GnRH antagonist treatment of malignant adrenocortical tumors

Endocr Relat Cancer.

2018 Nov 06

Doroszko M, Chrusciel M, Stelmaszewska J, Slezak T, Anisimowicz S, Plöckinger U, Quinkler M, Bonomi M, Wolczynski S, Huhtaniemi I.
PMID: 30400009 | DOI: 10.1530/ERC-17-0399

Aberrantly expressed G protein-coupled receptors in tumors are considered as potential therapeutic targets. We analyzed the expressions of receptors of gonadotropin-releasing hormone (GNRHR), luteinizing hormone/chorionic gonadotropin (LHCGR) and follicle-stimulating hormone (FSHR) in human adrenocortical carcinomas and assessed their response to GnRH antagonist therapy. We further studied the effects of the GnRH antagonist cetrorelix acetate (CTX) on cultured adrenocortical tumor (ACT) cells (mouse Cα1 and Y-1, and human H295R), and in vivo in transgenic mice (SV40 T-antigen expression under inhibin α promoter) bearing Lhcgr and Gnrhr in ACT. Both models were treated with control (CT), CTX, human chorionic gonadotropin (hCG) or CTX+hCG, and their growth and transcriptional changes were analyzed. In situ hybridization and qPCR analysis of human adrenocortical carcinomas (n = 11-13) showed expression of GNRHR in 54/73%, LHCGR in 77/100% and FSHR in 0%, respectively. CTX treatment in vitro decreased cell viability and proliferation, and increased caspase 3/7 activity in all treated cells. In vivo, CTX and CTX+hCG (but not hCG alone) decreased ACT weights and serum LH and progesterone concentrations. CTX treatment downregulated the tumor markers Lhcgr and Gata4. Upregulated genes included Grb10, Rerg, Nfatc and Gnas, all recently found to be abundantly expressed in healthy adrenal vs ACT. Our data suggest that CTX treatment may improve the therapy of human adrenocortical carcinomas by direct action on GNRHR-positive cancer cells inducing apoptosis and/or reducing gonadotropin release, directing tumor cells towards a healthy adrenal gene expression profile.

SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile

Genetics in medicine : official journal of the American College of Medical Genetics

2022 Mar 24

Al-Jawahiri, R;Foroutan, A;Kerkhof, J;McConkey, H;Levy, M;Haghshenas, S;Rooney, K;Turner, J;Shears, D;Holder, M;Lefroy, H;Castle, B;Reis, LM;Semina, EV;Lachlan, K;Chandler, K;Wright, T;Clayton-Smith, J;Hug, FP;Pitteloud, N;Bartoloni, L;Hoffjan, S;Park, SM;Thankamony, A;Lees, M;Wakeling, E;Naik, S;Hanker, B;Girisha, KM;Agolini, E;Giuseppe, Z;Alban, Z;Tessarech, M;Keren, B;Afenjar, A;Zweier, C;Reis, A;Smol, T;Tsurusaki, Y;Nobuhiko, O;Sekiguchi, F;Tsuchida, N;Matsumoto, N;Kou, I;Yonezawa, Y;Ikegawa, S;Callewaert, B;Freeth, M;Kleinendorst, L;Donaldson, A;Alders, M;De Paepe, A;Sadikovic, B;McNeill, A;University of Washington Center for Mendelian Genomics (UW-CMG), ;Genomics England Research Consortium, ;
PMID: 35341651 | DOI: 10.1016/j.gim.2022.02.013

This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants.Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope.We reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies.SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies.

	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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