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Ilene Sussman

Landmark scientific findings are applauded. However, at the time of discovery, the future impact that these types of new knowledge might have on patients is not foreseen. This article discusses how unraveling the structure of DNA has advanced medical treatment, particularly for patients with rare diseases. In addition, each new scientific discovery brings with it the emotion of hope for improved diagnosis and treatment, as well as enhanced outcomes and increased longevity for patients facing a life-long disease.

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Catherine Goudie, Fady Hannah-Shmouni, Mahmure Kavak, Constantine A Stratakis and William D Foulkes

As medicine is poised to be transformed by incorporating genetic data in its daily practice, it is essential that clinicians familiarise themselves with the information that is now available from more than 50 years of genetic discoveries that continue unabated and increase by the day. Endocrinology has always stood at the forefront of what is called today ‘precision medicine’: genetic disorders of the pituitary and the adrenal glands were among the first to be molecularly elucidated in the 1980s. The discovery of two endocrine-related genes, GNAS and RET, both identified in the late 1980s, contributed greatly in the understanding of cancer and its progression. The use of RET mutation testing for the management of medullary thyroid cancer was among the first and one of most successful applications of genetics in informing clinical decisions in an individualised manner, in this case by preventing cancer or guiding the choice of tyrosine kinase inhibitors in cancer treatment. New information emerges every day in the genetics or system biology of endocrine disorders. This review goes over most of these discoveries and the known endocrine tumour syndromes. We cover key genetic developments for each disease and provide information that can be used by the clinician in daily practice.

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Lois M Mulligan

The focus of precision cancer medicine is the use of patient genetic signatures to predict disease occurrence and course and tailor approaches to individualized treatment to improve patient outcomes. The rearranged during transfection (RET) receptor tyrosine kinase represents a paradigm for the power of personalized cancer management to change cancer impact and improve quality of life. Oncogenic activation of RET occurs through several mechanisms including activating mutations and increased or aberrant expression. Activating RET mutations found in the inherited cancer syndrome multiple endocrine neoplasia 2 permit early diagnosis, predict disease course and guide disease management to optimize patient survival. Rearrangements of RET found in thyroid and lung tumors provide insights on potential disease aggressiveness and offer opportunities for RET-targeted therapy. Aberrant RET expression in a subset of cases is associated with tumor dissemination, resistance to therapies and/or poorer prognosis in multiple cancers. The potential of RET targeting through repurposing of small-molecule multikinase inhibitors, selective RET inhibitors or other novel approaches provides exciting opportunities to individualize therapies across multiple pathologies where RET oncogenicity contributes to cancer outcomes.

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Hartmut P Neumann, William F Young Jr, Tobias Krauss, Jean-Pierre Bayley, Francesca Schiavi, Giuseppe Opocher, Carsten C Boedeker, Amit Tirosh, Frederic Castinetti, Juri Ruf, Dmitry Beltsevich, Martin Walz, Harald-Thomas Groeben, Ernst von Dobschuetz, Oliver Gimm, Nelson Wohllk, Marija Pfeifer, Delmar M Lourenço Jr, Mariola Peczkowska, Attila Patocs, Joanne Ngeow, Özer Makay, Nalini S Shah, Arthur Tischler, Helena Leijon, Gianmaria Pennelli, Karina Villar Gómez de las Heras, Thera P Links, Birke Bausch and Charis Eng

Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic Yes! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with >35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.

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William D Foulkes, Jérôme Bertherat and Charis Eng

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Lamis Yehia and Charis Eng

An average of 10% of all cancers (range 1–40%) are caused by heritable mutations and over the years have become powerful models for precision medicine practice. Furthermore, such cancer predisposition genes for seemingly rare syndromes have turned out to help explain mechanisms of sporadic carcinogenesis and often inform normal development. The tumor suppressor PTEN encodes a ubiquitously expressed phosphatase that counteracts the PI3K/AKT/mTOR cascade – one of the most critical growth-promoting signaling pathways. Clinically, individuals with germline PTEN mutations have diverse phenotypes and fall under the umbrella term PTEN hamartoma tumor syndrome (PHTS). PHTS encompasses four clinically distinct allelic overgrowth syndromes, namely Cowden, Bannayan-Riley-Ruvalcaba, Proteus and Proteus-like syndromes. Relatedly, mutations in other genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN also predispose patients to partially overlapping clinical manifestations, with similar effects as PTEN malfunction. We refer to these syndromes as ‘PTEN-opathies.’ As a tumor suppressor and key regulator of normal development, PTEN dysfunction can cause a spectrum of phenotypes including benign overgrowths, malignancies, metabolic and neurodevelopmental disorders. Relevant to clinical practice, the identification of PTEN mutations in patients not only establishes a PHTS molecular diagnosis, but also informs on more accurate cancer risk assessment and medical management of those patients and affected family members. Importantly, timely diagnosis is key, as early recognition allows for preventative measures such as high-risk screening and surveillance even prior to cancer onset. This review highlights the translational impact that the discovery of PTEN has had on the diagnosis, management and treatment of PHTS.

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Zi Ying Tan, Taosheng Huang and Joanne Ngeow

Hereditary cancer predisposition syndromes are associated with germline mutations that lead to increased vulnerability for an individual to develop cancers. Such germline mutations in tumour suppressor genes, oncogenes and genes encoding for proteins essential in DNA repair pathways and cell cycle control can cause overall chromosomal instability in the genome and increase risk in developing cancers. Gene correction of these germline mutations to restore normal protein functions is anticipated as a new therapeutic option. This can be achieved through disruption of gain-of-function pathogenic mutation, restoration of loss-of-function mutation, addition of a transgene essential for cell function and single nucleotide changes. Genome editing tools are applicable to precise gene correction. Development of genome editing tools comes in two waves. The first wave focuses on improving targeting specificity and editing efficiency of nucleases, and the second wave of gene editing draws on innovative engineering of fusion proteins combining deactivated nucleases and other enzymes that are able to create limitless functional molecular tools. This gene editing advancement is going to impact medicine, particularly in hereditary cancers. In this review, we discuss the application of gene editing as an early intervention and possible treatment for hereditary cancers, by highlighting a selection of highly penetrant cancer syndromes as examples of how this may be achieved in clinical practice.

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Luis V Syro, Fabio Rotondo, Leon D Ortiz and Kalman Kovacs

Temozolomide is an alkylating chemotherapeutic agent used in malignant neuroendocrine neoplasia, melanoma, brain metastases and an essential component of adjuvant therapy in the treatment of glioblastoma multiforme and anaplastic astrocytoma. Since 2006, it has been used for the treatment of pituitary carcinomas and aggressive pituitary adenomas. Here, we discuss the current indications and results of temozolomide therapy in pituitary tumors, as well as frequently asked questions regarding temozolomide treatment, duration of therapy, dosage, tumor recurrence and resistance.

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Chiara Verdelli, Irene Forno, Annamaria Morotti, Pasquale Creo, Vito Guarnieri, Alfredo Scillitani, Filomena Cetani, Leonardo Vicentini, Gianni Balza, Edoardo Beretta, Stefano Ferrero, Valentina Vaira and Sabrina Corbetta

Parathyroid tumors deregulate microRNAs belonging to the two clusters on the chromosome 19, the C19MC and miR-371-373 clusters. Here, we report that the embryonic miR-372 is aberrantly expressed in half of parathyroid adenomas (PAds) in most of atypical adenomas and carcinomas (n = 15). Through in situ hybridization, we identified that miR-372-positive parathyroid tumor cells were scattered throughout the tumor parenchyma. In PAd-derived cells, ectopic miR-372 inhibited the expression of its targets CDKN1A/p21 and LATS2 at both mRNA and protein levels. Although the viability of parathyroid cells was not affected by miR-372 overexpression, the miRNA blunted camptothecin-induced apoptosis in primary PAd-derived cultures. miR-372 overexpression in parathyroid tumor cells increased parathormone (PTH) mRNA levels, and it positively correlated in vivo with circulating PTH levels. Conversely, the parathyroid-specific genes TBX1 and GCM2 were not affected by miR-372 mimic transfection. Finally, miR-372 dampened the Wnt pathway in parathyroid tumor cells through DKK1 upregulation. In conclusion, miR-372 is a novel mechanism exploited by a subset of parathyroid tumor cells to partially decrease sensitivity to apoptosis, to increase PTH synthesis and to deregulate Wnt signaling.

Open access

J Crona, F Beuschlein, K Pacak and B Skogseid

This review aims to provide clinicians and researchers with a condensed update on the most important studies in the field during 2017. We present the academic output measured by active clinical trials and peer-reviewed published manuscripts. The most important and contributory manuscripts were summarized for each diagnostic entity, with a particular focus on manuscripts that describe translational research that have the potential to improve clinical care. Finally, we highlight the importance of collaborations in adrenal tumor research, which allowed for these recent advances and provide structures for future success in this scientific field.