Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
Department of Medicine, The Jewish Hospital of Cincinnati, Cincinnati, Ohio.
Cancer. 2019 Apr 15;125(8):1258-1266. doi: 10.1002/cncr.31839. Epub 2019 Jan 15.
Somatic mutations in hypoxia-inducible factor 2α (HIF2A) are associated with polycythemia-paraganglioma syndrome. Specifically, the classic presentation of female patients with recurrent paragangliomas (PGLs), polycythemia (at birth or in early childhood), and duodenal somatostatinomas has been described. Studies have demonstrated that somatic HIF2A mutations occur as postzygotic events and some to be associated with somatic mosaicism affecting hematopoietic and other tissue precursors. This phenomenon could explain the development of early onset of polycythemia in the absence of erythropoietin-secreting tumors.
Correlation analysis was performed between mosaicism of HIF2A mutant patients and clinical presentations.
Somatic HIF2A mutations (p.A530V, p.P531S, and p.D539N) were identified in DNA extracted from PGLs of 3 patients. No somatic mosaicism was detected through deep sequencing of blood genomic DNA. Compared with classic syndrome, both polycythemia and PGL in all 3 patients developed at an advanced age with polycythemia at age 30, 30, and 17 years and PGLs at age 34, 30, and 55 years, respectively. Somatostatinomas were not detected, and 2 patients had ophthalmic findings. The biochemical phenotype in all 3 patients was noradrenergic with F-fluorodopa PET/CT as the most sensitive imaging modality. All patients demonstrated multiplicity, and none developed metastatic disease.
These findings suggest that newer techniques need to be developed to detect somatic mosaicism in patients with this syndrome. Absence of HIF2A mosaicism in patients with somatic HIF2A mutations supports association with late onset of the disease, milder clinical phenotype, and an improved prognosis compared with patients who have HIF2A mosaicism.
缺氧诱导因子 2α（HIF2A）的体细胞突变与红细胞增多-副神经节瘤综合征有关。具体来说，已经描述了女性患者反复发生副神经节瘤（PGL）、红细胞增多症（出生时或幼儿期）和十二指肠生长抑素瘤的经典表现。研究表明，体细胞 HIF2A 突变是合子后事件的结果，一些与影响造血和其他组织前体的体细胞嵌合体有关。这种现象可以解释在没有分泌促红细胞生成素的肿瘤的情况下，早发性红细胞增多症的发展。
对 HIF2A 突变患者嵌合体与临床表现之间进行相关性分析。
从 3 名患者的 PGL 中提取的 DNA 中鉴定出 HIF2A 突变（p.A530V、p.P531S 和 p.D539N）。通过对血液基因组 DNA 的深度测序未检测到体细胞嵌合体。与经典综合征相比，所有 3 名患者的红细胞增多症和 PGL 均在较晚的年龄发病，分别在 30、30 和 17 岁出现红细胞增多症，在 34、30 和 55 岁出现 PGL。未发现生长抑素瘤，有 2 名患者有眼部表现。所有 3 名患者的生化表型均为去甲肾上腺素能，F-氟多巴 PET/CT 是最敏感的成像方式。所有患者均表现为多发性，均未发生转移性疾病。
这些发现表明需要开发新技术来检测此类综合征患者的体细胞嵌合体。在有体细胞 HIF2A 突变的患者中缺乏 HIF2A 嵌合体支持与疾病晚发、临床表型较轻以及与有 HIF2A 嵌合体的患者相比预后较好相关。
