Melanoma treatment have been revolutionized since 2010 by the development of immune checkpoint inhibitors, and, for BRAF-mutated melanoma, targeted therapies based on BRAF and MEK inhibitors, which is a model of effective targeted therapy in cancer.
Thirty-six tumor tissues from BRAF wild-type melanoma patients at Seoul National University Hospital (SNUH) were collected and deep-sequenced using the SNUH FIRST-Cancer NGS panel to assess single nucleotide variants, small insertions/deletions, copy number variations, and structural variations to estimate tumor mutation burden (TMB).
Recent high-throughput-sequencing of cancer genomes has identified oncogenic mutations in the B-Raf genetic locus as one of the critical events in melanomagenesis.
Reverse Phase Proteomic Array (RPPA, MD Anderson Cell Lines Project), RNAseq (Cancer Cell Line Encyclopedia) and vemurafenib sensitivity (Cancer Therapeutic Response Portal) data for BRAF-V600Ecancer cell lines were curated.
Associations between BRAFV600E and TERT promoter mutations and clinicopathological features, Tumor-Node-Metastasis stage, initial risk, response to therapy, follow-up, and final disease outcome were assessed according to American Thyroid Association 2015 criteria and the American Joint Committee on Cancer/Tumor-Node-Metastasis (8th edition) staging system.Median follow-up was 120 months.
Twelve of the 33 cell lines were trametinib-sensitive (IC<sub>50</sub> < 32 nmol/L), all 12 exhibited constitutive or serum-activated ERK1/2 phosphorylation, and 8 carried MAPK pathway cancer driver variants: NF1(2), BRAF(3), N/KRAS(3).
In serrated adenomas, BRAF-V600E mutation does not seem to be associated with age and sex, with the prevalence of dysplasia and cancer and with the morphology of the dysplastic component.
In this issue of Cancer Cell, Tao et al. provide compelling evidence that aging-like DNA methylation of multiple CpG islands, the CpG island methylator phenotype (CIMP), produces a cellular context that can tolerate BRAF activation avoiding senescence by dedicating 5-month culture of colon-derived organoids to epigenomic and stemness analysis.
Furthermore, our analysis carried out through the Genomic Data Commons (GDC) Data Portal shows the evidence that hsa-mir-132 is significantly associated with clinical outcome in melanoma cancer genomic data sets of BRAF-mutated patients.
Eleven of 31 cases with an indeterminate cytologic diagnosis and 9 of 12 cases that were suspicious for malignancy had somatic mutations, including the BRAFV600E mutation, which is highly definitive for papillary thyroid carcinoma (PTC).
Overall, our results suggest a molecular sub-cluster of colon cancer cells with low CDX2 and VDR expression is sensitive to chemotherapy, BRAF inhibitors and PI3K-mTOR inhibitors treatment and provide an example of translation of cancer classification to subgroup guided therapies.
The development of BRAF and MEK inhibitors (BRAFis and MEKis) and immune checkpoint inhibitors have changed the management of advanced stage melanoma and improved the outcomes of patients with this malignancy.
Here, we show that endothelial cell-restricted ablation of BRAF, a kinase frequently activated in cancer, prevents vascular leaking as well metastatic spread.
BRAF mutations were confirmed as highly specific but not able to improve cytological diagnosis, while RAS testing proved effective in assessing malignancy in nodules with indeterminate and benign cytology.
This study shows for the first time that E2F1 has a cancer protective role in oncogenic BRAF-activated melanoma cells and that loss of E2F1 can allow disease progression through a novel mechanism of E2F1-mediated MYLK regulation.
PGC1α-negative papillary cancer was associated with BRAFV600E mutation, large tumor size, extrathyroidal or lymphovascular invasion, lymph node metastasis, and advanced stage.