Université de Paris, PARCC, INSERM, Equipe Labellisée par la Ligue contre le Cancer, F-75015 Paris, France.
Genetic department, Adrenal Referral Center, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, F-75015 Paris, France.
J Clin Endocrinol Metab. 2021 Jan 23;106(2):459-471. doi: 10.1210/clinem/dgaa819.
Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors in which altered central metabolism appears to be a major driver of tumorigenesis, and many PPGL genes encode proteins involved in the tricarboxylic acid (TCA) cycle.
OBJECTIVE/DESIGN: While about 40% of PPGL cases carry a variant in a known gene, many cases remain unexplained. In patients with unexplained PPGL showing clear evidence of a familial burden or multiple tumors, we aimed to identify causative factors using genetic analysis of patient DNA and functional analyses of identified DNA variants in patient tumor material and engineered cell lines.
Patients with a likely familial cancer burden of pheochromocytomas and/or paragangliomas and under investigation in a clinical genetic and clinical research setting in university hospitals.
While investigating unexplained PPGL cases, we identified a novel variant, c.1151C>T, p.(Pro384Leu), in exon 14 of the gene encoding dihydrolipoamide S-succinyltransferase (DLST), a component of the multi-enzyme complex 2-oxoglutarate dehydrogenase. Targeted sequence analysis of further unexplained cases identified a patient carrying a tumor with compound heterozygous variants in DLST, consisting of a germline variant, c.1121G>A, p.(Gly374Glu), together with a somatic missense variant identified in tumor DNA, c.1147A>G, p.(Thr383Ala), both located in exon 14. Using a range of in silico and functional assays we show that these variants are predicted to be pathogenic, profoundly impact enzyme activity, and result in DNA hypermethylation.
The identification and functional analysis of these DLST variants further validates DLST as an additional PPGL gene involved in the TCA cycle.
嗜铬细胞瘤和副神经节瘤（PPGL）是神经内分泌肿瘤，其中改变的中枢代谢似乎是肿瘤发生的主要驱动因素，许多 PPGL 基因编码参与三羧酸（TCA）循环的蛋白质。
目的/设计：虽然大约 40%的 PPGL 病例携带已知基因的变异，但许多病例仍未得到解释。在有明确家族负担或多个肿瘤证据但原因不明的 PPGL 患者中，我们旨在通过对患者 DNA 的遗传分析以及对患者肿瘤组织和工程细胞系中鉴定的 DNA 变体的功能分析来确定致病因素。
具有嗜铬细胞瘤和/或副神经节瘤可能家族性癌症负担的患者，并在大学医院的临床遗传和临床研究环境中进行调查。
在研究原因不明的 PPGL 病例时，我们在编码二氢硫辛酰胺 S-琥珀酰基转移酶（DLST）的基因外显子 14 中发现了一个新的变异 c.1151C>T，p.（Pro384Leu），该基因是多酶复合物 2-氧戊二酸脱氢酶的组成部分。对进一步未解释的病例进行靶向序列分析发现，一名患者携带的肿瘤存在 DLST 复合杂合变异，包括胚系变异 c.1121G>A，p.（Gly374Glu），以及在肿瘤 DNA 中鉴定出的体细胞错义变异 c.1147A>G，p.（Thr383Ala），均位于外显子 14 中。通过一系列计算机模拟和功能测定，我们表明这些变体被预测为致病性的，严重影响酶活性，并导致 DNA 超甲基化。
这些 DLST 变体的鉴定和功能分析进一步验证了 DLST 是参与 TCA 循环的另一个 PPGL 基因。
