Precision oncology for RET-related tumors

Aberrant activation of the RET proto-oncogene is implicated in a plethora of cancers. RET gain-of-function point mutations are driver events in multiple endocrine neoplasia 2 (MEN2) syndrome and in sporadic medullary thyroid cancer, while RET rearrangements are driver events in several non-medullary thyroid cancers. Drugs able to inhibit RET have been used to treat RET-mutated cancers. Multikinase inhibitors were initially used, though they showed modest efficacy and significant toxicity. However, new RET selective inhibitors, such as selpercatinib and pralsetinib, have recently been tested and have shown good efficacy and tolerability, even if no direct comparison is yet available between multikinase and selective inhibitors. The advent of high-throughput technology has identified cancers with rare RET alterations beyond point mutations and fusions, including RET deletions, raising questions about whether these alterations have a functional effect and can be targeted by RET inhibitors. In this mini review, we focus on tumors with RET deletions, including deletions/insertions (indels), and their response to RET inhibitors

The legacy of the COVID-19 pandemics for thyroid cancer patients: towards the application of clinical practice recommendations

The outbreak of COVID-19 pandemic has acted as a significant stress test for healthcare systems worldwide, due to the need for hospitalization of an increasing number of infected patients. The shift of massive resources to the acute needs of the pandemic led to an upheaval of the usual diagnostic and therapeutic pathways of chronic diseases, including thyroid cancer disease. The motto was to reduce crowding at clinics and to maintain essential health services. However, thyroid cancer clinical practice recommendations already encouraged physicians to reduce “low-value” care: in particular, to avoid screening of general population, to reduce the number of unnecessary biopsies, and to adopt a conservative approach to indeterminate thyroid nodules and low-risk thyroid cancer

Prediction of response to vemurafenib in BRAF V600E mutant cancers based on a network approach

Lung adenocarcinoma is the tumor with the highest number of switch genes (298) compared to its normal tissue, followed by thyroid (227) and colorectal (183) cancers. Switch genes codifying for kinases were 14,7 and 3 respectively.We looked for three homology sequences identified across vemurafenib targets and we found that thyroid cancer and lung adenocarcinoma have a similar number of putative targetable switch genes kinase (5-6); on the contrary, colorectal cancer has just one,with minor homology sequence

Clinical epigenetics settings for cancer and cardiovascular diseases: real-life applications of network medicine at the bedside

Despite impressive efforts invested in epigenetic research in the last 50 years, clinical applications are still lacking. Only a few university hospital centers currently use epigenetic biomarkers at the bedside. Moreover, the overall concept of precision medicine is not widely recognized in routine medical practice and the reductionist approach remains predominant in treating patients affected by major diseases such as cancer and cardiovascular diseases. By its’ very nature, epigenetics is integrative of genetic networks. The study of epigenetic biomarkers has led to the identification of numerous drugs with an increasingly significant role in clinical therapy especially of cancer patients. Here, we provide an overview of clinical epigenetics within the context of network analysis. We illustrate achievements to date and discuss how we can move from traditional medicine into the era of network medicine (NM), where pathway-informed molecular diagnostics will allow treatment selection following the paradigm of precision medicine

Clinical epigenetics settings for cancer and cardiovascular diseases: real-life applications of network medicine at the bedside

Despite impressive efforts invested in epigenetic research in the last 50 years, clinical applications are still lacking. Only a few university hospital centers currently use epigenetic biomarkers at the bedside. Moreover, the overall concept of precision medicine is not widely recognized in routine medical practice and the reductionist approach remains predominant in treating patients affected by major diseases such as cancer and cardiovascular diseases. By its' very nature, epigenetics is integrative of genetic networks. The study of epigenetic biomarkers has led to the identification of numerous drugs with an increasingly significant role in clinical therapy especially of cancer patients. Here, we provide an overview of clinical epigenetics within the context of network analysis. We illustrate achievements to date and discuss how we can move from traditional medicine into the era of network medicine (NM), where pathway-informed molecular diagnostics will allow treatment selection following the paradigm of precision medicine

Circulating miR-26b-5p and miR-451a as diagnostic biomarkers in medullary thyroid carcinoma patients

Purpose/methodsThe determination of tumour biomarkers is paramount to advancing personalized medicine, more so in rare tumours like medullary thyroid carcinoma (MTC), whose diagnosis is still challenging. The aim of this study was to identify non-invasive circulating biomarkers in MTC. To achieve this goal, paired MTC tissue and plasma extracellular vesicle samples were collected from multiple centres and microRNA (miRNA) expression levels were evaluated.ResultsThe samples from a discovery cohort of 23 MTC patients were analysed using miRNA arrays. Lasso logistic regression analysis resulted in the identification of a set of circulating miRNAs as diagnostic biomarkers. Among them, miR-26b-5p and miR-451a, were highly expressed and their expression decreased during follow-up in disease-free patients in the discovery cohort. Circulating miR-26b-5p and miR-451a were validated using droplet digital PCR in a second independent cohort of 12 MTC patients.ConclusionThis study allowed the identification and validation of a signature of two circulating miRNAs, miR-26b-5p and miR-451a, in two independent cohorts reporting a significant diagnostic performance for MTC. The results of this study offer advancements in molecular diagnosis of MTC proposing a novel non-invasive tool to use in precision medicine

SEaCorAl: Identifying and contrasting the regulation-correlation bias in RNA-Seq paired expression data of patient groups

The Cancer Genome Atlas database offers the possibility of analyzing genome-wide expression RNA-Seq cancer data using paired counts, that is, studies where expression data are collected in pairs of normal and cancer cells, by taking samples from the same individual. Correlation of gene expression profiles is the most common analysis to study co-expression groups, which is used to find biological interpretation of -omics big data. The aim of the paper is threefold: firstly we show for the first time, the presence of a “regulation-correlation bias” in RNA-Seq paired expression data, that is an artifactual link between the expression status (up- or down-regulation) of a gene pair and the sign of the corresponding correlation coefficient. Secondly, we provide a statistical model able to theoretically explain the reasons for the presence of such a bias. Thirdly, we present a bias-removal algorithm, called SEaCorAl, able to effectively reduce bias effects and improve the biological significance of correlation analysis. Validation of the SEaCorAl algorithm is performed by showing a significant increase in the ability to detect biologically meaningful associations of positive correlations and a significant increase of the modularity of the resulting unbiased correlation network

Rare germline variants in DNA repair-related genes are accountable for papillary thyroid cancer susceptibility

Background: Understanding the molecular mechanisms underlying papillary thyroid cancer (PTC) proved to be vital not only for diagnostic purposes but also for tailored treatments. Despite the strong evidence of heritability, only a small subset of alterations has been implicated in PTC pathogenesis. To this reason, we used targeted next-generation sequencing (NGS) to identify candidate variants implicated in PTC pathogenesis, progression, and invasiveness. Methods: A total of 42 primary PTC tissues were investigated using a targeted next-generation sequencing (NGS) panel enlisting 47 genes involved in DNA repair and tumor progression. Results: We identified 57 point mutations in 78.5% of samples (n = 32). Thirty-two somatic mutations were identified exclusively in known thyroid cancer genes (BRAF, KRAS, NRAS, and TERT). Unpredictably, 45% of the all identified mutations (n = 25) resulted to be germline, most affecting DNA repair genes. Interestingly, none of the latter variants was in the main population databases. Following ACMG classification, 20% of pathogenic/likely pathogenic and 68% of variant of unknown significance were identified. Conclusions: Overall, our results support the hypothesis that rare germline variants in DNA repair genes are accountable for PTC susceptibility. More data, including the segregation analysis in affected families, should be collected before definitely annotate these alterations and to establish their potential prognostic and treatment implications

Thyroid hormone therapy in differentiated thyroid cancer

Surgery-with or without postoperative radioiodine-is the standard of care for most patients with differentiated thyroid carcinoma (DTC). Thyroid hormone replacement therapy is the mainstay of long-term medical management. Patients treated with total thyroidectomy and some who undergo lobectomy alone require thyroid hormone therapy to restore euthyroidism with normal serum thyroid-stimulating hormone (TSH) levels. Because TSH acts as a growth factor for thyroid follicular cells (including those that are neoplastic), it can potentially affect the onset and/or progression of follicular-cell derived thyroid cancer. For this reason, some patients are placed on thyroid hormone therapy at doses that suppress secretion of TSH (suppression therapy). This mini-review looks at the potential benefits and risks of this practice in patients diagnosed with DTC. Aggressive TSH-suppressive therapy is of little or no benefit to the vast majority of patients with DTC. Practice guidelines, therefore, recommend a graded algorithm in which the potential benefits of suppression are weighed against the associated cardiovascular and skeletal risks. Large randomized controlled studies are needed to confirm the presumed oncological benefits of TSH-suppression and its causal role in adverse cardiac, skeletal, and quality of life effects and to assess the efficacy of TSH normalization in reversing or reducing these effects