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Malignant Neoplasms
Published in Ayşe Serap Karadağ, Lawrence Charles Parish, Jordan V. Wang, Roxburgh's Common Skin Diseases, 2022
Mark Biro, Vesna Petronic-Rosic
Overview: In 2017, there were an estimated 87,110 new cases of melanoma and 9,730 melanoma-related deaths in the United States. The mean age at the time of melanoma diagnosis is 55 years old, and men are more frequently diagnosed with melanoma in the United States. The strongest risk factors for the development of melanoma include ultraviolet light exposure, fair skin complexion, having over 100 nevi, and a family history of melanoma. Multiple genes, including CDKN2A, which serves as a tumor suppressor gene, have been associated with the development of familial melanoma. Multiple gene mutations have been implicated in cutaneous melanoma. The BRAF gene and pathway, which regulates cell differentiation, growth, and proliferation, is commonly mutated in melanoma and is the target of new therapeutic agents.
Biomarkers for the Management of Malignancies with BRAF Mutation
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
BRAF gene mutation testing can assist with determining diagnosis, prognosis, and selection of treatment for patients with certain cancers [13]. For example, BRAF mutations assist with differentiating papillary thyroid cancer from other types of thyroid cancer and benign thyroid nodules; sporadic colorectal cancer with microsatellite instability-high (MSI-H) from hereditary nonpolyposis colorectal carcinoma (HNPCC) or Lynch syndrome; and HCL from other B-cell lymphomas with similar clinical and morphologic features. BRAF V600E mutations are associated with poorer outcomes in patients with papillary thyroid carcinoma and colorectal carcinoma. Most importantly, BRAF mutation testing determines treatment for patients with cancer. For patients with melanoma, NSCLC testing for BRAF V600E and BRAF V600K should be done before initiating treatment with a BRAF inhibitor. For patients with CRC, testing for BRAF mutations should be done at time of diagnosis of metastatic disease and can be used to guide treatment decisions. BRAF V600E mutations denotes low response to panitumumab and cetuximab among patients with CRC and wildtype KRAS but may be responsive to the combination of EGFR antibody with BRAF and MEK inhibitors [33].
Tumor Markers
Published in Paloma Tejero, Hernán Pinto, Aesthetic Treatments for the Oncology Patient, 2020
In melanoma, based on the results of published articles, experts recommend the determination of the BRAF gene mutational status, since it has implications for management. It is estimated to be mutated in 50% of cases and constitutes a prognostic and response-predictive marker to new targeted drugs (vemurafenib), which improve control and survival rates obtained with chemotherapy [20].
Surgery of metastatic melanoma after systemic therapy – the SUMMIST trial: study protocol for a randomized controlled trial
Published in Acta Oncologica, 2021
Carl Jacob Holmberg, Dimitrios Katsarelias, Henrik Jespersen, Ana Carneiro, Nils O. Elander, Hildur Helgadottir, Karolin Isaksson, Malin Jansson, Sara Wirén, Gustav J. Ullenhag, Lars Ny, Roger Olofsson Bagge
The advent of effective systemic therapies during the last decade has led to more robust treatment responses, where BRAF and checkpoint inhibitors were the first therapies to show tangible results [15,16]. BRAF inhibitors selectively target mutated BRAF that stimulate the mitogen activated protein (MAP) kinase signal-transduction pathway known to contribute to uncontrolled proliferation in cancer cells. Treatment in recent years is commonly given in combination with MEK-inhibitors, resulting in more long-lasting clinical efficacy and less toxicity. Activating mutations in the BRAF-gene is present in up to 60% of melanoma tumors [17]. Although the majority of patients experience an initial effect and the treatment leads to both prolonged progression-free survival (PFS) and increased OS, acquired resistance remains a significant problem and most patients experience disease progression within 12 months [18].
An update on: molecular genetics of high-risk chronic lymphocytic leukemia
Published in Expert Review of Hematology, 2020
Riccardo Moia, Andrea Patriarca, Clara Deambrogi, Silvia Rasi, Chiara Favini, Ahad Ahmed Kodipad, Mattia Schipani, Gianluca Gaidano
Despite the short follow up and the limited number of progressions upon venetoclax treatment, a few studies have tried to reveal the genetical lesions that characterize high risk patients destined to relapse upon venetoclax treatment [42–44]. In one of the first molecular analysis of patients treated with venetoclax, eight patients were analyzed by whole-exome-sequencing before the initiation of venetoclax therapy and at the time of venetoclax resistance [42]. All patients had shown a significant clinical response to venetoclax before developing disease progression or relapse. In most patients, mutations in cancer-related genes (i.e. BRAF, CD274, NOTCH1, RB1, SF3B1, and TP53) were identified. The variant allele frequency of such mutations dynamically changed during venetoclax treatment and at the time of progression [42]. More precisely, this study showed that molecular lesions associated with venetoclax resistance may include: i) recurrent mutations in the BTG1 gene; ii) homozygous deletions affecting CDKN2A/B that developed during treatment; iii) mutations in the BRAF gene; and iv) a high-level focal amplification of CD274 (PD-L1) [42]. Notably, BRAF mutations and CD274 amplifications might be used for targeted therapies with BRAF inhibitors or immune-checkpoint inhibitors, respectively [42].
Deciphering the genotype and phenotype of hairy cell leukemia: clues for diagnosis and treatment
Published in Expert Review of Clinical Immunology, 2019
Margot C.E. Polderdijk, Michiel Heron, Saskia Kuipers, Ger T. Rijkers
The BRAF gene is located on chromosome 7q34, and codes for the B-Raf protein. This protein, like other members of the Raf kinase family, has a function in signal transduction, specifically in a pathway affecting cell division, differentiation and secretion: the MAP kinase/ERKs signaling pathway (see Figure 3). B-Raf consists of 766 amino acids, from which three conserved regions can be identified, connected by a GTP-binding domain and a serine-rich hinge region. Various mutations in the BRAF gene have been linked to the development of certain types of cancer, for example colorectal cancer, thyroid cancer, melanoma, and hairy cell leukemia. Figure 4 shows the distribution of the currently published mutations over the gene. In BRAF, there are clearly several hotspots, which is different compared to the BRCA1 gene (Figure 5). Overall, BRAF mutations are found in 8% of human cancers [49]. Because of the many different signaling pathways in which BRAF participates, this finding is not very surprising. However, while the role of BRAF in pathogenesis of cancer might seem self-evident, the clinical implications across different forms of cancer types differ. Furthermore, determination of the exact role of BRAF is complicated when other, simultaneous, oncogenic mutations are involved.