Cincinnati Study Of Chernobyl Residents Uncovers New Cause Of Thyroid Cancer

Yuri E. Nukiforov led a team of researchers from both Cincinnati University and the University of Munich in identifying a novel oncogene (a mutated and/or overproduced version of a normal gene that alone or together with other changes can convert a cell into a tumor cell) in papillary thyroid carcinomas that developed in patients exposed to radiation at Chernobyl. Their results are published in the January 3 issue of the Journal of Clinical Investigation.

Mutations of the genes BRAF, RET, or RAS are found in 70% of all cases of papillary thyroid tumors. In sporadic tumors (where patients have not been exposed to high levels of radiation), the most common genetic mutational event occurs within the BRAF gene. In contrast, mutations observed in radiation-induced tumors most commonly involve fusion of one end of the RET gene to the opposite end of various other genes to create a "chimeric oncogene." The two most common gene rearrangement types are called RET/PTC1 and RET/PTC3. Both types of mutations promote transformation of normal cells into malignant cells.

In their current study, Nukiforov and colleagues identified a novel oncogene in Chernobyl residents with papillary thyroid cancer. This oncogene resulted from fusion of part of the AKAP9 gene with one end of the BRAF gene; both genes are present within chromosome 7. The intrachromosomal AKAP9-BRAF fusion event resulted in the loss of portions of the BRAF protein that normally inhibit the kinase activity of BRAF. BRAF is then able to transmit uncontrolled signals to normal cells that promote their division and transformation into malignant tumor cells.

In an accompanying commentary, Alfredo Fusco and colleagues from Università degli Studi di Napoli "Federico II", in Naples, state that this study "provides further evidence supporting the concept that chromosomal inversions represent the most typical molecular lesion in tumors occurring in Belarus and the surrounding region after the Chernobyl accident….the peculiar susceptibility of thyroid follicular cells to chromosomal rearrangement is remarkable."

This study represents a major breakthrough in our knowledge of the genetic events involved in papillary thyroid initiation. It demonstrates that while BRAF activation is a common feature of both sporadic and post-Chernobyl thyroid cancers, it is the genetic event underlying BRAF activation that can differentiate between the two types of tumors, with a higher proportion of point mutations occurring in sporadic thyroid cancers and intrachromosomal inversion responsible for a larger percentage of radiation-induced tumors. At this stage, the signaling pathway activated as a result of these mutational events (known as the MAPK pathway) is the most attractive target for new drugs that may intervene in the development of human papillary thyroid carcinomas.

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TITLE: Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer

AUTHOR: Yuri NikiforovUniversity of Cincinnati, Cincinnati, Ohio, USA.

A PDF of this article this article is available at: http://www.jci.org/cgi/content/full/115/1/94.

ACCOMPANYING COMMENTARY:

TITLE: A new mechanism of BRAF activation in human thyroid papillary carcinomas

AUTHOR: Alfredo FuscoUniversità degli Studi di Napoli "Federico II", Naples, Italy.

A PDF of this article this article is available at: http://www.jci.org/cgi/content/full/115/1/20.