BRAF
In databases :
● Entrez (http://www.ncbi.nlm.nih.gov/sites/gquery): 673 or BRAF
● Ensembl (http://www.ensembl.org/index.html): ENSG00000157764
● HGNC (http://www.genenames.org/): 1097 or BRAF
● Enzyme Number (IUBMB): EC 2.7.11.1
Gene locus:
7q34
Protein name:
v-raf murine sarcoma viral oncogene homolog B1
Protein Size:
766 amino acids; about 85 kDa
Function:
the gene encodes a serine-threonine protein kinase. This protein plays a role in regulating the MAP kinase / ERKs signaling pathway, which affects cell division, differentiation, and secretion.
Cancer-related alterations:
No germinal BRAF mutations have been described.
BRAF presents somatic mutations in different sort of tumors, predominantly in malignant melanoma, colorectal tumors, low-grade ovarian serous carcinoma and thyroid papillary cancer. 80% of these mutations correspond to the hot spot transversion mutation T1799A that causes the amino acidic substitution V600E. The other 20% accounts for a wide variable range of “missense” substitutions and all of them reside in the glycines of the G-loop in the exon 11 or in the activation segment in exon 15 near the V600. The mutation V600E confers transforming activity to the cells because it mimics the phosphorylation of T599 and/or S602 in the activation segment and so BRAF rests constitutively active in a RAS independent manner.
V600E in BRAF is the most frequent oncogenic protein kinase mutation known.
BRAF is mutated in 70% of malignant melanomas. The mutation V600E is an early event and alone is insufficient for the development of melanoma as it is present in 80% of primary melanomas and 80% of nevi, which are the first lesions associated with this tumor. No BRAF mutations are associated with uveal melanoma. In melanomas without BRAF mutation, alteration of NRAS (Q61R or Q61K) is often seen.
In colorectal cancers, BRAF mutation V600E is associated with mismatch repair deficiency (MSI) and found in 40% of the cases while in mismatch repair proficient tumors (MSS) the frequency is around 5%. Gastric and endometrial MSI and MSS tumors do not have BRAF mutations. In tumors from the hereditary nonpolyposis colorectal cancer (HNPCC), either with MLH1, MSH2 or MSH6 germline mutations or none, no BRAF mutations are detected.
In colorectal tumors without BRAF mutation, an alteration of KRAS (G12C, G12D, G12V, G13D) is often seen.
In ovarian and thyroid cancers, the only BRAF mutation present is V600E with a frequency around 30% and 50%, respectively
BRAF is involved in rare fusion events with AGTRAP (gastric cancer), AKAP9 (inv(7)(q21-22;q34) in papillary thyroid adenocarcinoma), FCHSD1 (t(5;7)(q31;q34) in congenital melanocytic nevus), SLC45A3 (prostate cancer), KIAA1549 (astrocytoma)
Therapy:
Given the frequent occurrence of BRAF mutations in human cancer and the continued requirement for BRAF activity in the tumors in which it is mutated, efforts are underway to develop targeted inhibitors of BRAF and its downstream effectors. These agents offer the possibility of greater efficacy and less toxicity than the systemic therapies currently available for tumors driven by activating mutations of MAPK pathway components. Early clinical results with the BRAF-selective inhibitors PLX4032 (vemurafenib) and GSK2118436 suggest that this strategy will prove successful in a select group of patients whose tumors are driven by oncogenic BRAF.
References (open access):
Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G, Burton EA, Wong B, Tsang G, West BL, Powell B, Shellooe R, Marimuthu A, Nguyen H, Zhang KY, Artis DR, Schlessinger J, Su F, Higgins B, Iyer R, D'Andrea K, Koehler A, Stumm M, Lin PS, Lee RJ, Grippo J, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, Chapman PB, Flaherty KT, Xu X, Nathanson KL, Nolop K. Nature. 2010 Sep 30;467(7315):596-9.
The BRAFV600E mutation: what is it really orchestrating in thyroid cancer? Nucera C, Lawler J, Hodin R, Parangi S. Oncotarget. 2010 Dec;1(8):751-6.
Potential therapeutic strategies to overcome acquired resistance to BRAF or MEK inhibitors in BRAF mutant cancers. Corcoran RB, Settleman J, Engelman JA. Oncotarget. 2011 Apr;2(4):336-46.
Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Palanisamy N, Ateeq B, Kalyana-Sundaram S, Pflueger D, Ramnarayanan K, Shankar S, Han B, Cao Q , Cao X , Suleman K, Kumar-Sinha C, Dhanasekaran SM, Chen YB, Esgueva R, Banerjee S, LaFargue CJ, Siddiqui J, Demichelis F, Moeller P, Bismar TA, Kuefer R, Fullen DR, Johnson TM, Greenson JK, Giordano TJ, Tan P, Tomlins SA, Varambally S, Rubin MA, Maher CA, Chinnaiyan AM. Nat Med. 2010 Jul;16(7):793-8
Aucun commentaire:
Enregistrer un commentaire