文章：

嗜铬细胞瘤和副神经节瘤的发病机制：从遗传异质性中学习

Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity

原文发布日期：2014-01-20

DOI: 10.1038/nrc3648

类型: Review Article

开放获取: 否

要点：

1. Pheochromocytomas and paragangliomas carry the highest degree of heritability (around 40%) of all human tumours and thus represent relevant models for the identification of driver mutations in cancer.
2. Genetic testing of inherited mutations allows the identification of co-occurring cancers in hereditary syndromes and screening of at-risk relatives, with an impact on health care.
3. More than 12 genes, belonging to a wide range of functional classes are mutated in the germ line or, less frequently, in somatic pheochromocytomas and paragangliomas, but many tumours remain genetically undefined.
4. Two main transcription signatures, associated with hypoxia-related signals (cluster 1) and increased kinase signalling (cluster 2), underlie the various driver mutations, revealing pathway interactions and enabling the discovery of novel predisposing genes.
5. Mutations of metabolism genes uncovered the cell growth-promoting effects of metabolism intermediates (succinate) through epigenetic (histone and DNA methylation) modulation and activation of a hypoxic response.
6. Mechanisms involved in the malignant transformation of pheochromocytomas and paragangliomas are not fully elucidated, and treatment options for these tumours are still limited.

要点翻译：

1. 嗜铬细胞瘤和副神经节瘤在所有人类肿瘤中具有最高遗传度（约40%），因此成为鉴定癌症驱动突变的重要模型。
2. 遗传性突变的基因检测有助于识别遗传综合征中的共发癌症，并对高危亲属进行筛查，从而影响医疗保健。
3. 超过12个功能类别各异的基因在种系或较少在体细胞嗜铬细胞瘤和副神经节瘤中发生突变，但许多肿瘤的遗传基础仍未明确。
4. 两种主要转录特征——分别与缺氧相关信号（簇1）和激酶信号增强（簇2）相关——构成了不同驱动突变的基础，揭示了通路相互作用，并促进了新的易感基因的发现。
5. 代谢基因突变通过表观遗传（组蛋白和DNA甲基化）调控及缺氧反应的激活，揭示了代谢中间产物（琥珀酸盐）促进细胞生长的机制。
6. 嗜铬细胞瘤和副神经节瘤恶性转化的机制尚未完全阐明，且这些肿瘤的治疗方案仍有限。

英文摘要：

The neuroendocrine tumours pheochromocytomas and paragangliomas carry the highest degree of heritability in human neoplasms, enabling genetic alterations to be traced to clinical phenotypes through their transmission in families. Mutations in more than a dozen distinct susceptibility genes have implicated multiple pathways in these tumours, offering insights into kinase downstream signalling interactions and hypoxia regulation, and uncovering links between metabolism, epigenetic remodelling and cell growth. These advances extend to co-occurring tumours, including renal, thyroid and gastrointestinal malignancies. Hereditary pheochromocytomas and paragangliomas are powerful models for recognizing cancer driver events, which can be harnessed for diagnostic purposes and for guiding the future development of targeted therapies.

摘要翻译： 

神经内分泌肿瘤中的嗜铬细胞瘤和副神经节瘤是人类肿瘤中遗传度最高的类型，使得通过家族遗传追踪基因改变与临床表型成为可能。已有超过12个不同的易感基因发生突变，涉及这些肿瘤中的多条信号通路，为激酶下游信号相互作用及缺氧调控提供了新见解，并揭示了代谢、表观遗传重塑与细胞生长之间的关联。这些进展也扩展到共发肿瘤，包括肾、甲状腺及胃肠道恶性肿瘤。遗传性嗜铬细胞瘤和副神经节瘤是识别癌症驱动事件的强有力模型，可用于诊断目的并指导未来靶向治疗的开发。

原文链接：

Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity