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Evaluation of heterogeneity of BRAF, MAP2K1 and MAP2K2 in primary and metastatic melanomas

Grant number: 17/10547-8
Support Opportunities:Regular Research Grants
Duration: December 01, 2017 - June 30, 2020
Field of knowledge:Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
Principal Investigator:Gilles Landman
Grantee:Gilles Landman
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated researchers:João Bosco Pesquero

Abstract

BRAF, MEK and KIT point mutations are widely known for inducing resistance to targeted therapy in systemic treatment of advanced cutaneous melanoma. To explain this phenomenon different mechanisms are proposed, including tumoral genomic heterogeneity, both in primary and metastatic tumors. We have previously tested the heterogeneity hypothesis in primary cutaneous melanomas (acral lentiginous type) and metastatic melanomas. Intratumoral heterogeneity in protein expression of BRAF (55%) and KIT (43%) has been found using immunohistochemistry (FAPESP 2011/20435-6). We have also found an association between BRAF and c-MYC as an independent predictor of malignancy (OR=90). Using the same samples, genomic heterogeneity was observed in BRAF exon 15 (65% of cases) (FAPESP 2012/11408-8) and KIT exon 11 e 13 (44% of cases) (FAPESP 2012/11513-6). However, these findings of tumor heterogeneity in cutaneous melanomas need to be validated by a more sensitive methodology. Next Generation Sequecing (NGS) technique provides simultaneous evaluation of multiple mutations in a wide range of genes. We aim to study and confirm the existence of intratumoral genetic heterogeneity in different histological subtypes of primary melanoma acral-lentiginous and non-acral (n=48) and metastasis (n=48), using a multigene platform. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
KEPPEKE, GERSON D.; BARCELOS, DENISE; FERNANDES, MARIANA; COMODO, ANDREIA N.; GUIMARAES, DAIANE P.; CARDILI, LEONARDO; CARAPETO, FERNANDO C. L.; ANDRADE, LUIS E. C.; LANDMAN, GILLES. IMP dehydrogenase rod/ring structures in acral melanomas. PIGMENT CELL & MELANOMA RESEARCH, . (17/20745-1, 17/10547-8)
KEPPEKE, GERSON D.; BARCELOS, DENISE; FERNANDES, MARIANA; COMODO, ANDREIA N.; GUIMARAES, DAIANE P.; CARDILI, LEONARDO; CARAPETO, FERNANDO C. L.; ANDRADE, LUIS E. C.; LANDMAN, GILLES. IMP dehydrogenase rod/ring structures in acral melanomas. PIGMENT CELL & MELANOMA RESEARCH, v. 33, n. 3, p. 490-497, . (17/20745-1, 17/10547-8)

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