Targeting NG2 relieves the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitors.

BRAFV600E represents a constitutively active onco-kinase and stands as the most prevalent genetic alteration in thyroid cancer. However, the clinical efficacy of small-molecule inhibitors targeting BRAFV600E is often limited by acquired resistance. Here, we find that nerve/glial antigen 2 (NG2), also known as chondroitin sulfate proteoglycan 4 (CSPG4), is up-regulated in thyroid cancers, and its expression is increased with tumor progression in a BRAFV600E-driven thyroid cancer mouse model. Functional studies show that NG2 knockout almost does not affect tumor growth, but significantly improves the response of BRAF-mutant thyroid cancer cells to BRAF inhibitor PLX4720. Mechanistically, the blockade of ERK-dependent feedback by BRAF inhibitor can activate receptor tyrosine kinase (RTK) signaling, causing the resistance to this inhibitor. NG2 knockout attenuates the PLX4720-mediated feedback activation of several RTKs, improving the sensitivity of BRAF-mutant thyroid cancer cells to this inhibitor. Based on this finding, we propose and demonstrate an alternative strategy for targeting NG2 to effectively treat BRAF-mutant thyroid cancers by combining multiple kinase inhibitor (MKI) Sorafenib or Lenvatinib with PLX4720. Thus, this study uncovers a new mechanism in which NG2 contributes to the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitor, and provides a promising therapeutic option for BRAF-mutant thyroid cancers.

High Wnt2 Expression Confers Poor Prognosis in Colorectal Cancer, and Represents a Novel Therapeutic Target in BRAF-Mutated Colorectal Cancer.

Background and Objectives: We aimed to investigate the role of Wnt2 expression in colorectal cancer (CRC) prognosis and evaluate its potential as a therapeutic target in BRAF-mutated CRC. Materials and Methods: Exactly 136 samples of formalin-fixed paraffin-embedded CRC tissue specimens were obtained from patients who underwent surgical resection for CRC. The gene mutation status of the samples was detected using fluorescence PCR. Wnt2 expression was detected using immunohistochemistry. Survival curves with high Wnt2 expression and BRAF mutations were compared using the Kaplan-Meier method. A nomogram was constructed to determine the estimated overall survival probability. We also predicted the 3-year and 5-year survival rates for patients with high Wnt2 expression and BRAF mutations. In total, 50 samples of BRAF-mutated CRC were collected and detected Wnt2 expression by immunohistochemistry. The Chi-squared test was used to analyze the association between Wnt2 expression and BRAF-mutated CRC. Results: High Wnt2 expression and BRAF mutations are associated with poor prognosis of CRC. Multivariate survival analyses indicated that high Wnt2 expression and BRAF mutations are significant independent predictors of CRC prognosis. Furthermore, high Wnt2 expression was significantly associated with BRAF-mutated CRC, and Wnt2 may be a potential therapeutic target for BRAF-mutated CRC. Conclusions: High Wnt2 expression confers poor prognosis in colorectal cancer and represents a novel therapeutic target in BRAF-mutated CRC.

Prevalence and patterns of mutations in RAS/RAF/MEK/ERK/MAPK signaling pathway in colorectal cancer in North Africa.

BACKGROUND: Our review discuss (i) the findings from analyzed data that have examined KRAS, NRAS and BRAF mutations in patients with colorectal cancer (CRC) in North Africa and to compare its prevalence with that shown in other populations and (ii) the possible role of dietary and lifestyle factors with CRC risk.  METHODS: Using electronic databases, a systematic literature search was performed for the KRAS, NRAS, and BRAF mutations in CRC patients from Morocco, Tunisia, Algeria and Lybia.  RESULTS: Seventeen studies were identified through electronic searches with six studies conducted in Morocco, eight in Tunisia, two in Algeria, and one in Libya. A total of 1843 CRC patients were included 576 (31.3%) in Morocco, 641 (34.8%) in Tunisia, 592 (32.1%) in Algeria, and 34 (1.8%) in Libya. Overall, the average age of patients was 52.7 years old. Patients were predominantly male (56.6%). The mutation rates of KRAS, NRAS and BRAF were 46.4%, 3.2% and 3.5% of all patients, respectively. A broad range of reported KRAS mutation frequencies have been reported in North Africa countries. The KRAS mutation frequency was 23.9% to 51% in Morocco, 23.1% to 68.2% in Tunisia, 31.4% to 50% in Algeria, and 38.2% in Libya. The G12D was the most frequently identified KRAS exon 2 mutations (31.6%), followed by G12V (25.4%), G13D (15.5%), G12C (10.2%), G12A (6.9%), and G12S (6.4%). G12R, G13V, G13C and G13R are less than 5%. There are important differences among North Africa countries. In Morocco and Tunisia, there is a higher prevalence of G12D mutation in KRAS exon 2 (≈50%). The most frequently mutation type in KRAS exon 3 was Q61L (40%). A59T and Q61E mutations were also found. In KRAS exon 4, the most common mutation was A146T (50%), followed by K117N (33.3%), A146P (8.3%) and A146V (8.3%). CONCLUSION: KRAS mutated CRC patients in North Africa have been identified with incidence closer to the European figures. Beside established anti-CRC treatment, better understanding of the causality of CRC can be established by combining epidemiology and genetic/epigenetic on CRC etiology. This approach may be able to significantly reduce the burden of CRC in North Africa.

Solute Carrier Family 27 Member 6 (SLC27A6) Possibly Promotes the Proliferation of Papillary Thyroid Cancer by Regulating c-MYC.

To investigate the expression and mechanism of LSC27A6 in papillary thyroid cancer (PTC). We analyzed the differential expression of SLC27A6 in PTC tissues and normal tissues based on the TCGA database and validated it using immunohistochemistry. Wilcoxon rank sum, chi-square test, or Fisher exact exam were used to analyze the relationship between the expression of SLC27A6 and clinicopathological information. Samples were divided into two groups according to whether BRAF was mutated or not, and Wilcoxon rank sum was used to determine whether the expression of SLC27A6 was related to BRAF mutation. The effects of SLC27A6 on the proliferation, migration, and apoptosis of PTC cells were detected by cell counting kit-8 (CCK8), colony formation assay, transwell assay, and flow cytometry. Spearman correlation analysis was used to evaluate the relationship between SLC27A6 and c-MYC. Protein expression was detected by Western blot. The expression of SLC27A6 was higher in PTC and positively correlated with N stage. SLC27A6 expression was higher in samples with BRAF mutations. Down-regulation of SLC27A6 inhibited cell proliferation, migration, and invasion and induced apoptosis. Spearman correlation analysis showed that SLC27A6 was positively correlated with c-MYC. Knockdown of SLC27A6 inhibited c-MYC expression. Our results suggest that SLC27A6 is overexpressed in PTC tissues and affects the progression of PTC by regulating c-MYC.

Is Melanoma Progression Affected by Thyroid Diseases?

Clinical and epidemiological evidence indicate a relationship between thyroid diseases and melanoma. In particular, the hypothyroidism condition appears to promote melanoma spread, which suggests a protective role of thyroid hormones against disease progression. In addition, experimental data suggest that, in addition to thyroid hormones, other hormonal players of the hypothalamic-pituitary-thyroid (HPT) axis, namely the thyrotropin releasing hormone and the thyrotropin, are likely to affect melanoma cells behavior. This information warrants further clinical and experimental studies in order to build a precise pattern of action of the HPT hormones on melanoma cells. An improved knowledge of the involved molecular mechanism(s) could lead to a better and possibly personalized clinical management of these patients.

Genetic alteration of Chinese patients with rectal mucosal melanoma.

BACKGROUND: Rectal mucosal melanoma (RMM) is a rare and highly aggressive disease with a poor prognosis. Due to the rarity of RMM, there are few studies focusing on its genetic mechanism. This retrospective study aimed to analyze the genetic spectrum and prognosis of RMM in China and lay a foundation for targeted therapy. METHODS: 36 patients with primary RMM from Peking University Cancer Hospital were enrolled in this study. The Next-generation sequencing (NGS) data of the tumor samples were fitted into the TruSight™ Oncology 500 (TSO500) Docker pipeline to detect genomic variants. Then, the univariate and multivariate Cox hazard analysis were performed to evaluate the correlations of the variants with the overall survival (OS), along with Kaplan-Meier and log-rank test to determine their significance. RESULTS: BRAF mutations, NRG1 deletions and mitotic index were significant prognostic factors in the univariate analysis. In multivariable analysis of the OS-related prognostic factors in primary RMM patients, it revealed 2 significant alterations: BRAF mutations [HR 7.732 (95%CI: 1.735-34.456), P = 0.007] and NRG1 deletions [HR 14.976 (95%CI: 2.305-97.300), P = 0.005]. CONCLUSIONS: This is the first study to show genetic alterations exclusively to Chinese patients with RMM. We confirmed genetic alterations of RMM differ from cutaneous melanoma (CM). Our study indicates that BRAF and NRG1 were correlated with a poor prognostic of RMM and may be potential therapeutic targets for RMM treatment.

A case report of simultaneous medullary and papillary carcinoma of thyroid.

Objective. Medullary (MTC) and papillary (PTC) thyroid carcinoma are two different types of thyroid carcinoma with significant differences in origin. Their co-occurrence in a patient is a rare phenomenon. We report a patient with simultaneous presentation of both MTC and PTC. Case presentation. A 62-year-old euthyroid woman with a cervical mass was evaluated, underwent total thyroidectomy, and neck dissection. The examination revealed a MTC large nodule as well as a small nodule of the tall cell variant of PTC, along with the concomitant cervical lymph node metastases. Subsequently, the genetic analysis showed BRAF mutations. Adjuvant treatments including radioiodine and thyroid hormone replacement therapies were performed for the patient. Conclusions. The cooccurrence of MTC and PTC in the same patient is a rare phenomenon. The clinical manifestations and biological behavior of these cancers are completely different. Since the therapeutic strategy and prognosis are very different in these patients, accurate diagnosis of this coexistence is very important.

Molecular and immunohistochemical analysis of BRAF gene in primary cutaneous melanoma: Discovery of novel mutations.

BACKGROUND: Determination of BRAF status is mandatory for targeted therapy but it is not currently available in most developing countries. AIM: We aimed to analyze BRAF mutations in a series of cutaneous melanoma of Tunisian patients and to compare BRAF V600E mutation detection by immunohistochemistry to DNA sequencing. PATIENTS AND METHODS: Archival formalin fixed paraffin embedded tissues from 28 patients with primary cutaneous melanoma were evaluated for the BRAF mutations by Sanger sequencing and immunohistochemistry. RESULTS: BRAF mutations were detected in 19/28 (68%) of analyzed tumors. The sensitivity and specificity of immunohistochemistry compared to DNA sequencing for identification of the BRAF V600E mutation were 100%. We found five novel mutations, one of them had deleterious effect. CONCLUSION: The present study shows an intermediate frequency of mutations of the BRAF gene in cutaneous melanoma of Tunisian patients, and supports the use of immunohistochemistry as a screening test for the assessment of the BRAF V600E status in the management of melanoma in clinical practice.

Unique characteristics of CpG island methylator phenotype (CIMP) in a Chinese population with colorectal cancer.

BACKGROUND: Molecular characteristics of CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) have been well documented in Western, but not in Chinese, populations. METHODS: We investigated the incidence of CIMP, BRAF/KRAS mutation, and microsatellite instability (MSI) in a Chinese population with CRC (n = 401) and analysed associations between CIMP status and clinicopathological and molecular features. RESULTS: A total of 41 cases, 310 cases, and 40 cases were classified as CIMP-high, CIMP-low, and CIMP-negative, respectively. We detected a significantly low incidence of BRAF mutation in adenomas (2%) and CRC (0.7%), and a relatively low incidence of KRAS mutation (24.9%) compared with that in other populations. We also detected a relatively low incidence of CIMP-high (10.2%), which was significantly associated with younger age (≤49 years of age), female sex, and proximal tumour location. CONCLUSIONS: This study revealed unique characteristics of CIMP in a Chinese population with colorectal cancer. Developing specific CIMP markers based on unique populations or ethnic groups will further help to fully elucidate CIMP pathogenesis.

Activation of mutant TERT promoter by RAS-ERK signaling is a key step in malignant progression of BRAF-mutant human melanomas.

Although activating BRAF/NRAS mutations are frequently seen in melanomas, they are not sufficient to drive malignant transformation and require additional events. Frequent co-occurrence of mutations in the promoter for telomerase reverse transcriptase (TERT), along with BRAF alterations, has recently been noted and correlated with poorer prognosis, implicating a functional link between BRAF signaling and telomerase reactivation in melanomas. Here, we report that RAS-ERK signaling in BRAF mutant melanomas is critical for regulating active chromatin state and recruitment of RNA polymerase II at mutant TERT promoters. Our study provides evidence that the mutant TERT promoter is a key substrate downstream of the RAS-ERK pathway. Reactivating TERT and hence reconstituting telomerase is an important step in melanoma progression from nonmalignant nevi with BRAF mutations. Hence, combined targeting of RAS-ERK and TERT promoter remodeling is a promising avenue to limit long-term survival of a majority of melanomas that harbor these two mutations.

Association of rs2282679 A>C polymorphism in vitamin D binding protein gene with colorectal cancer risk and survival: effect modification by dietary vitamin D intake.

BACKGROUND: The rs2282679 A>C polymorphism in the vitamin D binding protein gene is associated with lower circulating levels of vitamin D. We investigated associations of this SNP with colorectal cancer (CRC) risk and survival and whether the associations vary by dietary vitamin D intake and tumor molecular phenotype. METHODS: A population-based case-control study identified 637 incident CRC cases (including 489 participants with follow-up data on mortality end-points) and 489 matched controls. Germline DNA samples were genotyped with the Illumina Omni-Quad 1 Million chip in cases and the Affymetrix Axiom® myDesign™ Array in controls. Logistic regression examined the association between the rs2282679 polymorphism and CRC risk with inclusion of potential confounders. Kaplan-Meier curves and multivariable Cox models assessed the polymorphism relative to overall survival (OS) and disease-free survival (DFS). RESULTS: The rs2282679 polymorphism was not associated with overall CRC risk; there was evidence, however, of effect modification by total vitamin D intake (Pinteraction = 0.019). Survival analyses showed that the C allele was correlated with poor DFS (per-allele HR, 1.36; 95%CI, 1.05-1.77). The association of rs2282679 on DFS was limited to BRAF wild-type tumors (HR, 1.58; 95%CI, 1.12-2.23). For OS, the C allele was associated with higher all-cause mortality among patients with higher levels of dietary vitamin D (HR, 2.11; 95%CI, 1.29-3.74), calcium (HR, 1.93; 95%CI, 1.08-3.46), milk (HR, 2.36; 95%CI, 1.26-4.44), and total dairy product intakes (HR, 2.03; 95%CI, 1.11-3.72). CONCLUSION: The rs2282679 SNP was not associated with overall CRC risk, but may be associated with survival after cancer diagnosis. The association of this SNP on survival among CRC patients may differ according to dietary vitamin D and calcium intakes and according to tumor BRAF mutation status.

Serrated epithelial colorectal polyps (hyperplastic polyps, sessile serrated adenomas) with perineurial stroma: Clinicopathological and molecular analysis of a new series.

Serrated colorectal fibroblastic polyps (FPs) are rare benign mucosal lesions composed of serrated epithelial crypts separated and distorted by intimately associated bland spindle cell proliferations with perineurial-like phenotype. We herein describe 21 new FPs affecting 10 females and 9 males aged 45 to 80 yrs. (mean, 62 yrs). Lesions originated in the sigmoid colon/rectosigmoid junction (n = 16), rectum (n = 2), and other parts of the colon (n = 3). Most patients had additional synchronous or metachronous polyps: classical adenomas (12 patients), sessile serrated adenoma/SSA (1 patient), hyperplastic polyps/HPs (7 patients), both HPs and adenomas (6 patients) and colorectal cancer (2 patients). Size of the lesions varied from 1 to 6 mm (mean: 3 mm). Histologically, all lesions were composed of serrated epithelial crypts that were separated and distorted by spindle cell stromal proliferations (consistently EMA+, claudin-1+ and GLUT-1+). The epithelial component displayed features of HPs (n = 17) and SSA (n = 4). Laser-microdissection-guided molecular testing was successful for 13 epithelial and 9 stromal components (9 paired samples). The BRAF V600E mutation was detected in 54% of the epithelial but in none of the stromal components. In conclusion, colorectal FPs represent genuine serrated epithelial polyps corresponding either to HP or (less frequently) SSA and should be better classified as such with a note on the presence of the stromal component. A more concise terminology reflecting their epithelial nature is needed to fulfill the requirements for colorectal cancer risk assessment and hence adopt appropriate follow-up strategies.

Adjuvant FOLFOX +/- cetuximab in full RAS and BRAF wildtype stage III colon cancer patients.

Background: RAS mutations have been shown to confer resistance to anti- epidermal growth factor receptor (EGFR) treatment. We analysed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer. Patients and methods: Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research. The impact of cetuximab on time to recurrence (TTR), disease-free survival (DFS) and overall survival (OS) was investigated in pts with tumours harbouring RAS and BRAF WT, and RAS mutations. The prognostic value of each individual mutation was also tested. Results: Among the 2559 pts analysed, 745 pts (29%) were known to have KRAS exon 2 mutations and 163 pts (6.4%) the BRAF V600E mutation. Of the remaining 1651 pts, 1054 were assessed by NGS, showing that a further 227 pts (21%) had KRAS exon 2, 3, 4 or NRAS exon 2, 3, 4 mutations, and that 46 pts (4.4%) had a newly diagnosed BRAF mutation. Cetuximab added to FOLFOX did not significantly improve TTR, DFS or OS in pts with RAS WT or RAS and BRAF WT tumours (HR 0.77-1.03, all P > 0.05). Cetuximab addition was not either significantly deleterious in RAS mutant pts or in pts with rare RAS or BRAF mutations. In the overall trial population, NRAS and KRAS codon 61 mutations were the only rare mutations with the same pejorative prognostic value as KRAS exon 2 or BRAF V600E mutations. Conclusion: Though not significant, the clinically relevant 0.76 adjusted HR observed for DFS in favour of adding cetuximab to FOLFOX, in full RAS and BRAF WT stage III colon cancer pts, may justify a new randomized controlled trial testing EGFR inhibitors in this setting. Clinical trial number: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.

[Molecular mechanisms of primary and secondary resistance, molecular-genetic features and characteristics of KIT/PDGFRA non-mutated GISTs]. / Molekulární mechanizmy primární a sekundární rezistence, molekulárne-genetické znaky a vlastnosti KIT/PDGFRA nemutovaných GIST.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Most of them arise due to activating mutations in KIT (75 - 85 %) or PDGFRA (less than 10 %) genes. Identification of the activating mutations in KIT and PDGFRA genes, which code for receptor tyrosine kinases (RTKs), has improved the outcome of targeted therapy of metastatic, unresectable or recurrent GISTs. Primary and/or secondary resistance represents a significant problem in the targeted therapy by Imatinib mesylate (IM) in patients with GIST. An important mechanism of the secondary resistance is the evolvement of secondary mutations. Except for primary and secondary resistance, there is another problem of disease progression - a failure of tumor cells eradication even in the long term therapy of tyrosine kinase inhibitors. GISTs without mutations in KIT/PDGFRA genes constitute 10 - 15% GISTs in adults, and a majority (85 %) of pediatric GISTs. KIT/PDGFRA wild-type GISTs represent a heterogeneous group of tumors with several molecular-genetics and/or morphologic differences. KIT/PDGFRA wild-type GISTs are different in their molecular features, for example in mutations in the BRAF, KRAS, NF1 genes or defects of succinate dehydrogenase (SDH) subunits. KIT/PDGFRA wild-type GISTs are generally less sensitive to targeted therapy by tyrosine kinase inhibitors in comparison with KIT/PDGFRA mutated GISTs. Inhibitors of BRAF, PI3K (mTOR) or inhibitors of IGF1R and VEGFR receptors provide alternative therapeutic strategies.

TERT promoter mutations in melanoma survival.

Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at-risk primary melanoma patients. In this study, we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. Tumors from 300 patients with stage I/II melanoma were sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression-free and melanoma-specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease-free and melanoma-specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease-free survival was 2.3 (95% CI 1.2-4.4) and for melanoma-specific survival 5.8 (95% CI 1.9-18.3). The effect of the mutations on melanoma-specific survival in noncarriers of variant allele of the polymorphism was significant (HR 4.5, 95% CI 1.4-15.2) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.3, 95% CI 0.1-0.9). The data in this study provide preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter.

Low-grade serous ovarian cancer: A review.

Epithelial ovarian cancers can be divided into the more common, aggressive type II cancers and the less common, slow-growing type I cancers. Under this model, serous ovarian carcinomas can be subdivided into high-grade (type II) and low-grade (type I) tumours. The two-tier system for grading serous ovarian carcinomas is superior to more detailed grading systems in terms of predicting survival. Low-grade serous carcinomas typically present in young women and have a relatively good prognosis, despite being resistant to chemotherapy. Low-grade serous cancers have a high prevalence of KRAS and BRAF mutations, but a low prevalence of TP53 mutations (which are characteristic of high-grade serous cancers). Among women with low-grade serous ovarian cancer, the presence of a KRAS/BRAF mutation is a favorable prognostic factor. Studies of the mitogen-activated protein kinase (MAPK) inhibitor in low-grade serous ovarian cancer suggest that identifying MAPK mutations might eventually be useful in guiding treatment.

Targeted Therapies for Lung Cancer.

Targeted therapies have become standard therapies for patients with non-small cell lung cancer (NSCLC). A phase III trial of carboplatin and paclitaxel with and without bevacizumab in patients with advanced NSCLC with non-squamous histology demonstrated a statistically significant improvement in efficacy. In patients with NSCLC with an activating epidermal growth factor receptor (EGFR) mutation (defined as exon 19 deletion and exon 21 L858R point mutation), phase III trials of EGFR tyrosine kinase inhibitors (TKI) compared to platinum-based chemotherapy have demonstrated superior efficacy in the first-line setting. In patients with NSCLC with anaplastic lymphoma kinase (ALK) rearrangements, phase III trials of crizotinib have demonstrated superior efficacy compared to platinum-pemetrexed in the first-line setting and standard chemotherapy in the second-line setting. A second-generation ALK inhibitor, ceritinib, is available for patients who have progressed after or were intolerant of crizotinib. Crizotinib has also demonstrated activity on patients with ROS1 rearrangements, and BRAF inhibitors (dabrafenib, vemurafenib) have demonstrated activity in patients with NSCLC with BRAF V600E mutation. The oncogenic mutations that are susceptible to targeted therapy are mainly found in non-squamous NSCLC. The development of targeted therapy in patients with squamous NSCLC has been more challenging due to the genomic complexity observed in the squamous histology and the low prevalence of EGFR, ALK, and ROS1 molecular alterations. A phase III trial of cisplatin and gemcitabine with and without necitumumab in patients with advanced NSCLC with squamous histology demonstrated a statistically significant improvement in progression-free and overall survival.

Vemurafenib in pediatric patients with BRAFV600E mutated high-grade gliomas.

We present three pediatric patients with BRAFV600E mutant high-grade gliomas treated by vemurafenib on a nominative authorization level at our institution. One patient with anaplastic ganglioglioma experienced confirmed partial tumor response and significant clinical improvement and she is alive 20 months after start of treatment. A second patient with ganglioglioma responded transiently to re-introduction of vemurafenib after immunotherapy. Pharmacokinetic studies suggest that maximum concentration and exposure of vemurafenib at steady-state is dose-dependent and similar in children to that reported in adults. These cases suggest that BRAFV600 is an oncogenic driver in pediatric gliomas. Further exploration in clinical studies is ongoing.

Complexity of the Genetic Background of Oncogenesis in Ovarian Cancer-Genetic Instability and Clinical Implications.

Ovarian cancer is a leading cause of death among women with gynecological cancers, and is often diagnosed at advanced stages, leading to poor outcomes. This review explores genetic aspects of high-grade serous, endometrioid, and clear-cell ovarian carcinomas, emphasizing personalized treatment approaches. Specific mutations such as TP53 in high-grade serous and BRAF/KRAS in low-grade serous carcinomas highlight the need for tailored therapies. Varying mutation prevalence across subtypes, including BRCA1/2, PTEN, PIK3CA, CTNNB1, and c-myc amplification, offers potential therapeutic targets. This review underscores TP53's pivotal role and advocates p53 immunohistochemical staining for mutational analysis. BRCA1/2 mutations' significance as genetic risk factors and their relevance in PARP inhibitor therapy are discussed, emphasizing the importance of genetic testing. This review also addresses the paradoxical better prognosis linked to KRAS and BRAF mutations in ovarian cancer. ARID1A, PIK3CA, and PTEN alterations in platinum resistance contribute to the genetic landscape. Therapeutic strategies, like restoring WT p53 function and exploring PI3K/AKT/mTOR inhibitors, are considered. The evolving understanding of genetic factors in ovarian carcinomas supports tailored therapeutic approaches based on individual tumor genetic profiles. Ongoing research shows promise for advancing personalized treatments and refining genetic testing in neoplastic diseases, including ovarian cancer. Clinical genetic screening tests can identify women at increased risk, guiding predictive cancer risk-reducing surgery.

Incidence of BRAF mutations in cutaneous melanoma: histopathological and molecular analysis of a Ukrainian population.

Aim: This study aimed to investigate the incidence of BRAF mutation in cutaneous melanoma in the Ukrainian population with respect to clinical and histopathological data. Materials & methods: This single-center retrospective cohort study enrolled 299 primary CM with known BRAF status assessed by RT-PCR. Results: The overall BRAF mutation rate was 56.5% in CM and demonstrated a link with the younger age (p < 0.001), anatomical site (p < 0.001) and histological type of CM (p = 0.022). BRAF-positive CM possessed a slightly higher mitotic rate (p = 0.015) and Breslow thickness (p = 0.028) but did not relate to tumor-infiltrating lymphocytes. Conclusion: The high rate of BRAF mutations in CM patients in the Ukrainian cohort was associated with superficial spreading histology, higher depth of invasion and proliferation.