My lab tries to understand the mechanisms of gene amplification in human cancers. Gene amplification is a clinically important form of genome instability, as gene amplification drives aggressive tumor phenotypes, such as tumor progression and therapy resistance. Therefore, better understanding of amplification mechanism could lead to the improved survival of cancer patients. Two specific questions I am addressing by dissecting the mechanisms are: (1) how to detect cells undergoing gene amplification at the very early stage, and (2) how to find agents that specifically eliminate cells undergoing gene amplification.
Gene amplification occurs as a selective copy-number increase of a particular genomic segment by DNA rearrangements without a proportional increase of entire genome. We have shown previously that the inverted duplication of a genomic segment occurs by a DNA break and initiates gene amplification. Thus, the locations of the inverted duplication (DNA palindromes) mark initial breaks and rearrangements in the genome. Using our unique genomic technology (Genome-wide Analysis of Palindrome Formation), we have shown that DNA palindromes indeed mark the initial rearrangements, as palindromes localize at the boundaries of amplified genomic segments.
We are now applying Next Generation Sequencing to our genomic technology and are revealing the crucial role of DNA palindromes in initiating oncogene amplification in primary breast and colorectal tumors. Thus, DNA palindromes may serve as an early DNA marker for gene amplification. Furthermore, we are identifying agents that eliminate cells undergoing gene amplification using our cell culture model for DNA palindrome-initiated gene amplification.
Marotta, M., Chen, X., Inoshita, A., Stephens, R., Budd, T.G., Crowe, J., Lyones, J., Kondratova, A., Tubbs, R. and Tanaka, H. (2012) A common copy number breakpoint of ERBB2 amplification in breast cancer co-localizes with a complex block of segmental duplications. Breast Cancer Research in press.
Marotta, M, Piontokivska, H, and Tanaka, H. (2012) Molecular trajectories leading to the alternative fates of duplicated genes. PLoS ONE 7(6): e38958.
Zhao, Y., Marotta, M., Eichler, E.E., Eng, C. and Tanaka, H. (2009) Linkage disequilibrium between two high-frequency deletion polymorphisms: implications for association studies involving the glutathione-S transferase (GST) genes. PLoS Genet. 5, e1000472.
Tanaka, H*. and Yao, M. C. (2009). Palindromic gene amplification – an evolutionarily conserved role for DNA inverted repeats in the genome. Nat Reviews Cancer, 9, 216-224. (*corresponding author)
Lerner Research Institute
Mail Code NB21
9500 Euclid Avenue
Cleveland, Ohio 44195