TY - JOUR AB - The biochemical phenotype of paragangliomas (PGLs) is highly dependent on the underlying genetic background and tumor location. PGLs at extra-adrenal locations usually do not express phenylethanolamine N-methyltransferase (PNMT), the enzyme required for epinephrine production, which was explained by the absence of glucocorticoids. PGLs with pathogenic variants (PVs) in Harvey rat sarcoma viral oncogene homolog (HRAS) can occur in or outside of the adrenal, but always synthesize epinephrine independently of the localization. Here, we characterize the signaling pathways through which PVs in HRAS influence PNMT expression. Catecholamines, cortisol, and transcriptional features of PGL tissues with known genetic background were analyzed. Genetically modified rat pheochromocytoma cells carrying PVs in Hras were generated and analyzed for regulation of Pnmt expression. Elevated epinephrine contents in PGLs with PVs in HRAS were accompanied by enrichment in mitogen-activated protein kinase (MAPK) signaling compared to PGLs with PVs in genes that activate hypoxia pathways. In vitro, Hras PVs increased Pnmt expression and epinephrine biosynthesis through increased phosphorylation of stimulatory protein 1 via MAPK signaling. Here, we provide a molecular mechanism that explains the PV-dependent epinephrine production of PGLs. AU - Li, M.* AU - Richter, S.* AU - Mohr, H. AU - Drukewitz, S.* AU - Poser, I.* AU - Stanke, D.* AU - Calsina, B.* AU - Martinez-Montes, A.M.* AU - Quinkler, M.* AU - Timmers, H.J.L.M.* AU - Nölting, S.* AU - Beuschlein, F.* AU - Remde, H.* AU - Opocher, G.* AU - Rapizzi, E.* AU - Pacak, K.* AU - Pamporaki, C.* AU - Robledo, M.* AU - Liu, L.* AU - Jiang, J.* AU - Bornstein, S.* AU - Eisenhofer, G.* AU - Fliedner, S.M.J.* AU - Bechmann, N.* C1 - 68741 C2 - 54951 CY - Starling House, 1600 Bristol Parkway N, Bristol, England TI - Regulation of epinephrine biosynthesis in HRAS-mutant paragangliomas. JO - Endocr. Relat. Cancer VL - 30 IS - 12 PB - Bioscientifica Ltd PY - 2023 SN - 1351-0088 ER - TY - JOUR AB - Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Mitotane, a derivative of the pesticide dichlorodiphenyltrichloroethane, has been used successfully as first line chemotherapy since the 1960s, if maintained within a narrow therapeutic window. Spironolactone (SPL) is frequently used to treat glucocorticoid excess-associated adverse effects such as severe hypokalemia. Although data of a previous case report indicate a link, valid data regarding SPL use and mitotane plasma concentrations in a human cohort are lacking.This retrospective analysis includes data from 54 mitotane-receiving ACC patients (14 co-administered with SPL) treated between January 2005 and April 2020 (20 male, mean age 54.1 ± 2.2 years). All available mitotane concentrations, treatment doses, tumor stage and evidence of hormone activity were collected. Primary outcomes included mitotane levels and concentration/dose ratios as well as time-in-range (TR) in patients with and without additional SPL treatment. The SPL group was characterized by higher glucocorticoid secretion. Other features such as tumor stage, size and anthropometrics were similar between groups. Interestingly, the SPL group had significantly lower mitotane levels despite higher doses. Mitotane TR was significantly reduced in the SPL group, as was time-in-range to progression. These data provide first evidence in a human cohort for potential SPL-mitotane interactions (beyond mentioned case report), which affect dose response and may modulate treatment outcomes. This should caution clinicians to carefully adjust mitotane doses during SPL treatment in ACC patients or choose alternative therapeutic options. AU - Haberbosch, L.* AU - Maurer, L.* AU - Sandforth, A. AU - Wernicke, C.* AU - Spranger, J.* AU - Mai, K.* AU - Jumpertz von Schwartzenberg, R. C1 - 64283 C2 - 52168 CY - Starling House, 1600 Bristol Parkway N, Bristol, England SP - 121-128 TI - Spironolactone is associated with reduced mitotane levels in adrenocortical carcinoma patients. JO - Endocr. Relat. Cancer VL - 29 IS - 3 PB - Bioscientifica Ltd PY - 2022 SN - 1351-0088 ER - TY - JOUR AB - Aggressive pheochromocytomas and paragangliomas (PPGLs) are difficult to treat, and molecular targeting is being increasingly considered, but with variable results. This study investigates established and novel molecular-targeted drugs and chemotherapeutic agents for the treatment of PPGLs in human primary cultures and murine cell line spheroids. In PPGLs from 33 patients, including 7 metastatic PPGLs, we identified germline or somatic driver-mutations in 79% of cases, allowing us to assess potential differences in drug responsivity between pseudohypoxia-associated cluster 1- (n=10) and kinase signaling-associated cluster 2-related (n=14) PPGL primary cultures. Single anti-cancer drugs were either more effective in cluster 1 (cabozantinib, selpercatinib, 5-FU) or similarly effective in both clusters (everolimus, sunitinib, alpelisib, trametinib, niraparib, entinostat, gemcitabine, AR-A014418, high-dose zoledronic acid). High-dose estrogen and low-dose zoledronic acid were the only single substances more effective in cluster 2. Neither cluster 1- nor cluster 2-related patient primary cultures responded to HIF-2α inhibitors, temozolomide, dabrafenib, or octreotide. We showed particular efficacy of targeted combination treatments (cabozantinib/everolimus, alpelisib/everolimus, alpelisib/trametinib) in both clusters, with higher efficacy of some targeted combinations in cluster 2 and overall synergistic effects (cabozantinib/everolimus, alpelisib/trametinib) or synergistic effects in cluster 2 (alpelisib/everolimus). Cabozantinib/everolimus combination therapy, gemcitabine, and high-dose zoledronic acid appear to be promising treatment options with particularly high efficacy in SDHB-mutant and metastatic tumors. In conclusion, only minor differences regarding drug responsivity were found between cluster 1 and cluster 2: some single anti-cancer drugs were more effective in cluster 1 and some targeted combination treatments were more effective in cluster 2. AU - Wang, K.* AU - Schütze, I.* AU - Gulde, S. AU - Bechmann, N.* AU - Richter, S.* AU - Helm, J.* AU - Lauseker, M.* AU - Maurer, J.* AU - Reul, A.* AU - Spoettl, G.* AU - Klink, B.* AU - William, D.* AU - Knösel, T.* AU - Friemel, J.* AU - Bihl, M.* AU - Weber, A.* AU - Fankhauser, M.* AU - Schober, L.* AU - Vetter, D.* AU - Broglie Däppen, M.* AU - Ziegler, C.* AU - Ullrich, M.* AU - Pietzsch, J.* AU - Bornstein, S.R.* AU - Lottspeich, C.* AU - Kroiss, M.* AU - Fassnacht, M.* AU - Wenter, V.U.J.* AU - Ladurner, R.* AU - Hantel, C.* AU - Reincke, M.* AU - Eisenhofer, G.* AU - Grossman, A.B.* AU - Pacak, K.* AU - Beuschlein, F.* AU - Auernhammer, C.J.* AU - Pellegata, N.S. AU - Nölting, S.* C1 - 64827 C2 - 52510 SP - 285-306 TI - Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures. JO - Endocr. Relat. Cancer VL - 29 IS - 6 PY - 2022 SN - 1351-0088 ER - TY - JOUR AB - Thyroid carcinoma incidence rates in western societies are among the fastest rising, compared to all malignant tumors over the past two decades. While risk factors such as age and exposure to ionizing radiation are known, early-state carcinogenic processes or pre-lesions are poorly understood or unknown. This study aims at the identification and characterization of early-state radiation-associated neoplastic processes by histologic and transcriptomic analyses of thyroid tissues derived from a mouse model. Comprehensive histological examination of 246 thyroids (164 exposed, 82 non-exposed) was carried out. Proliferative and normal tissues from exposed cases and normal tissue from non-exposed cases were collected by laser-capture microdissection, followed by RNAseq transcriptomic profiling using a low input 3`-library preparation protocol, differential gene expression analysis and functional association by Gene Set Enrichment Analysis. Nine exposed samples exhibited proliferative lesions, while none of the non-exposed samples showed histological abnormalities, indicating an association of ionizing radiation exposure with histological abnormalities. Activated immune response signaling and deregulated metabolic processes were observed in irradiated tissue with normal histology compared to normal tissue from non-exposed samples. Proliferative lesions compared to corresponding normal tissues showed enrichment for mainly proliferation-associated gene sets. Consistently, proliferative lesion samples from exposed mice showed elevated proliferation-associated signaling and deregulated metabolic processes compared to normal samples from non-exposed mice. Our findings suggest that a molecular deregulation may be detectable in histologically normal thyroid tissues and in early proliferative lesions in the frame of multi-step progression from irradiated normal tissue to tumorous lesions. AU - Stauffer, E. AU - Weber, P. AU - Heider, T. AU - Dalke, C. AU - Blutke, A. AU - Walch, A.K. AU - Burgstaller, G. AU - Brix, N.* AU - Lauber, K.* AU - Zitzelsberger, H. AU - Unger, K. AU - Selmansberger, M. C1 - 61493 C2 - 50315 CY - Starling House, 1600 Bristol Parkway N, Bristol, England SP - 213-224 TI - Transcriptomic landscape of radiation-induced murine thyroid proliferative lesions. JO - Endocr. Relat. Cancer VL - 28 IS - 3 PB - Bioscientifica Ltd PY - 2021 SN - 1351-0088 ER - TY - JOUR AB - Extract: Prostate cancer (PCa) and type 2 diabetes mellitus are under the most frequent diseases in men with a tremendous impact on morbidity and mortality (Giovannucci, et al. 2010). Incidence of many common types of cancer is known to be higher in diabetes (Giovannucci et al. 2010). However, studies reported that incidence of PCa is not increased in men with type 2 diabetes, some studies even found reduced prevalence (Kasper, et al. 2009). In contrast, PCa survival is markedly reduced in patients with coincident type 2 diabetes (Chen, et al. 2017). The underlying molecular mechanisms for shortened survival are still under ongoing debate and not fully understood. They might include altered insulin or IGF-1 signaling and enhanced androgen receptor activity. Of note, diabetes and PCa share numerous risk factors, most importantly the nonmodifiable risk factor age and the modifiable risk factor obesity (Giovannucci et al. 2010). Although PCa incidence is not elevated in obese men, patients with excess bodyweight are reported to display higher cancer-related mortality (Ma, et al. 2008). Carefully adjusted studies for these risk factors investigating the impact of diabetes on PCa outcomes and aggressiveness are sparse. To better understand why PCa related survival is shortened in men with concommittant diabetes, we evaluated the relation of diabetes with TNM-staging and an established PCa risk score (Mohler, et al. 2016), independent of age and body weight ... AU - Lutz, S.Z. AU - Todenhöfer, T.* AU - Wagner, R. AU - Hennenlotter, J.* AU - Ferchl, J.M.* AU - Scharpf, M.O.* AU - Martus, P.* AU - Staiger, H. AU - Fritsche, A. AU - Stenzl, A.* AU - Häring, H.-U. AU - Heni, M. C1 - 52728 C2 - 44204 CY - Bristol SP - L19-L22 TI - Higher prevalence of lymph node metastasis in prostate cancer in patients with diabetes. JO - Endocr. Relat. Cancer VL - 25 IS - 3 PB - Bioscientifica Ltd PY - 2018 SN - 1351-0088 ER - TY - JOUR AB - Rats affected by the MENX syndrome spontaneously develop multiple neuroendocrine tumors (NETs) including adrenal, pituitary and thyroid gland neoplasms. MENX was initially reported to be inherited as a recessive trait and affected rats were found to be homozygous for the predisposing Cdkn1b mutation encoding p27. We here report that heterozygous MENX-mutant rats (p27+/mut) develop the same spectrum of NETs seen in the homozygous (p27mut/mut) animals but with slower progression. Consequently, p27+/mut rats have a significantly shorter lifespan compared with their wild-type (p27+/+) littermates. In the tumors of p27+/mut rats, the wild-type Cdkn1b allele is neither lost nor silenced, implying that p27 is haploinsufficient for tumor suppression in this model. Transcriptome profiling of rat adrenal (pheochromocytoma) and pituitary tumors having different p27 dosages revealed a tissue-specific, dose-dependent effect of p27 on gene expression. In p27+/mut rats, thyroid neoplasms progress to invasive and metastatic medullary thyroid carcinomas (MTCs) accompanied by increased calcitonin levels, as in humans. Comparison of expression signatures of late-stage vs early-stage MTCs from p27+/mut rats identified genes potentially involved in tumor aggressiveness. The expression of a subset of these genes was evaluated in human MTCs and found to be associated with aggressive RET-M918T-positive tumors. Altogether, p27 haploinsufficiency in MENX rats uncovered a novel, representative model of invasive and metastatic MTC exploitable for translational studies of this often aggressive and incurable cancer. AU - Molatore, S. AU - Kügler, A. AU - Irmler, M. AU - Wiedemann, T. AU - Neff, F. AU - Feuchtinger, A. AU - Beckers, J. AU - Robledo, M.* AU - Roncaroli, F.* AU - Pellegata, N.S. C1 - 52358 C2 - 43916 CY - Bristol SP - 145-162 TI - Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: A novel model of invasive medullary thyroid carcinoma. JO - Endocr. Relat. Cancer VL - 25 IS - 2 PB - Bioscientifica Ltd PY - 2018 SN - 1351-0088 ER - TY - JOUR AB - Pheochromocytomas (PCCs) are mostly benign tumors, amenable to complete surgical resection. However, 10–17% of cases can become malignant, and once metastasized, there is no curative treatment for this disease. Given the need to identify the effective therapeutic approaches for PCC, we evaluated the antitumor potential of the dual-PI3K/mTOR inhibitor BEZ235 against these tumors. We employed an in vivo model of endogenous PCCs (MENX mutant rats), which closely recapitulate the human tumors. Mutant rats with PCCs were treated with 2 doses of BEZ235 (20 and 30 mg/kg), or with placebo, for 2 weeks. Treatment with BEZ235 induced cytostatic and cytotoxic effects on rat PCCs, which could be appreciated by both staining the tumors ex vivo with appropriate markers and non-invasively by functional imaging (diffusion-weighted magnetic resonance imaging) in vivo. Transcriptomic analyses of tumors from rats treated with BEZ235 or placebo-identified potential mediators of therapy response were performed. Slc6a2, encoding the norepinephrine transporter (NET), was downregulated in a dose-dependent manner by BEZ235 in rat PCCs. Moreover, BEZ235 reduced Slc6a2/NET expression in PCC cell lines (MPC) also. Studies of a BEZ235-resistant derivative of the MPC cell line confirmed that the reduction of NET expression associates with the response to the drug. Reduction of NET expression after BEZ235 treatment in vivo could be monitored by positron emission tomography (PET) using a tracer targeting NET. Altogether, here we demonstrate the efficacy of BEZ235 against PCC in vivo, and show that functional imaging can be employed to monitor the response of PCC to PI3K/mTOR inhibition therapy. AU - Lee, M.S. AU - Minaskan Karabid, N. AU - Wiedemann, T. AU - Irmler, M. AU - Beckers, J. AU - Yousefi, B.H.* AU - Kaissis, G.* AU - Braren, R.* AU - Laitinen, I.* AU - Pellegata, N.S. C1 - 49972 C2 - 41946 CY - Bristol SP - 1-15 TI - Targeting PI3K/mTOR signaling exerts potent antitumor activity in pheochromocytoma in vivo. JO - Endocr. Relat. Cancer VL - 24 IS - 1 PB - Bioscientifica Ltd PY - 2017 SN - 1351-0088 ER - TY - JOUR AB - Animal models of cancer have been instrumental in advancing our understanding of the biology of tumor initiation and progression, in studying gene function and in performing preclinical studies aimed at testing novel therapies. Several animal models of the MEN1 syndrome have been generated in different organisms by introducing loss-of-function mutations in the orthologues of the human MEN1 gene. In this review, we will discuss MEN1 and MEN1-like models in Drosophila, mice and rats. These model systems with their specific advantages and limitations have contributed to elucidate the function of Menin in tumorigenesis, which turned out to be remarkably conserved from flies to mammals, as well as the biology of the disease. Mouse models of MEN1 closely resemble the human disease in terms of tumor spectrum and associated hormonal changes, although individual tumor frequencies are variable. Rats affected by the MENX (MEN1-like) syndrome share some features with MEN1 patients albeit they bear a germline mutation in Cdkn1b (p27) and not in Men1 Both Men1-knockout mice and MENX rats have been exploited for therapy-response studies testing novel drugs for efficacy against neuroendocrine tumors (NETs) and have provided promising leads for novel therapies. In addition to presenting well-established models of MEN1, we also discuss potential models which, if implemented, might broaden even further our knowledge of neuroendocrine tumorigenesis. In the future, patient-derived xenografts in zebrafish or mice might allow us to expand the tool-box currently available for preclinical studies of MEN1-associated tumors. AU - Mohr, H. AU - Pellegata, N.S. C1 - 51604 C2 - 43322 CY - Bristol SP - T161-T177 TI - Animal models of MEN1. JO - Endocr. Relat. Cancer VL - 24 IS - 10 PB - Bioscientifica Ltd PY - 2017 SN - 1351-0088 ER - TY - JOUR AB - X-linked acro-gigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and a microduplication in chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in 2 families was dominant with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight SDS score of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF-1 and prolactin, usually due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high somatostatin receptor subtype-2 expression in tumor tissue. Postoperative adjuvant pegvisomant achieved control of IGF-1 all 5 cases in which it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management. AU - Beckers, A.* AU - Lodish, M.* AU - Giampaolo, T.* AU - Rostomyan, L.* AU - Lee, M.S. AU - Faucz, F.R.* AU - Yuan, B.* AU - Choong, C.* AU - Caberg, J.H.* AU - Verrua, E.* AU - Naves, L.A.* AU - Cheetham, T.* AU - Young, J.* AU - Lysy, P.* AU - Petrossians, P.* AU - Cotterill, A.* AU - Shah, N.* AU - Metzger, D.* AU - Castermans, E.* AU - Ambrosio, M.R.* AU - Villa, C.* AU - Strebkova, N.* AU - Mazerkina, N.* AU - Gaillard, S.* AU - Barcelos Barra, G.* AU - Casulari, L.A.* AU - Neggers, S.* AU - Salvatori, R.* AU - Jaffrain-Rea, M.L.* AU - Zacharin, M.* AU - Lecumberri Santamaria, B.* AU - Zacharieva, S.* AU - Lim, E.M.* AU - Mantovani, G.* AU - Zatelli, M.C.* AU - Collins, M.T.* AU - Bonneville, J.F.* AU - Quezado, M.M.* AU - Chittiboina, P.* AU - Oldfield, E.* AU - Bours, V.* AU - Liu, P.* AU - de Herder, W.W.* AU - Pellegata, N.S. AU - Lupski, J.R.* AU - Daly, A.F.* AU - Stratakis, C.A.* C1 - 43513 C2 - 36559 CY - Bristol SP - 353-367 TI - X-Linked Acrogigantism (X-LAG) syndrome: Clinical profile and therapeutic responses. JO - Endocr. Relat. Cancer VL - 22 IS - 3 PB - Bioscientifica Ltd PY - 2015 SN - 1351-0088 ER - TY - JOUR AB - Gonadotroph pituitary adenomas (GPAs) often present as invasive macroadenomas not amenable to complete surgical resection. Radiotherapy is the only post-operative option for patients with large invasive or recurrent lesions. No medical treatment is available for these patients. The somatostatin analogues (SSAs) octreotide and lanreotide that preferentially target somatostatin receptor type 2 (SSTR2) have little effect on GPAs. It is widely accepted that the expression of specific SSTR subtypes determines the response to SSAs. Given that previous studies on mRNA and protein expression of SSTRs in GPAs generated conflicting results, we investigated the expression of SSTR2, SSTR3 and SSTR5 (the main targets of available SSAs) in a clinically and pathologically well characterized cohort of 108 patients with GPAs. A total of 118 samples were examined by immunohistochemistry using validated and specific monoclonal antibodies. Matched primary and recurrent tissues were available for 10 patients. The results obtained were validated in an independent cohort of 27 GPAs. We observed that SSTR3 was significantly more abundant than SSTR2 (P<0.0001) in GPAs, while full-length SSTR5 was only expressed in few tumors. SSTR3 expression was similar in primary and recurrent adenomas, was high in potentially aggressive lesions and did not significantly change in adenomas that recurred after irradiation. In conclusion, low expression of SSTR2 may account for the limited response of GPAs to octreotide and lanreotide. Given the potent anti-proliferative, pro-apoptotic and anti-angiogenic activities of SSTR3, targeting this receptor with a multireceptor ligand SSA such as pasireotide may be indicated for potentially aggressive GPAs. AU - Lee, M.S. AU - Lupp, A.* AU - Mendoza, N.M.* AU - Martin, N.M.* AU - Beschorner, R.* AU - Honegger, J.* AU - Schlegel, J.* AU - Shively, T.* AU - Pulz, E. AU - Schulz, S.* AU - Roncaroli, F.* AU - Pellegata, N.S. C1 - 43043 C2 - 35963 CY - Bristol SP - 111-119 TI - SSTR3 is a putative target for the medical treatment of gonadotroph adenomas of the pituitary. JO - Endocr. Relat. Cancer VL - 22 IS - 1 PB - Bioscientifica Ltd PY - 2015 SN - 1351-0088 ER - TY - JOUR AB - Germline mutations in p27kip1 are associated with increased susceptibility to multiple endocrine neoplasias both in rats and humans, however the potential role of common polymorphisms of this gene in endocrine tumor susceptibility and tumorigenesis remain mostly unrecognized. To assess the risk associated with polymorphism rs2066827 (p27 V109G), we genotyped a large cohort of Brazilian patients with sporadic endocrine tumors (pituitary adenomas [n=252]; pheochromocytomas [n=125]; medullary thyroid carcinoma [n=51] and parathyroid adenomas [n=19]) and 885 population-matched healthy controls and determined the odds ratios and 95% CIs. Significant associations were found for the group of patients with pituitary adenomas (p=0.01), particularly for those with ACTH-secreting pituitary adenomas (p=0.005). In contrast, no association was found with GH-secreting pituitary tumors alone or with MEN2-related tumors. Our in vitro analyses revealed increased colony formation and cell growth rate for an atT20 corticotropin mouse cell line over-expressing the p27 V109G variant compared to cells transfected with the wild-type p27. However, the genotypic effects in genetic and in vitro approaches were divergent. In accordance with our genetic data showing specificity for ACTH-secreting pituitary tissues, the over-expression of p27 V109G in a GH3 somatotropin rat cell line presented no difference compared to the wild type. Pituitary tumors are one of the major clinical components of syndromes associated with the p27 pathogenic mutations MENX and MEN4. Our genetic and in vitro data indicate that the common polymorphism rs2066827 may play a role in corticotropinoma susceptibility and tumorigenesis through a molecular mechanism not fully understood thus far. AU - Sekiya, T.* AU - Bronstein, M.D.* AU - Benfini, K. AU - Longuini, V.C.* AU - Jallad, R.S.* AU - Machado, M.C.* AU - Goncalves, T.D.* AU - Osaki, L.H.* AU - Higashi, L.* AU - Lima-Jr, J.V.* AU - Kater, C.E.* AU - Lee, M.* AU - Molatore, S. AU - Francisco, G.* AU - Chammas, R.* AU - Naslavsky, M.* AU - Schlesinger, D.* AU - Gama, P.* AU - Duarte, Y.A.* AU - Lebrao, M.L.* AU - Zatz, M.* AU - Meirelles, O.* AU - Liberman, B.* AU - Fragoso, M.C.* AU - Toledo, S.P.* AU - Pellegata, N.S. AU - Toledo, R.A.* C1 - 30798 C2 - 33878 SP - 395-404 TI - p27 variant and corticotropinoma susceptibility: A genetic and in vitro study. JO - Endocr. Relat. Cancer VL - 21 IS - 3 PY - 2014 SN - 1351-0088 ER - TY - JOUR AB - For an identification of novel candidate genes in thyroid tumourigenesis, we have investigated gene copy number changes in a Trk-T1 transgenic mouse model of thyroid neoplasia. For this aim, 30 thyroid tumours from Trk-T1 transgenics were investigated by comparative genomic hybridisation. Recurrent gene copy number alterations were identified and genes located in the altered chromosomal regions were analysed by Gene Ontology term enrichment analysis in order to reveal gene functions potentially associated with thyroid tumourigenesis. In thyroid neoplasms from Trk-T1 mice, a recurrent gain on chromosomal bands 1C4-E2.3 (10.0% of cases), and losses on 3H1-H3 (13.3%), 4D2.3-E2 (43.3%) and 14E4-E5 (6.7%) were identified. The genes Twist2, Ptma, Pde6d, Bmpr1b, Pdlim5, Unc5c, Srm, Trp73, Ythdf2, Taf12 and Slitrk5 are located in these chromosomal bands. Copy number changes of these genes were studied by fluorescence in situ hybridisation on 30 human papillary thyroid carcinoma (PTC) samples and altered gene expression was studied by qRT-PCR analyses in 67 human PTC. Copy number gains were detected in 83% of cases for TWIST2 and in 100% of cases for PTMA and PDE6D. DNA losses of SLITRK1 and SLITRK5 were observed in 21% of cases and of SLITRK6 in 16% of cases. Gene expression was significantly up-regulated for UNC5C and TP73 and significantly down-regulated for SLITRK5 in tumours compared with normal tissue. In conclusion, a global genomic copy number analysis of thyroid tumours from Trk-T1 transgenic mice revealed a number of novel gene alterations in thyroid tumourigenesis that are also prevalent in human PTCs. Endocrine-Related Cancer (2012) 19 409-421 AU - Heiliger, K.-J. AU - Hess J. AU - Vitagliano, D.* AU - Salerno, P.* AU - Braselmann, H. AU - Salvatore, G.* AU - Ugolini, C.* AU - Summerer, I. AU - Bogdanova, T.* AU - Unger, K.* AU - Thomas, G.* AU - Santoro, M.* AU - Zitzelsberger, H. C1 - 8393 C2 - 30095 SP - 409-421 TI - Novel candidate genes of thyroid tumourigenesis identified in Trk-T1 transgenic mice. JO - Endocr. Relat. Cancer VL - 19 IS - 3 PB - Bioscientifica Ltd. PY - 2012 SN - 1351-0088 ER - TY - JOUR AB - Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP account only for 15-25% of FIPA families. CDKN1B mutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations in CDKN1B occur among a large cohort of AIP mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA families were studied and 124 affected subjects underwent sequencing of CDKN1B. Functional analysis of putative CDKN1B mutations was performed using in silico and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T). In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27(I119T) shows an abnormal migration pattern by SDS-PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic because In vitro effects were not seen. In conclusion, two patients had germline sequence changes in CDKN1B, which led to functional alterations in the encoded p27 proteins in vitro. Such rare CDKN1B variants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients make CDKN1B sequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role of CDKN1B in pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4. AU - Tichomirowa, M.A.* AU - Lee, M.S. AU - Barlier, A.* AU - Daly, A.F.* AU - Marinoni, I. AU - Jaffrain-Rea, M.L.* AU - Naves, L.A.* AU - Rodien, P.* AU - Rohmer, V.* AU - Faucz, F.R.* AU - Caron, P.* AU - Estour, B.* AU - Lecomte, P.* AU - Borson-Chazot, F.* AU - Penfornis, A.* AU - Yaneva, M.* AU - Guitelman, M.* AU - Castermans, E.* AU - Verhaege, C.* AU - Wémeau, J.L.* AU - Tabarin, A.* AU - Fajardo Montañana, C.* AU - Delemer, B.* AU - Kerlan, V.* AU - Sadoul, J.L.* AU - Cortet Rudelli, C.* AU - Archambeaud, F.* AU - Zacharieva, S.* AU - Theodoropoulou, M.* AU - Brue, T.* AU - Enjalbert, A.* AU - Bours, V.* AU - Pellegata, N.S. AU - Beckers, A.* C1 - 7464 C2 - 29724 SP - 233-241 TI - Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds. JO - Endocr. Relat. Cancer VL - 19 IS - 3 PB - Bioscientifica Ltd. PY - 2012 SN - 1351-0088 ER - TY - JOUR AB - Chromosomal copy number alterations and chromosomal rearrangements are frequent mutations in human cancer. Unlike copy number alterations, little is known about the role and occurrence of chromosomal rearrangements in breast cancer. This may be due to the fact that chromosome-based breakpoint analysis is widely restricted to cultured cells. In order to identify gene rearrangements in breast cancer we studied the chromosomal breakpoints in radiation-transformed epithelial breast cell lines using a high-resolution array-based approach using 1Mb BAC arrays. The breakpoints were further narrowed down by FISH with clones from the 32k BAC library. The analysis of the cell lines B42-11 and B42-16 revealed rearrangements of chromosomes 7, 8, 10 and 12. We identified the genes Has2, Grid1, Ret, Cpm, Tbx3, Tbx5, Tuba1a, Wnt1 and Arf3 within the breakpoint regions. Quantitative RT-PCR showed a deregulated expression of all of these candidate genes except for Tbx5 and Tbx3. This is the first study demonstrating gene rearrangements and their deregulated mRNA expression in radiation-transformed breast cells. Since the gene rearrangements occurred in the transformed and tumourigenic cell lines only it is likely that these were generated in conjunction with malignant transformation of the epithelial breast cells and therefore might reflect early molecular events in breast carcinogenesis. Initial studies indicate that these gene alterations are also found in sporadic breast cancers. AU - Unger, K. AU - Wienberg, J.* AU - Riches, A.* AU - Hieber, L. AU - Walch, A.K. AU - Brown, A. AU - O'Brien, P.C.* AU - Briscoe, C.* AU - Gray, L.* AU - Rodriguez, E. AU - Jackl, G. AU - Knijnenburg, J.* AU - Tallini, G.* AU - Ferguson-Smith, M.* AU - Zitzelsberger, H. C1 - 1079 C2 - 26688 SP - 87-98 TI - Novel gene rearrangements in transformed breast cells identified by high-resolution breakpoint analysis of chromosomal aberrations. JO - Endocr. Relat. Cancer VL - 17 IS - 1 PB - Bioscientifica Ltd PY - 2010 SN - 1351-0088 ER -