Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma.
Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma.
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DOI：
10.3389/fendo.2022.1070074
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发表时间：
2022
影响因子：
5.2
通讯作者：
Cascon, Alberto
中科院分区：
文献类型：
--
作者：
Mellid, Sara;Gil, Eduardo;Leton, Rocio;Caleiras, Eduardo;Honrado, Emiliano;Richter, Susan;Palacios, Nuria;Lahera, Marcos;Galofre, Juan C.;Lopez-Fernandez, Adria;Calatayud, Maria;Herrera-Martinez, Aura D.;Galvez, Maria A.;Matias-Guiu, Xavier;Balbin, Milagros;Korpershoek, Esther;Lim, Eugenie S.;Maletta, Francesca;Lider, Sofia;Fliedner, Stephanie M. J.;Bechmann, Nicole;Eisenhofer, Graeme;Canu, Letizia;Rapizzi, Elena;Bancos, Irina;Robledo, Mercedes;Cascon, Alberto
在过去的二十年中，携带已知的超过15种易感基因突变的嗜铬细胞瘤和副神经节瘤（共PPGL）患者的百分比急剧增加，占PPGL患者的35-40%。此外，将NGS应用于PPGL的诊断可以检测到不同易感基因中致病性等位基因变异的意外共现。本文中，我们通过靶向测序发现了NF1和其他PPGL基因双突变的几个病例。我们研究了共发生突变的肿瘤的分子特征，使用组学工具来深入了解这些事件在肿瘤发展中的作用。在23例携带种系NF1突变的患者中，靶向测序发现DLST （n=1）和MDH2 （n=2）中有额外的致病种系变异，H3-3A和PRKAR1A中有两个体细胞突变。另外三名NF1体细胞突变的患者被发现携带SDHB或DLST的种系致病突变，以及ATRX的体细胞截断突变。两例双种系突变的病例显示多发性嗜铬细胞瘤或肾上腺外副神经节瘤，这在NF1患者中是极为罕见的临床发现。转录和甲基化分析以及代谢物评估显示了一种“中间特征”，表明这两种变体在肿瘤发展中具有病理作用。综上所述，影响不同途径（假性缺氧和受体酪氨酸激酶信号传导）基因的突变在同一患者中共同发生，可能为PPGL的发展提供了选择优势，并解释了在某些患者中观察到的可变表达性和不完全外显性。
The percentage of patients diagnosed with pheochromocytoma and paraganglioma (altogether PPGL) carrying known germline mutations in one of the over fifteen susceptibility genes identified to date has dramatically increased during the last two decades, accounting for up to 35-40% of PPGL patients. Moreover, the application of NGS to the diagnosis of PPGL detects unexpected co-occurrences of pathogenic allelic variants in different susceptibility genes. Herein we uncover several cases with dual mutations in NF1 and other PPGL genes by targeted sequencing. We studied the molecular characteristics of the tumours with co-occurrent mutations, using omic tools to gain insight into the role of these events in tumour development. Amongst 23 patients carrying germline NF1 mutations, targeted sequencing revealed additional pathogenic germline variants in DLST (n=1) and MDH2 (n=2), and two somatic mutations in H3-3A and PRKAR1A. Three additional patients, with somatic mutations in NF1 were found carrying germline pathogenic mutations in SDHB or DLST, and a somatic truncating mutation in ATRX. Two of the cases with dual germline mutations showed multiple pheochromocytomas or extra-adrenal paragangliomas - an extremely rare clinical finding in NF1 patients. Transcriptional and methylation profiling and metabolite assessment showed an “intermediate signature” to suggest that both variants had a pathological role in tumour development. In conclusion, mutations affecting genes involved in different pathways (pseudohypoxic and receptor tyrosine kinase signalling) co-occurring in the same patient could provide a selective advantage for the development of PPGL, and explain the variable expressivity and incomplete penetrance observed in some patients.
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影响因子：
4.3
作者：
Bendl J;Stourac J;Salanda O;Pavelka A;Wieben ED;Zendulka J;Brezovsky J;Damborsky J
通讯作者：
Damborsky J
影响因子：
50.3
作者：
Fishbein L;Leshchiner I;Walter V;Danilova L;Robertson AG;Johnson AR;Lichtenberg TM;Murray BA;Ghayee HK;Else T;Ling S;Jefferys SR;de Cubas AA;Wenz B;Korpershoek E;Amelio AL;Makowski L;Rathmell WK;Gimenez-Roqueplo AP;Giordano TJ;Asa SL;Tischler AS;Cancer Genome Atlas Research Network;Pacak K;Nathanson KL;Wilkerson MD
通讯作者：
Wilkerson MD
影响因子：
5.2
作者：
Choi YM;Lim J;Jeon MJ;Lee YM;Sung TY;Hong EG;Lee JY;Jang SJ;Kim WG;Song DE;Chun SM
通讯作者：
Chun SM
影响因子：
56.9
作者：
KAJIWARA, K;BERSON, EL;DRYJA, TP
通讯作者：
DRYJA, TP
影响因子：
4.8
作者：
Jones, Georgette N.;Tep, Chhavy;Kirschner, Lawrence S.
通讯作者：
Kirschner, Lawrence S.