This project aims to develop comprehensive, rapid, and economical methods for detecting recurrent chromosomal aberrations in cancer. The methods will allow detection of recurrent chromosomal aberrations in hundreds of small (< 1000 cells) specimens at the Kbp level of resolution, including small deletions and aberrant joins induced by balanced rearrangements. This development project employs next-generation technologies and methodologies essential for large-scale genome sequencing and mapping .To enable analyses of resulting data by basic scientists and clinicians who are not experts in genomics, the methods will be supported by Genboree, a turnkey web- accessible informatic system developed in the context of genome mapping projects at the BCM Human Genome Sequencing Center. Recurrent rearrangements have both biological and clinical importance: 1) they have been implicated as causative events in cancer progression, 2) they can be used as highly informative diagnostic and prognostic markers, and 3) they have served as therapeutic targets. Comprehensive high-resolution mapping of genomes in multiple transformed cell lines and primary tumor samples will reveal novel biologically and clinically significant recurrent chromosomal aberrations. Recurrent chromosomal aberrations are best understood in leukemias, lymphomas, and sarcomas. However, recent evidence suggests that carcinomas also contain biologically important highly recurrent rearrangements, which we aim to discover using the proposed methods. Due to the more complex structure of rearrangements and heterogeneity of cell populations in carcinomas, recurrent rearrangements are only partially detectable using current cytogenetic methods. The study of highly rearranged genomes such as those found in breast cancer and other carcinomas will particularly benefit from an increase in resolution beyond currently available technologies. This project will develop a novel technology for identifying gene aberrations that are involved in the progression of breast cancer, the most common cancer among women, and in the progression of other solid tumors. The knowledge about specific gene aberrations gained through the application of the technology will enable development of novel highly targeted cancer therapies. ? ? ?
| Hampton, Oliver A; Koriabine, Maxim; Miller, Christopher A et al. (2011) Long-range massively parallel mate pair sequencing detects distinct mutations and similar patterns of structural mutability in two breast cancer cell lines. Cancer Genet 204:447-57 |
| Miller, Christopher A; Settle, Stephen H; Sulman, Erik P et al. (2011) Discovering functional modules by identifying recurrent and mutually exclusive mutational patterns in tumors. BMC Med Genomics 4:34 |
| Miller, Christopher A; Hampton, Oliver; Coarfa, Cristian et al. (2011) ReadDepth: a parallel R package for detecting copy number alterations from short sequencing reads. PLoS One 6:e16327 |
