NEW YORK (Reuters Health) - In papillary thyroid cancers that developed in the wake of the 1986 Chernobyl nuclear plant accident, paracentric inversions in chromosome 7q ultimately lead to activation of the mitogen-activated protein kinase (MAPK) pathway, new research suggests.
Point mutations activating the BRAF serine/threonine kinase were recently identified as the most common genetic event in sporadic thyroid papillary carcinoma (see Reuters Health report April 21, 2003).
For the current report, published in the January issue of the Journal of Clinical Investigation, senior author Dr. Yuri E. Nikiforov, a pathologist at the University of Cincinnati in Ohio, and colleagues obtained tissue samples from Belarussian patients who underwent surgery in the 1990s for papillary thyroid cancer.
They found that chromosomal rearrangement of BRAF resulted in its fusion with the A-kinase anchor protein 9 (AKAP9) gene. As a result, BRAF was transformed into an oncogene, losing its autoinhibitory N-terminal portion and leading to elevated basal kinase activity.
When the authors transfected NIH3T3 cells with wildtype BRAF, cells were transformed at very low efficiency, the authors report. Transformation activity was high, however, when the cells were transfected with the AKAP9-BRAF fusion protein. When these cells were injected into nude mice, tumors formed within 2 weeks.
“Tumors arising early after [radiation] exposure are likely to be initiated through direct radiation damage-related genetic events, such as chromosomal rearrangements occurring after double-stranded DNA breaks,” Dr. Nikiforov’s team writes.
This is “the first example of an intracellular effector in the MAPK pathway activated by recombination occurring in vivo,” Dr. Alfredo Fusco and colleagues at Universita degli Studi di Napoli “Federico II” in Naples, write in a related commentary.
“At this stage, this pathway is the most attractive target for novel pharmacological intervention in human papillary thyroid cancers,” they add.
Source: J Clin Invest 2005;115:20-23,94-101. [ Google search on this article ]
MeSH Headings:Protein-Serine-Threonine Kinases: Ca(2+)-Calmodulin Dependent Protein Kinase: Mitogen-Activated Protein Kinase KinasesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
