Premium
Oncogenic mutations in KEAP1 disturbing inhibitory Nrf2‐Keap1 interaction: Activation of antioxidative pathway in papillary thyroid carcinoma
Author(s) -
Danilovic Debora Lucia Seguro,
Mello Evandro Sobroza,
Frazzato Eliana Salgado Turri,
Wakamatsu Alda,
Jorge Alexander Augusto,
Hoff Ana Oliveira,
Marui Suemi
Publication year - 2018
Publication title -
head and neck
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.012
H-Index - 127
eISSN - 1097-0347
pISSN - 1043-3074
DOI - 10.1002/hed.25105
Subject(s) - keap1 , missense mutation , immunohistochemistry , cancer research , gene , transcription factor , mutation , biology , papillary carcinoma , thyroid carcinoma , pathology , thyroid , microbiology and biotechnology , medicine , genetics
Background Nuclear factor erythroid 2‐like 2 ( NFE2L2 ) encodes Nrf2, transcription factor of antioxidative genes. In the presence of reactive oxygen species, Keap1 (Kelch‐ECH‐associating protein‐1) inhibitor complex undergoes conformational changes disrupting Keap1‐Nrf2 binding and Nrf2 translocates into nucleus. We evaluated the presence of mutations in NFE2L2 and KEAP1 in papillary thyroid carcinomas (PTCs) and correlated them with clinical presentation. Methods Coding regions of NFE2L2 and KEAP1 were sequenced in 131 patients with PTC. Clinical and histopathological features were analyzed. Immunohistochemical analysis of Nrf2 expression was performed in mutated carcinomas. Results Although no mutations were found in NFE2L2 , missense mutations in KEAP1 were observed in 6 patients with PTC (4.6%). Immunohistochemistry showed increased Nrf2 expression in nuclei of all mutated carcinomas, which presented poor prognostic features in histopathology. Conclusion We identified mutations in KEAP1 associated with Nrf2 overexpression in PTC. Mutations favored disruption of inhibitory interaction Nrf2‐Keap1 to enable increased antioxidant Nrf2 activity, possibly with prognostic consequences.