Protein kinases play critical roles in cell survival, proliferation, and motility. Their dysregulation is therefore a common feature in the pathogenesis of a number of solid tumors, including thyroid cancers. Inhibiting activated protein kinases has revolutionized thyroid cancer therapy, offering a promising strategy in treating tumors refractory to radioactive iodine treatment or cytotoxic chemotherapies. However, despite satisfactory early responses, these drugs are not curative and most patients inevitably progress due to drug resistance. This review summarizes up-to-date knowledge on various mechanisms that thyroid cancer cells develop to bypass protein kinase inhibition and outlines strategies that are being explored to overcome drug resistance. Understanding how cancer cells respond to drugs and identifying novel molecular targets for therapy still represents a major challenge for the treatment of these patients.
Marie-Claude Hofmann, Muthusamy Kunnimalaiyaan, Jennifer R Wang, Naifa L Busaidy, Steven I Sherman, Stephen Y Lai, Mark Zafereo, and Maria E Cabanillas
Sasha R Howard, Sarah Freeston, Barney Harrison, Louise Izatt, Sonali Natu, Kate Newbold, Sabine Pomplun, Helen A Spoudeas, Sophie Wilne, Tom R Kurzawinski, and Mark N Gaze
This guideline is written as a reference document for clinicians presented with the challenge of managing paediatric patients with differentiated thyroid carcinoma up to the age of 19 years. Care of paediatric patients with differentiated thyroid carcinoma differs in key aspects from that of adults, and there have been several recent developments in the care pathways for this condition; this guideline has sought to identify and attend to these areas. It addresses the presentation, clinical assessment, diagnosis, management (both surgical and medical), genetic counselling, follow-up and prognosis of affected patients. The guideline development group formed of a multi-disciplinary panel of sub-speciality experts carried out a systematic primary literature review and Delphi Consensus exercise. The guideline was developed in accordance with The Appraisal of Guidelines Research and Evaluation Instrument II criteria, with input from stakeholders including charities and patient groups. Based on scientific evidence and expert opinion, 58 recommendations have been collected to produce a clear, pragmatic set of management guidelines. It is intended as an evidence base for future optimal management and to improve the quality of clinical care of paediatric patients with differentiated thyroid carcinoma.
Segolene Hescot, Abir Al Ghuzlan, Theophraste Henry, Hala Sheikh-Alard, Livia Lamartina, Isabelle Borget, Julien Hadoux, Eric Baudin, Corinne Dupuy, Alyaksandr V Nikitski, Yuri E Nikiforov, Martin Schlumberger, Marina N Nikiforova, and Sophie Leboulleux
The prognosis of poorly differentiated thyroid carcinomas (PDTC) defined by the Turin criteria is variable. The aim of this study on 51 PDTC patients was to determine clinical, histological and molecular prognostic factors associated with recurrence in patients with localized disease at initial treatment and with overall survival in patients with distant metastases. Of 40 patients for whom next-generation sequencing (NGS) by ThyroSeq v3 was able to be performed on historical samples, we identified high-risk molecular signature (TERT, TP53 mutations) in 24 (60%) cases, intermediate risk signature in 9 (22.5%) cases and low-risk signature in 7 (17.5%) cases. Potentially actionable mutations were identified in 10% of cases. After a median follow-up of 57.5 months, recurrence occurred in 11 (39%) of the 28 patients with localized disease. The American Thyroid Association (ATA) high risk of relapse, high mitotic count, high molecular risk signature and CD163 expression were associated with recurrence (P = 0.009, 0.01, 0.049, 0.03 respectively). After a median follow-up of 49.5 months, thyroid cancer-related death occurred in 53% of the patients with distant metastases. There was no significant prognostic factor associated with death in univariate analysis. However, none of the patients with intermediate ATA risk of recurrence and none of the patients with low-risk molecular signature died from the disease. In addition, high molecular-risk signature was associated with the presence of synchronous or metachronous distant metastasis (P = 0.007) and with poor overall survival (P = 0.01). In conclusion, ATA risk of relapse and high mitotic count was associated with higher rate of recurrence in localized PDTC. High molecular-risk signature was associated with the presence of distant metastasis and poor overall survival. Further studies are needed to determine if molecular testing adds to ATA risk stratification or response to therapy in predicting outcomes.
Isadora P Cavalcante, Marthe Rizk-Rabin, Christopher Ribes, Karine Perlemoine, Constanze Hantel, Annabel Berthon, Jérôme Bertherat, and Bruno Ragazzon
is a tumor suppressor gene frequently mutated in primary bilateral macronodular adrenal hyperplasia (PBMAH), an adrenal cause of Cushing’s syndrome. The function of ARMC5 is poorly understood, aside from the fact that it regulates cell viability and adrenal steroidogenesis by mechanisms still unknown. Tumor suppressor genes play an important role in modifying intracellular redox response, which in turn regulates diverse cell signaling pathways. In this study, we demonstrated that inactivation in adrenocortical cells increased the expression of actors scavenging reactive oxygen species, such as superoxide dismutases (SOD) and peroxiredoxins (PRDX) by increasing the transcriptional regulator NRF1. Moreover, ARMC5 is involved in the NRF1 ubiquitination and in its half-life. Finally, inactivation alters adrenocortical steroidogenesis through the activation of p38 pathway and decreases cell sensitivity to ferroptosis participation to increase cell viability. Altogether, this study uncovers a function of ARMC5 as a regulator of redox homeostasis in adrenocortical cells, controlling steroidogenesis and cell survival.
Masaki Shiota, Shusuke Akamatsu, Shigehiro Tsukahara, Shohei Nagakawa, Takashi Matsumoto, and Masatoshi Eto
Hormonal therapies including androgen deprivation therapy and androgen receptor (AR) pathway inhibitors such as abiraterone and enzalutamide have been widely used to treat advanced prostate cancer. However, treatment resistance emerges after hormonal manipulation in most prostate cancers, and it is attributable to a number of mechanisms, including AR amplification and overexpression, AR mutations, the expression of constitutively active AR variants, intra-tumor androgen synthesis, and promiscuous AR activation by other factors. Although various AR mutations have been reported in prostate cancer, specific AR mutations (L702H, W742L/C, H875Y, F877L, and T878A/S) were frequently identified after treatment resistance emerged. Intriguingly, these hot spot mutations were also revealed to change the binding affinity of ligands including steroids and antiandrogens and potentially result in altered responses to AR pathway inhibitors. Currently, precision medicine utilizing genetic and genomic data to choose suitable treatment for the patient is becoming to play an increasingly important role in clinical practice for prostate cancer management. Since clinical data between AR mutations and the efficacy of AR pathway inhibitors are accumulating, monitoring the AR mutation status is a promising approach for providing precision medicine in prostate cancer, which would be implemented through the development of clinically available testing modalities for AR mutations using liquid biopsy. However, there are few reviews on clinical significance of AR hot spot mutations in prostate cancer. Then, this review summarized the clinical landscape of AR mutations and discussed their potential implication for clinical utilization.
Maria Eugenia Sabatino, Juan Pablo Petiti, Liliana del Valle Sosa, Pablo Anibal Pérez, Silvina Gutiérrez, Carolina Leimgruber, Alexandra Latini, Alicia Inés Torres, and Ana Lucía De Paul
Kreepa G Kooblall, Victoria J Stokes, Omair A Shariq, Katherine A English, Mark Stevenson, John Broxholme, Benjamin Wright, Helen E Lockstone, David Buck, Simona Grozinsky-Glasberg, Christopher J Yates, Rajesh V Thakker, and Kate E Lines
Multiple endocrine neoplasia type 1 (MEN1), caused by mutations in the MEN1 gene encoding menin, is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic neuroendocrine tumours (NETs). Development of these tumours is associated with wide variations in their severity, order and ages (from <5 to >80 years), requiring life-long screening. To improve tumour surveillance and quality of life, better circulating biomarkers, particularly for pancreatic NETs that are associated with higher mortality, are required. We, therefore, examined the expression of circulating miRNA in the serum of MEN1 patients. Initial profiling analysis followed by qRT-PCR validation studies identified miR-3156-5p to be significantly downregulated (−1.3 to 5.8-fold, P < 0.05–0.0005) in nine MEN1 patients, compared to matched unaffected relatives. MEN1 knock-down experiments in BON-1 human pancreatic NET cells resulted in reduced MEN1 (49%, P < 0.05), menin (54%, P < 0.05) and miR-3156-5p expression (20%, P < 0.005), compared to control-treated cells, suggesting that miR-3156-5p downregulation is a consequence of loss of MEN1 expression. In silico analysis identified mortality factor 4-like 2 (MOR4FL2) as a potential target of miR-3156-5p, and in vitro functional studies in BON-1 cells transfected with either miR-3156-5p mimic or inhibitors showed that the miR-3156-5p mimic significantly reduced MORF4L2 protein expression (46%, P < 0.005), while miR-3156-5p inhibitor significantly increased MORF4L2 expression (1.5-fold, P < 0.05), compared to control-treated cells, thereby confirming that miR-3156-5p regulates MORF4L2 expression. Thus, the inverse relationship between miR-3156-5p and MORF4L2 expression represents a potential serum biomarker that could facilitate the detection of NET occurrence in MEN1 patients.
Han Chen, Ming Ni, Yun Xu, and Li-Yong Zhong
Children with intracranial germ cell tumors may present premature sexual development via either gonadotrophin-releasing hormone (GnRH)-dependent cause or GnRH-independent cause. We conducted a single-center retrospective study on 37 precocious puberty (PP) patients with intracranial germ cell tumors and 25 age-matched prepubertal patients with elevated human chorionic gonadotropin (hCG) levels. Classification of PP was derived from hCG, gonadotropin and sex steroid levels and their changes. Five boys were assigned to GnRH-dependent group (G1). Thirty-one boys and one girl were assigned to GnRH-independent group (G2) with a median hCG of 76.75 (8.29–2747) IU/L. Seven boys and 18 girls were conducted as controls, with a median hCG of 17.12 (2.91–1062) IU/L. Patients in G1 had constant pubertal LH and testosterone levels after tumor complete response. Patients in G2 had hCG levels that decreased simultaneously with testosterone/estradiol levels, prior to tumor regression. The differences in hCG levels and the gender ratio were significant between G2 and controls (P = 0.006 and P < 0.001, separately). Among intracranial germ cell tumor patients with positive hCG, boys with significantly higher hCG levels more easily developed PP. Our results suggest that GnRH-independent PP commonly regresses together with tumor regression. In comparison, results were inconclusive in tying tumor regression to the regression of GnRH-dependent PP.
Julien Hadoux, Thomas Walter, Christina Kanaan, Ségolène Hescot, Vincent Hautefeuille, Marine Perrier, Igor Tauveron, Sandrine Laboureau, Christine Do Cao, Caroline Petorin, Odile Blanchet, Matthieu Faron, Emmanuelle Leteurtre, Marie-Christine Rousselet, Juliette Joubert Zakeyh, Aude Marchal, Denis Chatelain, Clément Beaulaton, Valérie Hervieu, Catherine Lombard-Bohas, Michel Ducreux, Jean-Yves Scoazec, Eric Baudin, , and
Neuroendocrine carcinomas (NEC) are aggressive malignant diseases. Etoposide-based rechallenge (EBR) and the prognostic role of RB transcriptional corepressor 1 (RB1) status in second-line chemotherapy (2L) have not been studied. The objectives of this study were to report the results of 2L including EBR as well as prognostic factors in a national retrospective multicentre study. NEC patients treated with 2L and further, with tissue samples available, were included. RB1 status and morphological classification were reviewed centrally. Among the 121 NEC patients (40% female, median age 61 years) included, there were 73 small-cell NEC (60%), 34 large-cell NEC (28%) and 14 NEC (not otherwise specified, 12%). Primary sites were lung (39%), gastroenteropancreatic (36%), other (13%) and unknown (12%). Median Ki-67 index was 80%. Median progression-free survival (PFS) and overall survival (OS) under 2L were 2.1 and 6.2 months, respectively. No difference was observed between patients who received an ‘adenocarcinoma-like’ or a ‘neuroendocrine-like’ 2L or according to the RB1 status. Thoracic NEC primary was the only adverse prognostic factor for OS. EBR, administered to 31 patients, resulted in a 62% disease control rate with a median PFS and OS of 3.2 and 11.7 months, respectively. In the 94 patients with a relapse-free interval of ≥3 months after first-line platinum–etoposide chemotherapy, the median OS was 12 months in patients who received EBR as compared to 5.9 months in patients who did not (P = 0.043). EBR could be the best 2L option for patient with initial response to first-line platinum–etoposide lasting at least 3 months. RB1 status does not provide prognostic information in this setting.
Paul Benjamin Loughrey, Federico Roncaroli, Estelle Healy, Philip Weir, Madhu Basetti, Ruth T Casey, Steven J Hunter, and Márta Korbonits
Pituitary neuroendocrine tumours (PitNETs) associated with paragangliomas or phaeochromocytomas are rare. SDHx variants are estimated to be associated with 0.3–1.8% of PitNETs. Only a few case reports have documented the association with MAX variants. Prolactinomas are the most common PitNETs occurring in patients with SDHx variants, followed by somatotrophinomas, clinically non-functioning tumours and corticotrophinomas. One pituitary carcinoma has been described. SDHC, SDHB and SDHA mutations are inherited in an autosomal dominant fashion and tumorigenesis seems to adhere to Knudson’s two-hit hypothesis. SDHD and SDHAF2 mutations most commonly have paternal inheritance. Immunohistochemistry for SDHB or MAX and loss of heterozygosity analysis can support the assessment of pathogenicity of the variants. Metabolomics is promising in the diagnosis of SDHx-related disease. Future research should aim to further clarify the role of SDHx and MAX variants or other genes in the molecular pathogenesis of PitNETs, including pseudohypoxic and kinase signalling pathways along with elucidating epigenetic mechanisms to predict tumour behaviour.