DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (08) Genomics, and Specific Challenge Topic 03-CA-101 Fingerprints for the Early Detection and Treatment of Cancer. Project Summary /Abstract Chromosomal structural aberration includes translocation, inversion, insertion, and deletion. Such changes could directly disrupt the structure of normal genes and form fusion genes between two genes. Such changes have been well demonstrated in leukemia and increasingly revealed in solid tumors as well. Many chromosomal structural aberrations have been demonstrated to play important roles in tumorogenesis, and used widely as genetic markers in clinical applications including diagnosis, treatment and prognosis. Although great progress has been made, we are still far away from comprehensive understanding of the spectrum of structural aberrations in a cancer genome. In many cancers, genetic structural changes have not been identified. Those unknown genetic mutations could have specific structural features or affect smaller loci that may be difficult to identify using the conventional techniques. On the other hand, for the genetic structural aberrations already identified, it is still difficult to distinguish between the "passenger" mutations that are not the causes of the cancer but random mutations following the process of tumorogenesis, and the "driver" mutations that directly contribute to tumorogenesis. mRNA is the functional readouts of the active genes in the cell under a given condition. The presence of fusion transcripts between unrelated mRNAs may provide direct evidence for the presence of the genomic structural aberration in the genome, and for its functional involvement in tumorogenosis, which is critical in distinguishing the "driver" mutation from the "passenger" mutation. The recently developed RNA-Seq method provides a powerful tool for detecting the fusion transcripts. It only needs simple sample preparation and can collect massive short cDNA sequences from the next-generation DNA sequencers at low cost. The large quantity of sequences provides rich resources for comprehensive identification of fusion transcripts and their original genomic aberrations. In this proposal, we plan to perform a systematic analysis for the fusion transcripts and their chromosomal structural aberrations in AML (acute myeloid leukemia), a major type of leukemia. Although consistent chromosomal structural changes have been identified in AML, half of AML cases do not contain those known chromosomal structural aberrations. The clinical outcomes of these AML cases differ from those with known translocations, suggesting that the normal karyotype AML may contain different genetic aberrations. In this proposal, we plan to use the RNA-Seq method to obtain a comprehensive transcriptome from 50 AML samples. We plan to perform extensive informatics analysis to identify the fusion transcripts and other changes in order to locating their original structural aberrations in the disease genome. The potential impact of the study will be to provide a comprehensive map of fusion and genetic aberrations in AML, to identify new candidate genes involved in AML, to provide new candidate genes for identifying the "driver" mutations, and to provide new genetic markers for cancer subtype classification and for better diagnosis, treatment and prognosis of AML PUBLIC HEALTH RELEVANCE: The proposal plans to perform a comprehensive detection of fusion transcripts in acute myeloid leukemia, with the aims to identify new genes contributing to this disease and to identify new markers for clinical diagnosis, treatment and prognosis of this disease.
|Effective start/end date||9/30/09 → 8/31/12|
- National Institutes of Health: $294,000.00
- National Institutes of Health: $500,000.00
- National Institutes of Health: $205,133.00