Endocrine-related cancer最新文献

Pheochromocytomas and paragangliomas are neuroendocrine tumors. The development of these tumors is associated with more than 20 genes. These genes are divided into 3 clusters: pseudohypoxic, kinase-signaling, and Wnt. The pseudohypoxic cluster is the only one that is associated with DNA methylation changes, including changes in the 11p15.5 region. The aim of this study was to identify changes in the 11p15.5 region and their frequency in pheochromocytomas and paragangliomas. And compare with genomic and somatic mutations that cluster pheochromocytomas and paragangliomas. To identify alterations in the 11p15.5 region, we used the MS-MLPA technique. The results of this assay were then compared with those obtained from the SNP array (850k, Illumina). 150 samples were examined by both techniques. A total of 90 cases (60%) exhibited no alterations in the 11p15.5 region. The most common changes were maternal allele loss in 45 cases (30%), pUPD in 5 cases (3.33%) and paternal allele gain in 4 cases (2.67%). A statistically significant difference was observed in the frequency of alterations in the 11p15.5 region when comparing cluster 1 and cluster 2 (p-value <0.0001). We found that there are other alternations in the 11p15.5 region in pheochromocytomas and paragangliomas in addition to the previously described deletion of the maternal allele. This study is the first to describe pUPD and paternal allele gain in pheochromocytomas and paragangliomas. We also show that alterations in the 11p15.5 region are not unique to cluster 1.

Therapeutic options of advanced pediatric adrenocortical carcinoma (pACC) are limited, and achieving valuable risk stratification remains challenging. We refined the value of prognostic factors, with an emphasis on resection status. Retrospective, international data from 106 patients with advanced pACC from various collaborating centers of the international pACC working groups ENSAT-PACT, IC-PACT, and/ or from individual international collaboration diagnosed were collected. 106 patients aged 0.1 to 18.1 (median 7.6) years were diagnosed with pACC with 42 tumor stage III and 64 stage IV, respectively. 80% (85/106) of the tumors were hormone-producing with a mean Ki67 index for both stage groups of 29%. Patient survival was 45% (48/106) with mean follow-up of 17.7 months. Higher age, tumor stage IV, and increased Ki67 index worsened the prognosis on overall survival. Resection status had an essential impact on survival as the patients with R0 resection (n=32) had a better overall survival (71% for stage III patients; 80% for stage IV patients) than patients with R1 (n=24) (45% for stage III; 69% for stage IV), R2 (n=33) (17% for stage III; 15% for stage IV), and Rx (n=7) (0% for stage III; 17% for stage IV). Of the 10 patients with tumor spillage only few (57% of stage III; 0% of stage IV patients) survived. The resection status has an significant impact on overall survival in pACC. Therefore, tumor surgery should only be undertaken by experienced surgeons proficient in adrenalectomy and oncology, ideally within specialized pediatric oncological centers with an multi-disciplinary team setting.

The genetic component is thought to play an important role in the development of familial non-medullary thyroid carcinoma (fNMTC), but the involved molecular mechanisms and genes are poorly understood. The MAPK kinase cascade, particularly involving RAS and BRAF, is crucial in cancer development, with RIN1 emerging as a notable gene due to its differential expression across various tumor types. We identified a frameshift mutation (c.798delC: p.V267Sfs*83) in the RIN1 gene in a family with non-medullary thyroid cancer (NMTC) through Whole-Exome Sequencing. Paraffin-embedded tumor tissues were analyzed to investigate the mutation's characteristics and its potential implications within the thyroid cellular context. Functional assays and RNA sequencing using CRISPR/Cas9-edited Nthy-ori 3-1 thyroid cell line and xenograft zebrafish models confirmed the mutation effect and the putative RIN1 tumor suppressor role. The study revealed significant alterations in cellular behavior upon RIN1 knockout, including increased cell viability, proliferation, and colony formation, alongside morphological changes indicative of epithelial-mesenchymal transition. Enhanced phosphorylation of ERK and AKT suggested MAPK pathway dysregulation following RIN1 depletion, supporting its potential tumor suppressive role. Phenotypic rescue experiments confirmed that reintroduction of wild-type RIN1 restored normal cellular behavior. RNA sequencing demonstrated differential gene expression between RIN1-/- and control cells, particularly affecting pathways associated with cancer progression, closely resembled signatures specific to NMTC. This study provides compelling evidence supporting RIN1 as a tumor suppressor gene within thyroid cells. Additionally, the findings highlight its potential significance as novel gene involved in FNMTC pathogenesis.

RET is a key oncogene in neuro-endocrine cancer. Pathogenic germline variants lead to multiple different phenotypes, including multiple endocrine neoplasia type 2 (MEN2), medullary thyroid cancer (MTC), Hirschsprung disease, and kidney malformations. Pathogenic somatic variants are also associated with MTC; and RET rearrangements are observed in papillary thyroid cancer, non-small cell lung cancer (NSCLC) and pan-cancer syndromes. Testing for both germline and somatic variants is now feasible in everyday clinical practice; and their identification has important clinical consequences, both for affected individuals and their families. This mini review will discuss current germline and somatic testing strategies in the UK and worldwide, reporting, and test outcomes (including variants of uncertain significance or incidental findings). It will explore actions following identification of a pathogenic germline variant, including predictive, reproductive, and childhood testing; and somatic testing of RET variants in solid tumours informing personalised cancer treatment. Lastly, it will discuss the challenge of delivering rapid and equitable access to genomic testing, to ensure that all individuals can benefit promptly and appropriately, to improve clinical outcomes.

Pancreatic neuroendocrine tumors (PanNETs) have an age-adjusted incidence of 1.5 per 100,000 people, with a notable rise in the incidence of small (≤ 2 cm) non-functional (NF-PanNETs) in recent decades. While surgery is traditionally the preferred treatment for localized NF-PanNETs, active surveillance is now an accepted management strategy for tumors smaller than 2 cm due to their relatively benign behavior. However, this approach has not yet been fully integrated into routine clinical practice. There is considerable histopathological heterogeneity observed in NF-PanNETs which results in significant variability in clinical presentation, behavior and treatment outcomes. Hence, tumor size alone does not provide sufficient certainty regarding a benign clinical course for decision-making. Although studies advocate for incorporating WHO grade into clinical prognostic assessments, also this marker has limitations. Several established tissue-based markers, such as ATRX and DAXX alterations, alternative lengthening of telomeres (ALT), and copy number variations can be used for PanNET subtyping and correlate with metastatic risk. Combining these markers with traditional histopathological parameters may yield a more comprehensive and accurate prognostic assessment. This review discusses advantages and limitations of current prognostication methods for small NF-PanNETs and highlights recently established prognostic markers, along with the requirements for their implementation into routine clinical practice. It also proposes practical solutions to address the challenges associated with an immediate integration of these biomarkers into routine care.

The association between RET and multiple endocrine neoplasia type 2 was established in 1993 and remains one of the very few oncogenes for which distinct phenotypes (medullary thyroid cancer or pheochromocytoma) are associated with the same hot-spot variants occurring in either germline or somatic DNA. Somatic RET fusion events have also been described in several cancers, including papillary thyroid cancer, non-small-cell lung cancer, breast cancer, salivary gland cancer and pancreatic cancer. Highly selective RET inhibitors have improved outcomes in RET-altered cancers and have been well-tolerated. Nevertheless, primary and acquired drug resistance has been observed, arising from distinct genomic alterations either in RET (on-target resistance) or via alternate oncogenic pathways (bypass resistance). The same mechanisms of resistance have been observed across multiple cancer types, which implies RET-altered cancers evolve away from RET addiction via stochastic subclonal events. Understanding these mechanisms is crucial for identifying therapeutic opportunities to overcome resistance. Successful treatment targeting bypass oncogenes has been reported in several instances, at least for short-term outcomes; in contrast, although several compounds have been reported to overcome on-target RET alterations, none have yet been translated into routine clinical practice and this remains an area of urgent clinical need.

The CHAARTED study showed that adding docetaxel (Doc) to androgen deprivation therapy (ADT) in men initiating treatment for metastatic hormone-sensitive prostate cancer (mHSPC) prolongs survival, particularly in high-volume disease. Androgens drive both mHSPC and metastatic castration-resistant prostate cancer (mCRPC). Lower nadir serum testosterone concentrations are associated with better outcomes in men treated with ADT for biochemical relapse, while higher androgens at mCRPC are associated with better prognosis and increased benefit from abiraterone. We evaluated the association of serum steroids at 24 weeks with overall survival (OS) and time to CRPC (TTCRPC) in 588 men with available samples from the CHAARTED study. Steroid concentrations were measured using mass spectrometry. The median testosterone concentration at 24 weeks was 8 ng/dL and did not differ in ADT alone vs ADT plus Doc arm. Achieving nadir testosterone below 20 ng/dL was not associated with OS or TTCRPC in either arm. In high-volume disease, Doc conferred an OS and TTCRPC benefit regardless of steroid concentrations. In low-volume disease, steroid concentrations in the lowest quartile at 24 weeks identified a subset of men with poor survival outcomes more like high-volume disease, and in whom Doc was also associated with improved OS and TTCRPC. The known OS benefit of Doc in high-volume mHSPC is not modified by serum steroid concentrations achieved on treatment. In low-volume disease, steroid concentrations in the lowest quartile may identify a poor prognosis subset in whom Doc also confers OS benefit.

The molecular biology of pituitary neuroendocrine tumors (PitNETs) revealed few recurrent mutations and extensive chromosomal alterations, with the latter being the driving force in a subset of these lesions. Addressing the need for an easily applicable diagnostic tool, we conducted a retrospective study of 61 PitNETs operated at a tertiary care center. All cases were subtyped according to the 2022 WHO Classification of Endocrine Tumors. A genome-wide next-generation sequencing panel targeting 1500 single nucleotide polymorphisms (SNPs) was used to classify chromosomal imbalances, loss of heterozygosity, and copy number variations in DNA from formalin-fixed paraffin-embedded tissues. We identified four distinct chromosomal patterns, with varying distribution among different tumor lineages. Forty-two of 61 (69%) PitNETs showed chromosomal alterations. Gonadotroph PitNETs showed mostly quiet genomes. The majority of lactotroph PitNETs (19/20, 95%) were altered, exhibiting a gained genome and a remarkably low recurrence rate. Nine of ten (90%) corticotroph PitNETs harbored chromosomal alterations, of which two aggressive corticotroph tumors and one metastatic corticotroph PitNET showed massive chromosomal losses, leading to near-haploid/near-homozygous genomes. The comparison of the molecular profile of primary and recurrent PitNETs of five patients showed no significant accumulation of alterations over time. A simple genome-wide 1500-SNP test can be used in the identification of outspoken aggressive subsets of PitNETs by the occurrence of a near-haploid/near-homozygous genome. Furthermore, the presence of neoplastic tissue in the resected material can be potentially confirmed for non-gonadotroph PitNETs under suboptimal histological assessment conditions.

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Abstract: Rearranged during transfection (RET) is a developmentally important receptor tyrosine kinase that has been identified as an oncogenic driver in a number of cancers. Activating RET point mutations gives rise to the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN2), characterized by medullary thyroid carcinoma. There are two MEN2 subtypes, MEN2A and MEN2B, that differ in tumour aggressiveness and the associated constellation of other disease features, which are caused by distinct patterns of RET amino acid substitution mutations. MEN2A-RET mutations affecting extracellular cysteine residues promote ligand-independent dimerization and constitutive RET activity, while MEN2B is caused by a single amino acid change in the tyrosine kinase domain of RET, releasing autoinhibition and producing a more active MEN2B-RET kinase that can promote signalling as monomers or dimers in the absence of a ligand. These mutations cause intrinsic biochemical changes in the RET structure and activation but also trigger extrinsic effects that alter RET cellular location, interactions and mechanisms of downregulation that can prolong or mislocate RET activity, changing or enhancing functional outcomes. Furthermore, changes in specific combinations of RET-mediated effects associated with different mutations give rise to the distinct MEN2 disease phenotypes. Here, we discuss the current understanding of the intrinsic and extrinsic characteristics of RET MEN2A cysteine and MEN2B mutants and how these contribute to transforming cellular processes and to the differences in tumour progression and disease aggressiveness.