Genetic Origins of Melanoma: Mechanism of BRAF Gene Mutation

NB: We do not resell your papers. Upon ordering, we do an original paper exclusively for you.

NB: All your data is kept safe from the public.

Melanoma Background

Melanoma in the early years was described as a benign mole that continued to grow and could be recognized by an irregular shape and discoloration of the mole (Sober et al., 1979). These cancer cells were well known for their ability to spread around the body quickly and avoid the therapeutic treatment, creating a dangerous situation (Li et al., 2001). When detected early, Melanoma could be removed successfully by a surgical procedure, but when metastasized, the cancer cells were much harder to kill, and treatment with chemotherapy and radiation were not much help, leading to a poor prognosis. (Sober et al., 1979; Irie et al., 2004). This led to copious amounts of research. Researchers linked that the first step in progression of Melanoma comes from a common melanocytic nevus, whose cells lost a checkpoint in the cell cycle and began to over proliferate (Clark et al., 1984; Carson et al., 2012). Inside these melanocytic nevi, over proliferation could be caused by a mutation in a proto-oncogene that activated the MAPK pathway, inhibited tumor suppressors, and allowed melanoma characterized cells to proliferate wildly (Florenes et at., 1998; Florenes et al., 1999; Kortylewski et al., 2001). Specifically, a high percentage of melanoma cases were linked to a mutation in the proto-oncogene BRAF (Colombino et al., 2012; Davies et al., 2002). Understanding this allowed scientist to tackle new ways of therapy. For example, immunotherapy and targeted therapy in melanoma cases were shown to be more successful than the previous therapies when studied and showed great room for more research (Deken et al., 2016; Moreno et al., 2015; Koya et al., 2012; Larkin et al., Long et al., 2014; Ribas et al., 2019; Robert et al., 2015) These findings struck a lot of interest in research that focused on the BRAF gene, its mutations, and its effects that lead to melanoma. By taking this knowledge about melanoma and emphasizing the focus on targeted therapies that will inhibit the effects caused by mutated BRAF in the MAPK pathway, the prognosis of Melanoma cancer will improve tremendously.

BRAF Gene

Characterization of the gene: BRAF

Improving the prognosis of melanoma and future treatments all starts by understanding this important gene, as it plays a lead role in a lot of actions. This proto-oncogene which encodes for serine/threonine kinase activates the MAPK signaling pathway by signaling to MEK which then sends a signal cascade down to ERK 1 and 2 (Kyriakis et al., 1992; Wajapeyee et al., 2008). The MAPK pathway is an important priority in understanding cancer cell proliferation and cancer cell survival (Kyriakis et al., 1992). Understanding the roll of activated MAPK brings hope for future therapeutics for melanoma patients (Cohen et. al., 2002). BRAF is located on chromosome 7 and is often mutated (Stagni et al., 2018). Studies have shown that when there are gains at chromosome 7 in the BRAF gene, there are high correlations of mutant melanoma diagnosis (Greshock et al., 2009; Helias-Rodzewicz et al., 2015; Stagni et al. 2018) A gene mutation in BRAF is found around 50% of the time in melanoma cells, and when this happens there is continuous activation of the kinase that starts the cascade signaling in cell proliferation (Curtin et al., 2005; Davies et al., 2002; Long et al., 2011; Si et al., 2018). With such a specific mutation linked to melanoma, there is prestigious information to be known about the BRAF mutation.

Mutations within BRAF can lead to melanoma

BRAF is most commonly mutated at the 600th amino acid, in which the amino acid Valine is switched to Glutamic Acid, giving the cell the newly mutated BRAF V600E gene (Davies et. al., 2002; Can et al, 2018). This gene may also mutate from Valine to Lysine at the 600th amino acid, which is called BRAF V600K (Wan et al., 2004). These mutations are very different from each other in ways, but both lead to big changes. As a result, these differences are best demonstrated by evaluation cohorts of Melanoma patients. For example, the proportion of melanoma cases that have a mutation in BRAF are more likely to have the V600E mutation (73%-76% of population) compared to the V600K mutation (19%-24% of population), and the V600K was mostly found in older patients compared to the younger patients with the V600E mutant gene. (Menzies et al., 2012; Ardakani et al. 2017; Bucheit et al., 2013). The mutations are also different in correlation with the prognosis and tumor characteristics, as the V600K mutant is found within patients with a short survival until stage IV and the tumor found in the neck and head area, compared to the V600E mutant found in longer survival times and in the areas such as limbs and trunk (Bucheit et al., 2013). This amino acid shift in either way (Valine to Glutamic acid or Valine to Lysine) leads to continuous signaling in the MAPK pathway, allowing cells in the pathway to have advantages when it comes to survival and making way for them to over proliferate (Can et al., 2018). This MAPK pathway being activated is an early event in the progression of melanoma (Cohen et al., 2002). Understanding this has led to therapeutic inhibition of proteins in the MAPK pathway.

References

Bucheit AD, Syklawer E, Jakcob JA, Bassett Jr RL, Curry JL, Gershewald. Davies MA. Clinical Characteristics and outcomes with specific BRAF and NRAS mutations in patients with metastatic melanoma. Cancer. 2013; 119(21): 3821-3829 doi:10.1002/cncr.28306
Can N, Tastekin E, Deniz Yalta T, Sut N, Korkmaz S, Usta U. Tozkir H. BRAF V600 Mutation Profile of Metastic Melanoma in the Thrace Region of Turkey. Turkish Journal of Pathology. 2018; 34(2):134-142 doi: 10.5146/tjpath.2018.01422
Carson C, Omolo B, Chou H, Zhou Y, Sambade MJ, Peters EC. Kaufmann WK. Aprognostic signature of defective p53-dependent G1 checkpoint function inmelanoma cell lines. Pigment Cell Melanoma. 2012; 25(4): 513-526 doi:10.1111/j.1755148X.2012.01010.x
Clark WH, Elder DE, Guerra D, Epstein MN, Greene MH, Van Horn M. A Study of Tumor Progression: The Precursor Lesions of Superficial Spreading and Nodular Melanoma.Human Pathology. 1984; 15(12): 1147-1165. Doi: 10.1016/ss0046 8177(84)80310
Cohen C, Zavala-Pompa A, Sequeria JH, Shoji M, Sexton DG, Cotsonis G. Arbiser J. Mitogen-activated Protein Kinase Activation Is and Early Even in Melanoma Progression. Clinical Cancer Research. 2002; 8: 3728-3733
Colombino M, Capone M, Lisboa A, Cossu A, Rubino C, De Giorgi V… Palmieri G. BRAF/NRAS Mutation frequencies amongprimary tumors and metastases in patients with melanoma. Journal of Clinical Oncology. 2012; 30(20): 2522-2529 doi: 10.1200/jco.2011.41.2452
Curtain JA, Fridlyand J, Kagoshima T, Patel HN, Busam KJ, Kutzner H. Bastian BC. Distanct set of genetic alterations in melanoma. N England J Med. 2005; 353: 2135-2147 doi: 10.1056/NEJMoa050092
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S. Futreal PA. Mutations of the BRAF gene human cancer. Nature. 2002; 417(6892): 949-954; doi: 10.1038/nature007766
Deken MA, Gadiot J, Jordanova ES, Lacroix R, van Gool M, Kroon P… Blank CU. Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma. OncoImmunology. 2016; 5(12) doi: 10.1080/2162402x.2016.1238557
Florenes VA, Lu C, Bhattacharya N, Rak J, Sheehan C, Slingerland JM, Kerbel RS. Interleukin 6 dependent induction of the cycling dependent kinase inhibitor p21WAF1/CIP1 is lost during progression of human malignant melanoma. Oncogene. 1999; 18(4): 1023-1032 doi: 10.1038/sj.onc.1202382
Florenes VA, Maelandsmo GM, Kerbel RS, Slingerland JM, Nesland JM, Holm R. Protein expression of the cell-cycle inhibitor p27Kip1 in malignant melanoma: inverse correlation with disease-free survival. The American Journal of Pathology. 1998; 153(1): 305-312 doi:10.1016/S0002-9440(10)655572-1
Greshock J, Nathanson K, Medina A, Ward MR, Herlyn M, Weber BL, Zaks TZ. Distict patterns of DNA copy number alterations associate with BRAF mutations in melanomas and melanoma derived cell lines. Genes Chromosome Cancer. 2009; 48(5): 419-428 doi:10.1002/gcc.20651
Helias-Rodzewicz Z, Funck-Bretano E, Baudoux L, Jung CK, Zimmerman U, Marin C… Emile JF. Variations of BRAF mutant allele percentages in melanomas. BMC Cancer. 2015; 15: 497 doi: 10,1186/s12885-015-1515-3
Homet Moreno B, Mok S, Comin-Andruix B, Hy-Lieskovan S, Ribas A. Combined treatment with dabrafenib and trametinib with immune-stimulating antibodies for BRAF mutant melanoma. OncoImmunology. 2015; 5(7) doi: 10.1080/2162402×2015.1052212
Irie RF, Ollila DW, O’Day S, Morton DL. Phase 1 pilot clinical trial of human IgM monoclonal antibody to ganglioside GM3 in patients with metastatic melanoma. Cancer Immunology. 2003; 53(2): 110-117 doi:10.1007/s00262-003-0436-1
Kortylewski M, Heinrich PC, Kauffman ME, Bohm M, Mackiewicz A, Behrnmann I. Mitogen- activated protein kinases control p27/Kip1 expression and growth of human melanoma cells. Biochemical Journal. 2003; 357(1): 297-303 doi:10.1042/0264 6021:3570297
Koya RC, Mok S, Otte N, Blacketor KJ, Comin-Anduix B, Tumed PC… Ribas A. BRAF Inhibitor Vemurafenib the Antitumor Activity of Adoptive Cell Immunotherapy. Cancer Res. 2012; 72(16): 3928-3937 doi: 10.1158/0008-5472.CAN-11-2837
Kyriakis JM, App H, Zhang X, Bangerjee P, Braughtigan DL, Rapp UR, Avruch J. RAF-1 Activates MAP kinase-kinase. Nature. 1992; 358(6385): 417-421 doi: 10.1038/358417a0
Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M… Ribas A, Combined Vemurafenib and Cobimetinib in BRAF-mutated Melanoma. New England Journal of Medicine. 2014;371(20); 1867-1876 doi: 10.1056/nejmoa1408868
Li G, Schaider H, Satyamoorthy K, Hanakawa Y, Hashimoto K, Herlyn M. Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. Oncogene. 2001; 20(56): 8125-8135 doi:10.1038/sj.onc.1205034
Long GV, Menzies AM, Nagrial AM, Haydn LE, Hamilton AL, Mann GJ… Kefford RF. Prognostic and CLinicopathological Associations of Oncogenic BRAF in Metastatic Melanoma. Journal of Clinical Oncology. 2011; 29(10); 1239-1246 doi: 10.1200/jco.2010.32.4327
Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J…Flaherty K. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. New England Journal of Medicine. 2014; 371(20): 1877-1888 doi: 10.1056/nejmoa1406037
Menzies AM, Hayde LE, Visintin L, Carlino MS, Howle JR, Thompson… Long GV. Distingushing Clinicopathologic Features of Patients with V600E and V600K BRAF Mutant Metastatic Melanoma. Human Cancer Biology. 2012; 18(12):3242-3249 doi: 10.1158/1078-0432.CCR-12-0052
Mesbah Ardakani N, Leslie C, Greiu-lacopetta F, Lam WS, Budgeon C, Millward M, Amanuel B. Clinical and therapeutic implications of BRAF mutation heterogeneity in metastatic melanoma. Pigment Cell and Melanoma Research. 2017; 30(2): 233-242 doi:10.1111/pcmr.12569
Ribas A, Lawrence D, Atkinson V, Agarwal S, Miller Jr. WH, Carlino MS… Hamid O. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nature Medicine. 2019; 25(6): 936-940doi: 10.1038/s41591 019-0476-5
Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D… Schadendorf D. Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib. New England Journal of Medicine. (2015); 372(1): 30-39 doi: 10.1056/nejmoa1412690
Si L, Zhang X, Zhen X, Jiang Q, Bu L, Wang X… Guo J. Vemurafenib in Chinese patients with BRAFV600 mutation-positive unresectable or metastatic melanoma: an open label, multicenter phase 1 study. BMC Cancer. 2018; 18(1) doi:10.1186/s12885-018 4336-3
Sober AJ, Fitzpatrick TB, Mihm MC, Wise TG, Pearsons BJ, Clark WH, Knopf AW. Early Recognition of Cutaneous Melanoma. The Journal of the American Medical Association. 1979; 242(25): 2795-2799 doi: 10.1001/jama.1979.03300250051033
Stagni C, Zamuner C, Elefanti L, Zanin T, Del Bianco P, Sommariva A… Menin C. BRAF gene copy number and mutant allele frequency correlate with time and progression in metastatic melanoma patients treated with MAPK inhibitors. Molecular Cancer Therapeutics. 2018; 17(6): 1332-1340 doi: 10.1158/1535-7163.MCT-17-1124
Wajapeyee N, Serra RW, Zhu X, Mahalignam M, Green MR. Oncogenic BRAF Induces senescence and Apoptosis through Pathways Mediated by Secreted Protein IGFBP7. Cell. 2008; 132(3): 363-374 doi: 10.1016/jell.2007.12.032
Wan PTC, Garnett MJ, Roe MS, Lee S, Niculescu-Duvaz D, Good… Marais R. Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF. Cell. 2004; 116: 855-867 doi: 10.1016/s0092-8674(04)00215-6

Click Here To Order Now!

Genetic Origins of Melanoma: Mechanism of BRAF Gene Mutation

Do you need this or any other assignment done for you from scratch?

We have qualified writers to help you.

We assure you a quality paper that is 100% free from plagiarism and AI.

You can choose either format of your choice ( Apa, Mla, Havard, Chicago, or any other)