MDM2-Containing Double Minute Chromosomes And Methods Therefore

Abstract

Contemplated systems and methods allow for computational genomic analysis using paired-end sequence analysis and split read refinement to thereby identify high-confidence breakpoints associated with high copy numbers and orientation of rearrangements, which is then the basis for full reconstruction of double minutes (DM). In especially preferred aspects, the DM will also include an oncogene or tumor suppressor gene, and/or may be found in blood or blood derived fluids.

Description

[0001]This application claims priority to U.S. provisional patent application Ser. Nos. 61 / 568,513 filed Dec. 8, 2011 and 61 / 616,535 filed Mar. 28, 2012. This and all other extrinsic materials discussed herein are incorporated by reference in their entirety. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.FIELD OF THE INVENTION[0002]The field of the invention is molecular diagnostics, especially as it relates to analysis and identification of genomic rearrangements.BACKGROUND[0003]The introduction of whole-genome sequencing has provided researchers with an unprecedented ability to measure the complex state of genomic rearrangements characteristic of most cancers. Numerous methods for inferring structural variation from paired-end sequencing data have been developed (Bioinformat...

AI Technical Summary

Benefits of technology

[0007]The inventive subject matter is drawn to methods and computational systems in which whole genome paired-end sequence analysis enables rapid and comprehensive identification of genetic rearrangements via identification of high-confidence breakpoints and associated high copy numbers to fully reconstruct intact DMs that typically contain highly amplified oncogenes associated with the neoplasm.

Problems solved by technology

The difficulty in discovering all true structural variants and filtering out false positives makes it hard to use the output of currently known methods to reassemble large regions of the tumor genome.

Such difficulties are particularly unfortunate as proper tumor genome assemblies help reveal the complex structure of the tumor genome and could be used to infer a mechanism by which somatic alterations such as amplifications of oncogenes and deletions of tumor suppressors occur.

Other monitoring techniques, such as measuring circulating tumor cells, require significant enrichment efforts that are only feasible when tumors with metastatic potential are present (Cancer Lett.

Both of these techniques present technical challenges that make them unsuitable for initial tumor diagnosis.

Double minutes (DMs) have been shown to confer resistance to certain drugs, as well as pass along this resistance non-uniformly to daughter cells.

Since DMs lack centromeres, they are randomly distributed to daughter cells during cell division, and they are generally lost in future generations unless there is some selective pressure to maintain them.

Images