BRAF V600E Positive Hairy Plasma Cell Leukemia; Are the Cytoplasmic Projections in Plasma Cells Predictive of a Particular Molecular Characterization?

Introduction: Plasma cell leukemia (PCL) is a rare and clinically aggressive form of plasma cell dyscrasia. Despite the significant role of BRAF mutation in plasma cell neoplasms, this mutation has been rarely considered in these cases. Finding evidence guiding us toward assessing the BRAF mutation in patients with plasma cell neoplasms could help make the suitable decision for targeted therapy. Case Presentation: A 79-year-old man presented with leukocytosis. Peripheral blood smear exhibited marked lymphocytosis and infiltration of about 50% abnormal lymphoid cells with slender cell-surface projections and oval shape nucleus. These findings raised the provisional diagnosis of hairy cell leukemia (HCL) or HCL variants (HCL-v). Molecular analysis confirmed the presence of BRAFV600E mutation, which was in agreement with HCL diagnosis, albeit the flow cytometric assessment of abnormal lymphocytes corroborated PCL. Conclusions: Together with the previous comprehensive analysis regarding the association of cytoplasmic projections and BRAF mutations, our findings could suggest this morphological characteristic in plasma cells (PCs) as an indication for the assessment of BRAF V600E mutation in PC dyscrasias.

Association of miR-21 and miR-335 to microsatellite instability and prognosis in stage III colorectal cancer

BACKGROUND: MicroRNAs (miRs) are frequently altered in colorectal cancer (CRC) and can be used as prognostic factors. OBJECTIVE: To confirm in stage III CRC patients a reported miR signature that was associated to the presence of metastatic disease. To correlate miR expression with microsatellite instability (MSI) and mutations in RAS and BRAF. METHODS: miR-21, miR-135a, miR-206, miR-335 and miR-Let-7a expression was analyzed by RT-qPCR in 150 patients out of the 329 patients used to analyze MSI and RAS and BRAF mutations. Association with disease free survival (DFS) and overall survival (OS) was analyzed. Data was confirmed by a multivariate analysis. RESULTS: MiR-21 high expression (p= 0.034) and miR-335 low expression (p= 0.0061) were significantly associated with MSI-H. A positive trend (p= 0.0624) between miR-135a high expression and RAS mutations was found. Lower miR-21 expression levels are associated with DFS (HR = 2.654, 95% CI: 1.066–6.605, p= 0.036) and a trend with OS (HR = 2.419, 95% CI: 0.749–7.815, p= 0.140). MiR-21 high expression significantly improves DFS of the poor prognosis group (T4 or N2) (p= 0.03). CONCLUSIONS: Association of increased expression of miR-21 and better prognosis in the poor prognostic group may be of interest and could be explored in future prospective clinical trials.

MOLECULAR-GENETIC CRITERIA AND PROSPECTIVE BIOMARKERS OF SERRATED ADENOMAS OF COLORECTAL LOCALIZATION

A retrospective analysis of the database of patients with histologically verified serrated adenomas of the colon was carried out as part of an observational study. Inclusion criteria: patients with serrated colon adenomas who underwent a molecular genetic study to detect mutations and further sequencing 16 sRNAs of intestinal microbiota from January 2021 to October 2021. The exclusion criteria: patients with a primary tumor of the colon who had previously received complex treatment, who had accompanying pathologies of the other organs and systems, which did not allow for the planned examination. According to the results of the study, BRAF mutations are diagnosed in half of the cases in serrated adenomas and in one-third of cases - KRAS mutations. As a result of a comparative analysis of the intestinal microbiome of young patients with serrated colon adenomas with summary statistical data on the presence of bacteria in the intestines of people from the Russian population; promising markers were found for the development of effective approaches for the early diagnosis of colorectal cancer.

Oxidative Stress-Related Mechanisms in Melanoma and in the Acquired Resistance to Targeted Therapies

Melanoma is a highly aggressive cancer with the poorest prognosis, representing the deadliest form of skin cancer. Activating mutations in BRAF are the most frequent genetic alterations, present in approximately 50% of all melanoma cases. The use of specific inhibitors towards mutant BRAF variants and MEK, a downstream signaling target of BRAF in the MAPK pathway, has significantly improved progression-free and overall survival in advanced melanoma patients carrying BRAF mutations. Nevertheless, despite these improvements, resistance still develops within the first year of therapy in around 50% of patients, which is a significant problem in managing BRAF-mutated advanced melanoma. Understanding these mechanisms is one of the mainstreams of the research on BRAFi/MEKi acquired resistance. Both genetic and epigenetic mechanisms have been described. Moreover, in recent years, oxidative stress has emerged as another major force involved in all the phases of melanoma development, from initiation to progression until the onsets of the metastatic phenotype and chemoresistance, and has thus become a target for therapy. In the present review, we discuss the current knowledge on oxidative stress and its signaling in melanoma, as well as the oxidative stress-related mechanisms in the acquired resistance to targeted therapies.

Epigenetic modification and BRAF gene mutation in thyroid carcinoma

Thyroid cancer remains the most prevailing endocrine malignancy, and a progressively increasing incidence rate has been observed in recent years, with 95% of thyroid cancer represented by differentiated thyroid carcinomas. The genetics and epigenetics of thyroid cancer are gradually increasing, and gene mutations and methylation changes play an important roles in its occurrence and development. Although the role of RAS and BRAF mutations in thyroid cancer have been partially clarified,but the pathogenesis and molecular mechanisms of thyroid cancer remain to be elucidated. Epigenetic modification refer to genetic modification that does not change the DNA sequence of a gene but causes heritable phenotypic changes in its expression. Epigenetic modification mainly includes four aspects: DNA methylation, chromatin remodelling, noncoding RNA regulation, and histone modification. This article reviews the importance of thyroid cancer epigenetic modification and BRAF gene mutation in the treatment of thyroid cancer.

Systematic population-based identification of NTRK and RET fusion-positive thyroid cancers

Objective: The aim of the study was to identify patients with NTRK fusion-positive or RET fusion/mutation-positive thyroid cancers, who could benefit from TRK or RET inhibitors. Methods: Patients were identified in the Calgary prospective thyroid cancer database (N=482). Patients were “pre-screened” with clinically available MassARRAY® BRAF Test, Colon Panel, Melanoma Panel, or ThyroSPEC™. Mutation-negative tumors were “screened” for NTRK fusions and RET fusions/mutations with the Oncomine™ Comprehensive Assay v3 (OCAv3). Results: A total of 86 patients were included in one of two separate analyses. Analysis A included 42 patients with radioactive iodine (RAI)-resistant distant metastases. After pre-screening, 20 BRAF and RAS mutation-negative patients underwent OCAv3 screening, resulting in the detection of four patients with NTRK fusions and four patients with RET fusions (8/20, 40% of analyzed patients). Analysis B included 44 patients, 42 with American Thyroid Association (ATA) high and intermediate risk of recurrence and two with medullary thyroid carcinoma. During pre-screening one patient with an NTRK fusion, one patient with a RET fusion and 30 patients with BRAF mutations were identified. The remaining nine patients received OCAv3 screening, resulting in detection of one patient with an NTRK fusion and one with a RET fusion (4/11, 36% of analyzed patients). Conclusions: Our findings indicate a high rate of NTRK fusions and RET fusions in patients with thyroid cancer with RAI-resistant distant metastases, ATA high/intermediate risk of recurrence. This highlights the importance of early screening, to enable intervention with a TRK or RET inhibitor.

Melanoma Targeted Therapies beyond BRAF-Mutant Melanoma: Potential Druggable Mutations and Novel Treatment Approaches

Melanomas exhibit the highest rate of somatic mutations among all different types of cancers (with the exception of BCC and SCC). The accumulation of a multimode of mutations in the driver oncogenes are responsible for the proliferative, invasive, and aggressive nature of melanomas. High-resolution and high-throughput technology has led to the identification of distinct mutational signatures and their downstream alterations in several key pathways that contribute to melanomagenesis. This has enabled the development of individualized treatments by targeting specific molecular alterations that are vital for cancer cell survival, which has resulted in improved outcomes in several cancers, including melanomas. To date, BRAF and MEK inhibitors remain the only approved targeted therapy with a high level of evidence in BRAFV600E/K mutant melanomas. The lack of approved precision drugs in melanomas, relative to other cancers, despite harboring one of the highest rates of somatic mutations, advocates for further research to unveil effective therapeutics. In this review, we will discuss potential druggable mutations and the ongoing research of novel individualized treatment approaches targeting non-BRAF mutations in melanomas.