Genomic and Signaling of Endocrine Tumors team, INSERM U1016, CNRS UMR8104, Cochin Institute, Paris Cité University, Paris, 75005, France.
Department of Endocrinology, Diabetes and Nutrition, Rennes University Hospital, Rennes, 35000, France.
Hormones (Athens). 2024 Dec;23(4):601-610. doi: 10.1007/s42000-024-00608-0. Epub 2024 Oct 10.
Adrenal Cushing represents 20% of cases of endogenous hypercorticism. Unilateral cortisol-producing adenoma (CPA), a benign tumor, and adrenocortical carcinoma (ACC), a malignant tumor, are more frequent than bilateral adrenal nodular diseases (primary bilateral macronodular adrenal hyperplasia (PBMAH) and primary pigmented nodular adrenal disease (PPNAD)).In cortisol-producing adrenal tumors, the signaling pathways mainly altered are the protein kinase A and Wnt/β-catenin pathways. Studying components of these pathways and exploring syndromic and familial cases of these tumors has historically enabled identification of many of the predisposing genes. More recently, pangenomic sequencing revealed alterations in sporadic tumors.In ACC, mainly due to TP53 alterations causing Li-Fraumeni syndrome, germline predisposition is frequent in children, while it is rare in adults. Pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, MSH6, and PMS2, which cause Lynch syndrome or alterations of IGF2 and CDKN1C (11p15 locus) in Beckwith-Wiedemann syndrome, can also cause ACC. Rarely, ACC is described in other hereditary tumor syndromes due to germline pathogenic variants in MEN1 or APC and, in very rare cases, NF1, SDH, PRKAR1A, or BRCA2. Concerning ACC somatic alterations, TP53 and genetic or epigenetic alterations at the 11p15 locus are also frequently described, as well as CTNNB1 and ZNRF3 pathogenic variants.CPAs mainly harbor somatic pathogenic variants in PRKACA and CTNNB1 and, less frequently, PRKAR1A, PRKACB, or GNAS1 pathogenic variants. Isolated PBMAH is due to ARMC5 inactivating pathogenic variants in 20 to 25% of cases and to KDM1A pathogenic variants in food-dependent Cushing. Syndromic PBMAH may be due to germline pathogenic variants in MEN1, APC, or FH, causing type 1 multiple endocrine neoplasia, familial adenomatous polyposis, or hereditary leiomyomatosis-kidney cancer syndrome, respectively. PRKAR1A germline pathogenic variants are the main alteration causing PPNAD (isolated or part of Carney complex).
肾上腺库欣病占内源性皮质醇增多症的 20%。单侧产生皮质醇的腺瘤（CPA），一种良性肿瘤，和肾上腺皮质癌（ACC），一种恶性肿瘤，比双侧肾上腺结节性疾病（原发性双侧大结节性肾上腺增生（PBMAH）和原发性色素性结节性肾上腺疾病（PPNAD））更常见。在产生皮质醇的肾上腺肿瘤中，主要改变的信号通路是蛋白激酶 A 和 Wnt/β-连环蛋白通路。研究这些通路的组成部分，并探索这些肿瘤的综合征和家族病例，历史上已经能够识别许多易患基因。最近，泛基因组测序揭示了散发性肿瘤的改变。在 ACC 中，主要由于 TP53 改变导致 Li-Fraumeni 综合征，种系易感性在儿童中常见，而在成人中罕见。错配修复基因 MLH1、MSH2、MSH6 和 PMS2 的致病性变异，导致 Lynch 综合征或 Beckwith-Wiedemann 综合征中 IGF2 和 CDKN1C（11p15 位点）的改变，也可导致 ACC。由于 MEN1 或 APC 中的种系致病性变异，以及非常罕见的情况下 NF1、SDH、PRKAR1A 或 BRCA2，在其他遗传性肿瘤综合征中也会偶尔描述 ACC。关于 ACC 的体细胞改变，TP53 以及 11p15 位点的遗传或表观遗传改变，以及 CTNNB1 和 ZNRF3 的致病性变异，也经常被描述。CPAs 主要携带 PRKACA 和 CTNNB1 的体细胞致病性变异，以及较少见的 PRKAR1A、PRKACB 或 GNAS1 致病性变异。孤立性 PBMAH 是由于 ARMC5 在 20%至 25%的病例中失活的致病性变异和食物依赖库欣的 KDM1A 致病性变异所致。综合征性 PBMAH 可能是由于 MEN1、APC 或 FH 的种系致病性变异，分别导致 1 型多发性内分泌肿瘤、家族性腺瘤性息肉病或遗传性平滑肌瘤病-肾癌综合征。PRKAR1A 种系致病性变异是导致 PPNAD（孤立性或 Carney 复合体的一部分）的主要改变。
