Enrichment of SOX2-Positive Cells in BRAF V600E Mutated and Recurrent Ameloblastoma

Ameloblastoma is the most common benign odontogenic neoplasm, but with an aggressive behavior and a high recurrence rate. Nowadays wide surgical resection is the current recommended treatment, which can cause further loss of function and esthetics. Recent studies point to the stem/progenitor cells as both initiators and propagators of the tumors. Elucidation of the cellular and molecular mechanisms underlying the tumor stem cells is of broad interest for understanding tumorigenesis and for developing effective targeted therapies. SRY related HMG box gene 2 (SOX2) is a transcription factor that plays important roles in development, stem cell renewal, and cancer formation. Few studies have revealed increased SOX2 expression in atypical ameloblastoma and ameloblastic carcinoma. For the development of personalized medicine for ameloblastoma, biomarkers that provide prognostic or predictive information regarding a tumor’s nature or its response to treatment are essential. Thus, in this study, we aimed to study if SOX2-positive cells exist in ameloblastomas and their correlation with the clinicopathologic parameters. Our data suggested BRAF(V600E) mutation might contribute to the expansion of SOX2-positive cells. The identification of BRAF(V600E) mutation and the amplification of SOX2-positive cells in ameloblastomas imply the possible benefit of applying BRAF and SOX2 inhibitors in recurrent and un-resectable ameloblastomas.

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BRAF V600E mutation in hairy cell leukemia: from bench to bedside

Blood ◽

10.1182/blood-2016-07-418434 ◽

2016 ◽

Vol 128 (15) ◽

pp. 1918-1927 ◽

Cited By ~ 41

Author(s):

Brunangelo Falini ◽

Maria Paola Martelli ◽

Enrico Tiacci

Keyword(s):

Hairy Cell Leukemia ◽

Molecular Mechanisms ◽

Braf V600e Mutation ◽

Braf V600e ◽

Specific Gene ◽

Hairy Cell ◽

Braf Inhibitors ◽

Cell Leukemia ◽

Genetic Event ◽

Mek Inhibitors

AbstractHairy cell leukemia (HCL) is a distinct clinicopathological entity whose underlying genetic lesion has remained a mystery for over half a century. The BRAF V600E mutation is now recognized as the causal genetic event of HCL because it is somatic, present in the entire tumor clone, detectable in almost all cases at diagnosis (encompassing the whole disease spectrum), and stable at relapse. BRAF V600E leads to the constitutive activation of the RAF-MEK-extracellular signal-regulated kinase (ERK) signaling pathway which represents the key event in the molecular pathogenesis of HCL. KLF2 and CDNK1B (p27) mutations may cooperate with BRAF V600E in promoting leukemic transformation. Sensitive molecular assays for detecting BRAF V600E allow HCL (highly responsive to purine analogs) to be better distinguished from HCL-like disorders, which are treated differently. In vitro preclinical studies on purified HCL cells proved that BRAF and MEK inhibitors can induce marked dephosphorylation of MEK/ERK, silencing of RAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression profile signature, change of morphology from “hairy” to “smooth,” and eventually apoptosis. The overall response rate of refractory/relapsed HCL patients to the BRAF inhibitor vemurafenib approached 100%, with 35% to 40% complete remissions (CRs). The median relapse free-survival was about 19 months in patients who had achieved CR and 6 months in those who had obtained a partial response. Future therapeutic perspectives include: (1) combining BRAF inhibitors with MEK inhibitors or immunotherapy (anti-CD20 monoclonal antibody) to increase the percentage of CRs and (2) better understanding of the molecular mechanisms underlying resistance of HCL cells to BRAF inhibitors.

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Clinical and molecular markers of immune checkpoint inhibitor (ICI) response in dMMR colorectal cancer (CRC) patients (pts).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.225 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 225-225 ◽

Cited By ~ 1

Author(s):

Ibrahim Halil Sahin ◽

Subir Goyal ◽

Yoanna S Pumpalova ◽

Mohamad Bassam Sonbol ◽

Satya Das ◽

...

Keyword(s):

Braf V600e Mutation ◽

Braf V600e ◽

Rank Test ◽

Loss Of Function ◽

Protein Loss ◽

Exact Test ◽

Best Response ◽

Emory University ◽

Cox Hazard Model ◽

Mmr Proteins

225 Background: ICIs induce durable responses in dMMR CRC patients. However, clinical and molecular biomarkers of response to ICIs have not been well-established. In this study, we investigated impact of specific MMR gene loss, BRAF V600E mutation and clinical characteristics of pts on clinical outcomes of ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or MSI-H by PCR and received ICIs between 01/01/2012 and 05/01/2019 at Winship Cancer Institute of Emory University, Mayo Clinic, Vanderbilt or Stanford University. Due to the functional dependency, the groups were categorized as protein loss of MLH1+PMS2 vs MSH2+MSH6. Log-rank test, Cox hazard model and Fisher’s exact test were used for survival outcomes, the best response and the distribution of variables among the subgroups. Results: A total of 66 pts with dMMR CRC were identified and BRAF status was available for 41 pts. ORRs in MLH1+PMS2 and MSH2+MSH6 groups were 72.9% and 56.5% respectively (P = 0.189). At 2 years, PFS rates were 55.6% and 78.2% for MLH1+PMS2 and MSH2+MSH6 groups respectively (P < 0.001). Pts with BRAF V600E mutations had significantly worse outcomes as compared to pts with wild-type BRAF (2-year PFS rate of 35.0% and 73.3% respectively; P < 0.001). Notably pts < 65 had better 2-year disease control rates when compared to > 65 (71.1% and 41.5% respectively; P < 0.001). We also observed worse 2-year PFS rates in pts with liver metastases (P = 0.014). CRC side and tumor volume did not impact 2-year PFS rates in our cohort. Conclusions: Our data suggest that pts with loss of function in MSH2+MSH6 may have better 2 year-PFS rates compared pts with MLH1+PMS2 even though ORR favored MLH1+PMS2 group suggesting that ORR may not reflect the durability of ICI response in dMMR CRC patients. Consistently, pts with BRAF V600E mutation which is associated with MLH1 promoter methylation had significantly worse 2-year PFS rates. Overall, our findings suggest that BRAFV600E mutation, the affected MMR proteins, pt age, and site of metastasis may impact durability of ICI response in dMMR CRC patients.

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Genetic Study of BRAF V600E and SMO L412F Mutations in Japanese Patients with Ameloblastoma

International Journal of Surgical Pathology ◽

10.1177/10668969211064203 ◽

2022 ◽

pp. 106689692110642

Author(s):

Katsutoshi Kokubun ◽

Kei Yamamoto ◽

Yoshihiko Akashi ◽

Takatoshi Chujo ◽

Kei Nakajima ◽

...

Keyword(s):

Sanger Sequencing ◽

Japanese Patients ◽

Braf V600e Mutation ◽

Clinicopathological Features ◽

Braf V600e ◽

Unicystic Ameloblastoma ◽

Formalin Fixed Paraffin ◽

Formalin Fixed Paraffin Embedded ◽

Odontogenic Neoplasm ◽

The Relationship

Background and aim: Ameloblastoma is a benign, intraosseous, progressively growing, epithelial, odontogenic neoplasm. BRAF and SMO mutations have been reported in ameloblastoma. In this study, we evaluated BRAF V600E and SMO L412F mutations; and assessed the relationship between BRAF V600E mutant expression and the clinicopathological features in Japanese patients with ameloblastoma. Methods: We examined 24 formalin-fixed paraffin-embedded samples. All specimens were from patients with mandibular ameloblastoma: 20 were conventional ameloblastoma and 4 were unicystic ameloblastoma. The BRAF V600E mutation was assessed by Sanger sequencing and immunohistochemistry, and the SMO L412F mutation was assessed only by Sanger sequencing. Results: Twenty of the 24 (83%) ameloblastoma samples carried the BRAF V600E mutation; 22 of the 24 (92%) samples were immunohistochemically positive for BRAF V600E. However, the SMO L412F mutation was not detected in any of them. The BRAF V600E mutation status did not correlate with the clinicopathological features, such as age, sex, location, method, recurrence, and subtype. Conclusion: BRAF inhibitors could be a potential treatment option for Japanese patients with ameloblastoma, harboring the BRAF V600E mutation.

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Detection of the BRAF V600E mutation in melanocytic lesions using the ligase detection reaction

Yearbook of Pathology and Laboratory Medicine ◽

10.1016/s1077-9108(08)70313-x ◽

2007 ◽

Vol 2007 ◽

pp. 100-101

Author(s):

D.M. Jukic

Keyword(s):

Braf V600e Mutation ◽

Braf V600e ◽

Ligase Detection Reaction ◽

Melanocytic Lesions

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Therapie des BRAF-mutierten NSCLC

Onkologische Welt ◽

10.1055/s-0038-1677603 ◽

2018 ◽

Vol 09 (05) ◽

pp. 239-239

Author(s):

Dr. Susanne Krome

Keyword(s):

Phase Ii ◽

Braf V600e Mutation ◽

Braf V600e ◽

Alk Rearrangement

BRAF-mutierte nicht kleinzellige Bronchialkarzinome (NSCLC) sind besonders aggressiv. Gezielte Antikörpertherapien verbesserten die Behandlungsergebnisse. Bei einem ALK-Rearrangement ging eine lange progressionsfreie Zeit nicht zu Lasten der Post-Progressionsphase. Die Sekundäranalyse einer nicht randomisierten Phase-II-Studie zeigt dies nun auch für Patienten mit einer BRAF-V600E-Mutation.

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