 of 14, 14%; 1 liposarcoma, 1 unspecified type) were the most common nonneural cancers. Cutaneous neurofibromas (7 of 14, 50%) and schwannomas (2 of 14, 14%) were also common. In 1 US family, a father and son with MAS had clinical diagnoses of neurofibromatosis type 1 (NF1). Genetic testing of the son detected a pathogenic CDKN2A splicing variant (c.151-1G>C) and was negative for NF1 genetic alterations. In UK Biobank, 2 in 150 (1.3%) individuals with clinical NF1 diagnoses had likely pathogenic variants in CDKN2A, including 1 individual with no detected variants in the NF1 gene.This cohort study estimates the prevalence and describes the tumors of MAS. Additional studies are needed in genetically diverse populations to further define population prevalence and disease phenotypes.