Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.
Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
JAMA Dermatol. 2023 Oct 1;159(10):1112-1118. doi: 10.1001/jamadermatol.2023.2621.
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.
DESIGN, SETTING, AND PARTICIPANTS: 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.
关于 CDKN2A 相关黑色素瘤-神经胶质瘤综合征 (MAS) 的流行率和肿瘤类型的知识有限，这可能有助于提高对疾病的认识。
估计 MAS 的流行率并描述其肿瘤类型。
设计、地点和参与者：这项回顾性队列研究分析了来自美国（2 个地点）和欧洲（2 个地点）的医疗中心以及来自英国生物银行（英国）、盖辛格 MyCode（美国）生物医学人群基因组数据库的所有 MAS 病例，这些病例的时间范围为 1976 年 1 月 1 日至 2020 年 12 月 31 日。纳入了携带 CDKN2A 种系致病性变异且有 1 种或多种神经肿瘤的 MAS 患者。数据分析时间为 2022 年 6 月 1 日至 2023 年 1 月 31 日。
疾病流行率和肿瘤频率。
MAS 的流行率范围为 1/170503（n=1 例；95%CI，1:30098-1:965887）在盖辛格 MyCode（n=170503；平均[标准差]年龄为 58.9[19.1]岁；60.6%为女性；96.2%为白人）到 1/39149（n=12 例；95%CI，1:22396-1:68434）在英国生物银行（n=469789；平均[标准差]年龄为 70.0[8.0]岁；54.2%为女性；94.8%为白人）。在使用无偏基因组鉴定方法在英国生物银行中确定的 MAS 患者（n=12）中，脑肿瘤（12 例中的 4 例，33%；1 例为胶质母细胞瘤，1 例为胶质肉瘤，1 例为星形细胞瘤，1 例为未指明类型）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。在美国和欧洲的另外 14 例 MAS 患者的病例系列中，脑肿瘤（14 例中的 4 例，29%；2 例为胶质母细胞瘤，2 例为未指明类型）和恶性外周神经鞘瘤（14 例中的 2 例，14%）是最常见的神经癌，而皮肤黑色素瘤（14 例中的 4 例，29%）和肉瘤（14 例中的 2 例，14%；1 例为脂肪肉瘤，1 例为未指明类型）是最常见的非神经癌。皮肤神经纤维瘤（14 例中的 7 例，50%）和神经鞘瘤（14 例中的 2 例，14%）也很常见。在美国的 1 个家族中，1 对患有 MAS 的父子患有 1 型神经纤维瘤病（NF1）的临床诊断。对儿子的基因检测发现了致病性 CDKN2A 剪接变异（c.151-1G>C），而 NF1 基因的遗传改变为阴性。在英国生物银行中，150 名（1.3%）有临床 NF1 诊断的个体中，CDKN2A 可能存在致病性变异，其中 1 名个体未检测到 NF1 基因的变异。
这项队列研究估计了 MAS 的流行率并描述了其肿瘤。需要在遗传多样性人群中进行更多研究，以进一步确定人群流行率和疾病表型。
