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The combination of pituitary adenomas (PA) and phaeochromocytomas (phaeo) or paragangliomas (PGL) is a rare event. Although these endocrine tumours may occur together by coincidence, there is mounting evidence that, in at least some cases, classical phaeo/PGL-predisposing genes may also play a role in pituitary tumorigenesis. A new condition that we termed ‘3Pas’ for the association of PA with phaeo and/or PGL was recently described in patients with succinate dehydrogenase mutations and PAs. It should also be noted that the classical tumour suppressor gene, MEN1 that is the archetype of the PA-predisposing genes, is also rarely associated with phaeos in both mice and humans with MEN1 defects. In this report, we review the data leading to the discovery of 3PAs, other associations linking PAs with phaeos and/or PGLs, and the corresponding clinical and molecular genetics.
Département de Médecine Génomique des Tumeurs et des Cancers, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
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Biomedical Research Networking Centre on Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain
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Mays Cancer Center at UTHSCSA, San Antonio, Texas, USA
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Paragangliomas (PGL) of the adrenal (also known as pheochromocytomas) or extra-adrenal neural crest-derived cells are highly heritable tumors, usually driven by single pathogenic variants that occur mutually exclusively in genes involved in multiple cellular processes, including the response to hypoxia, MAPK/ERK signaling, and WNT signaling. The discovery of driver mutations has led to active clinical surveillance with outcome implications in familial PGL. The spectrum of mutations continues to grow and reveal unique mechanisms of tumorigenesis that inform tumor biology and provide the rationale for targeted therapy. Here we review recent progress in the genetics and molecular pathogenesis of PGLs and discuss new prospects for advancing research with new disease models and ongoing clinical trials presented at the recent International Symposium of Pheochromocytomas and Paragangliomas (ISP2022) held in October 2022 in Prague.
Hereditary Endocrine Cancer Group, ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Department of Pediatric Oncology, Endocrinology Division, Department of Endocrinology and Nutrition, Endocrinology Service, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain
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Hereditary Endocrine Cancer Group, ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Department of Pediatric Oncology, Endocrinology Division, Department of Endocrinology and Nutrition, Endocrinology Service, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain
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Hereditary Endocrine Cancer Group, ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Department of Pediatric Oncology, Endocrinology Division, Department of Endocrinology and Nutrition, Endocrinology Service, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain
Search for other papers by Mercedes Robledo in
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Human Cancer Genetics Program, Spanish National Cancer Research Center, Madrid, Spain
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Human Cancer Genetics Program, Spanish National Cancer Research Center, Madrid, Spain
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Pheochromocytomas and paragangliomas (PPGLs) are adrenal or extra-adrenal autonomous nervous system-derived tumors. Most PPGLs are benign, but approximately 15% progress with metastases (mPPGLs). mPPGLs are more likely to occur in patients with large pheochromocytomas, sympathetic paragangliomas, and norepinephrine-secreting tumors. Older subjects, those with larger tumors and synchronous metastases, advance more rapidly. Germline mutations of SDHB, FH, and possibly SLC25A11, or somatic MAML3 disruptions relate to a higher risk for metastatic disease. However, it is unclear whether these mutations predict outcome. Once diagnosed, there are no well-established predictors of outcome in mPPGLs, and aggressive tumors have few therapeutic options and limited response. High-specific activity (HSA) metaiodine-benzyl-guanidine (MIBG) is the first FDA approved treatment and shows clinical effectiveness for MIBG-avid mPPGLs. Ongoing and future investigations should involve validation of emerging candidate outcome biomarkers, including somatic ATRX, TERT, and microRNA disruptions and identification of novel prognostic indicators. Long-term effect of HSA-MIBG and the role of other radiopharmaceuticals should be investigated. Novel trials targeting molecular events prevalent in SDHB/FH mutant tumors, such as activated hypoxia inducible factor 2 (HIF2), angiogenesis, or other mitochondrial defects that might confer unique vulnerability to these tumors should be developed and initiated. As therapeutic options are anticipated to expand, multi-institutional collaborations and well-defined clinical and molecular endpoints will be critical to achieve higher success rates in improving care for patients with mPPGLs.
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German Center for Diabetes Research (DZD), Neuherberg, Germany
Technische Universität München, Chair of Experimental Genetics, Freising, Germany
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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.
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Hereditary Endocrine Cancer Group, Department of Pathology, Laboratory of Pathology and Oncology, Department of Medical Oncology, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Human Genetics Group, Department of Obstetrics and Gynecology, Human Cancer Genetics Programme, Spanish National Cancer Research Center, Melchor Fernández Almagro 3, 28029 Madrid, Spain
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Hereditary Endocrine Cancer Group, Department of Pathology, Laboratory of Pathology and Oncology, Department of Medical Oncology, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Human Genetics Group, Department of Obstetrics and Gynecology, Human Cancer Genetics Programme, Spanish National Cancer Research Center, Melchor Fernández Almagro 3, 28029 Madrid, Spain
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Hereditary Endocrine Cancer Group, Department of Pathology, Laboratory of Pathology and Oncology, Department of Medical Oncology, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Human Genetics Group, Department of Obstetrics and Gynecology, Human Cancer Genetics Programme, Spanish National Cancer Research Center, Melchor Fernández Almagro 3, 28029 Madrid, Spain
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Hereditary Endocrine Cancer Group, Department of Pathology, Laboratory of Pathology and Oncology, Department of Medical Oncology, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Human Genetics Group, Department of Obstetrics and Gynecology, Human Cancer Genetics Programme, Spanish National Cancer Research Center, Melchor Fernández Almagro 3, 28029 Madrid, Spain
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Hereditary Endocrine Cancer Group, Department of Pathology, Laboratory of Pathology and Oncology, Department of Medical Oncology, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Human Genetics Group, Department of Obstetrics and Gynecology, Human Cancer Genetics Programme, Spanish National Cancer Research Center, Melchor Fernández Almagro 3, 28029 Madrid, Spain
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Ovarian cancer remains one of the leading causes of cancer deaths. Thus, new biomarkers predictive of response to the standard paclitaxel–carboplatin treatment are needed to improve chemotherapy strategies. MicroRNAs have the potential to modify drug outcomes. Based on this, we have demonstrated in this study that patients with a high expression of the miR-200 family show low levels of β-tubulin class III in ovarian carcinoma. In addition, we have established the clinical relevance of these microRNAs for ovarian cancer patients' treatment response and survival. In a well-characterized series of 72 ovarian carcinomas, the expressions of miR-141, miR-200a, miR-200b, miR-200c, and miR-429 were quantified by quantitative reverse transcription-PCR, and the protein content of β-tubulin isotypes I, II, and III was determined by immunohistochemistry. The relationship between these microRNAs, β-tubulin expression, response to paclitaxel-based treatment, progression-free survival (PFS) and overall survival was determined. While isotype I had constant high levels, protein expression of β-tubulins II and III was mutually exclusive. Low tumoral miR-200 expression was significantly associated with high β-tubulin III protein content (P values range, 0.047–<0.0001), and patients without complete response (CR) had lower miR-200c levels than patients with CR (hazard ratio (HR)=1.43, 95% confidence interval (CI)=1.02–1.99, P=0.037, multivariate analysis). Additionally, low miR-200 family expression had a trend toward poor PFS (HR>2.0, P values 0.051, 0.054, and 0.079 for miR-200c, miR-141, and miR-429 respectively, multivariate analysis). In conclusion, miR-200 family members affect the final β-tubulin III protein content of ovarian carcinomas. Furthermore, these microRNAs might constitute the biomarkers of response to paclitaxel-based treatments and relapse/progression of advanced stage ovarian carcinoma patients.
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Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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Department of Medical and Molecular Genetics, Cancer Research UK Renal Molecular Oncology Research Group, Hereditary Endocrine Cancer Group, The Tumour Bank, Department of Nephrology, Institute of Biomedical Research
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The molecular genetics of inherited phaeochromocytoma have received considerable attention, but the somatic genetic and epigenetic events that characterise tumourigenesis in sporadic phaeochromocytomas are less well defined. Previously, we found considerable overlap between patterns of promoter region tumour suppressor gene (TSG) hypermethylation in two neural crest tumours, neuroblastoma and phaeochromocytoma. In order to identify candidate biomarkers and epigenetically inactivated TSGs in phaeochromocytoma and neuroblastoma, we characterised changes in gene expression in three neuroblastoma cell lines after treatment with the demethylating agent 5-azacytidine. Promoter region methylation status was then determined for 28 genes that demonstrated increased expression after demethylation. Three genes HSP47, homeobox A9 (HOXA9) and opioid binding protein (OPCML) were methylated in >10% of phaeochromocytomas (52, 17 and 12% respectively). Two of the genes, epithelial membrane protein 3 (EMP3) and HSP47, demonstrated significantly more frequent methylation in neuroblastoma than phaeochromocytoma. These findings extend epigenotype of phaeochromocytoma and identify candidate genes implicated in sporadic phaeochromocytoma tumourigenesis.
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Hereditary Endocrine Cancer Group, University Magna Graecia, Institute for Genetic Research IRGS, Genotyping Unit, ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Human Cancer Genetics Programme, Spanish National Cancer Centre, Centro Nacional de Investigaciones Oncológicas (CNIO), Calle Melchor Fernández Almagro, 3, 28029 Madrid, Spain
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Hereditary Endocrine Cancer Group, University Magna Graecia, Institute for Genetic Research IRGS, Genotyping Unit, ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Human Cancer Genetics Programme, Spanish National Cancer Centre, Centro Nacional de Investigaciones Oncológicas (CNIO), Calle Melchor Fernández Almagro, 3, 28029 Madrid, Spain
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Hereditary Endocrine Cancer Group, University Magna Graecia, Institute for Genetic Research IRGS, Genotyping Unit, ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Human Cancer Genetics Programme, Spanish National Cancer Centre, Centro Nacional de Investigaciones Oncológicas (CNIO), Calle Melchor Fernández Almagro, 3, 28029 Madrid, Spain
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Hereditary Endocrine Cancer Group, University Magna Graecia, Institute for Genetic Research IRGS, Genotyping Unit, ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Human Cancer Genetics Programme, Spanish National Cancer Centre, Centro Nacional de Investigaciones Oncológicas (CNIO), Calle Melchor Fernández Almagro, 3, 28029 Madrid, Spain
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Hereditary Endocrine Cancer Group, University Magna Graecia, Institute for Genetic Research IRGS, Genotyping Unit, ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Human Cancer Genetics Programme, Spanish National Cancer Centre, Centro Nacional de Investigaciones Oncológicas (CNIO), Calle Melchor Fernández Almagro, 3, 28029 Madrid, Spain
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The aim of this study is to assess if common genetic variants located in the CDKN1B locus, coding for the cell cycle inhibitor p27Kip1, are involved in thyroid cancer susceptibility. Based on the literature and functional predictions, we selected three polymorphisms within the CDKN1B gene (rs2066827 (T326G, V109G), rs34330 (−79C>T) and rs36228499 (−838C>A)) to perform the first case–control study in thyroid cancer involving this locus. We had 649 Spanish patients with sporadic thyroid cancer and 385 healthy representative controls available. Luciferase reporter gene assays, real-time quantitative reverse transcription-PCR and immunoblot experiments were carried out to demonstrate the putative effect of the associated variant. The polymorphism rs34330 (−79C>T) was identified as a risk factor for developing the follicular variant of papillary thyroid carcinoma (FVPTC), fitting a recessive model (odds ratio=2.12; 95% confidence interval=1.09–4.15; P value=0.023). The risk allele (T) of this single nucleotide polymorphism led to a lower transcription rate in cells transfected with a luciferase reporter driven by the polymorphic p27Kip1 promoter (P value <0.001). This effect was observed in −79TT genotype control carriers, who showed a tendency towards lower CDKN1B mRNA levels in lymphocytes, as well as at the protein level. This is the first study that identifies CDKN1B as a low-penetrance gene in thyroid cancer, and specifically in FVPTC subtype. We propose a reduced CDKN1B gene transcription depending on the genotype of the −79C>T (rs34330) variant as a novel mechanism underlying p27Kip1 downregulation.
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Loss of expression of the cyclin-dependent kinase inhibitor p27 through enhanced protein degradation frequently occurs in human cancer. Degradation of p27 requires ubiquitination by the S-phase kinase-associated protein 2 (Skp2), a member of the F-box family of Skp1–Cullin–F-box protein ubiquitin ligases. In the present study, we have investigated the role of Skp2 in human thyroid tumours. Immunohistochemistry analysis showed that Skp2 was overexpressed significantly in thyroid carcinomas (26 out of 51) compared with goitres (0 out of 12, P<0.001) or adenomas (1 out of 10, P<0.05), and that high Skp2 expression was detected more often in anaplastic thyroid (ATC; 83%, n=12) than follicular thyroid (FTC; 40%, n=20) or papillary thyroid (PTC; 42%, n=19) carcinomas (P<0.05). Thyroid cancer cell lines and tissues with high levels of Skp2 protein presented high p27 degradation activity and there was an inverse correlation between Skp2 and p27 expression in thyroid cancer tissues (n=68; P<0.05). In most cases, the observed overexpression of Skp2 protein was paralleled by an increase in the levels of Skp2 mRNA, and we observed Skp2 gene amplification at 5p13 in 2 out of 6 cell lines and in 9 out of 23 primary tumours (six out of eight ATCs, two out of nine PTCs and one out of six FTCs) using Q-PCR and/or fluorescence in situ hybridization analysis. Finally, in vitro experiments demonstrated that suppression of Skp2 expression drastically reduced proliferation of thyroid cancer cells and, conversely, forced expression of Skp2 circumvented serum dependency and contact inhibition in Skp2-negative cells by promoting p27 degradation. These findings indicate that Skp2 plays an important role for the development of thyroid cancer.
Hereditary Endocrine Cancer Group, ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Pathology Department, Histopathology Core Unit, Endocrinology Division, Endocrinology Service, Human Cancer Genetics Programme, Spanish National Cancer Center (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain
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Hereditary Endocrine Cancer Group, ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Pathology Department, Histopathology Core Unit, Endocrinology Division, Endocrinology Service, Human Cancer Genetics Programme, Spanish National Cancer Center (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain
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Hereditary Endocrine Cancer Group, ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Pathology Department, Histopathology Core Unit, Endocrinology Division, Endocrinology Service, Human Cancer Genetics Programme, Spanish National Cancer Center (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain
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Hereditary Endocrine Cancer Group, ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Pathology Department, Histopathology Core Unit, Endocrinology Division, Endocrinology Service, Human Cancer Genetics Programme, Spanish National Cancer Center (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain
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The therapeutic options for patients with metastatic medullary thyroid carcinoma (MTC) have recently increased due to the development of tyrosine kinase inhibitors (TKIs), some of which have achieved remarkable clinical responses in MTC patients. However, the molecular basis for the large variability in TKI responses is unknown. In this exploratory study, we investigated the expression of eight key TKI target proteins (EGFR, KIT, MET, PDGFRB, VEGF (VEGFA), VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4)) by immunohistochemistry in 103 molecularly characterized MTC samples and identified the associated clinical and molecular features. A number of MTC samples exhibited a high expression of VEGFR2 and VEGFR3, which were overexpressed in 57 and 43% of the MTC samples respectively. VEGFR1, PDGFRB, VEGF, KIT, and MET were present in 34–20% of the cases, while EGFR was highly expressed in only 10% of the MTC samples. Some proteins exhibited large differences in expression between sporadic and familial cases, suggesting that different RET mutations may be associated with the immunohistochemical profiles. MTC samples with the C634 RET mutation exhibited a higher expression of VEGFR3 and KIT than the M918T RET-mutated and non-mutated RET tumor samples (P=0.005 and P=0.007 respectively) and a lower expression of VEGFR1 (P=0.04). Non-mutated RET MTC cases exhibited a lower expression of PDGFRB (P=0.04). Overall, this is the first study, to our knowledge, to show that multiple TKI targets are highly expressed in a subset of MTCs, suggesting that molecular stratification of patients may have the potential to improve TKI therapies for MTC.
