IGH Translocation Breakpoint Mapping for Oncogene Overexpression
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Solution Overview
Problem
Current methods for detecting oncogene overexpression through IGH translocations in hematological malignancies are limited by their reliance on specific probes, low-resolution hybridization, and inability to accurately assess the impact of breakpoint distance on oncogene activation, hindering personalized diagnosis and treatment strategies.
Innovation Solution
A method for detecting oncogene overexpression by identifying translocations with breakpoints within 1.3Mb of the oncogene's transcription start site, allowing for personalized cancer treatment strategies through targeted therapies or chemotherapies based on breakpoint proximity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If FISH with specific probes is used to detect IGH translocations, then detection sensitivity for known translocations is improved, but the ability to detect unknown or rare translocations and assess breakpoint distance impact is limited
Solution Approach 1:
The patent employs next-generation sequencing (NGS) technology that can simultaneously detect known and unknown IGH translocations, assess breakpoint distances, and identify fusion partners in a single assay. This universal approach replaces the need for multiple specific FISH probes, enabling comprehensive translocation analysis across diverse hematological malignancies including Burkitt lymphoma, multiple myeloma, and acute lymphoblastic leukemia.
Solution Approach 2:
The invention changes the detection parameter from qualitative probe-based signal detection (FISH) to quantitative sequence-based analysis (NGS). By sequencing the IGH locus and analyzing breakpoint sequences, the method can precisely measure distance from the IGH enhancer to the oncogene, a parameter that cannot be assessed by traditional FISH. This parameter change enables correlation between breakpoint distance and oncogene overexpression levels.
2Loss of information
If traditional cytogenetic methods are used, then chromosomal translocations can be identified, but precise breakpoint localization and distance measurement from oncogene transcription start sites cannot be achieved
Solution Approach 1:
The patent replaces mechanical cytogenetic methods (karyotyping, FISH) with molecular sequencing technology. NGS provides base-pair resolution of breakpoints, replacing the low-resolution visual assessment of traditional methods. This substitution enables precise measurement of the distance between the IGH breakpoint and the transcription start site of the oncogene, information that is completely lost in conventional cytogenetics.
3Ease of operation
If IGH translocation detection is performed without considering breakpoint distance, then translocation presence is identified, but the ability to predict oncogene overexpression and guide targeted therapy is reduced
Solution Approach 1:
The patent implements a feedback mechanism where the measured breakpoint distance directly informs clinical decision-making. By correlating the distance from the IGH enhancer to the oncogene TSS with overexpression levels, the method provides predictive feedback that guides targeted therapy selection. Patients with breakpoints within a specific distance threshold are identified as candidates for targeted therapies against the fused oncogene, creating a actionable feedback loop from detection to treatment.
Data Source
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AI summary
Provided herein are methods related to detecting overexpression of an oncogene through translocations in the immunoglobulin heavy (IGH) locus, as well as methods of treatment, uses, and kits related thereto. As demonstrated herein, IGH translocations lead to oncogene overexpression when the distance from a breakpoint of the translocation to the transcription start site (TSS) of an oncogene is within 0-1.3 Mb. As such, detecting IGH translocations in which a breakpoint is 1.3Mb or less from an oncogene TSS may find use, e.g., in detecting oncogene overexpression, providing assessment/diagnosis, identifying individuals for treatment, selecting therapies, identifying treatment options, and treating or delaying progression of cancer, e.g., using relevant targeted and/or non-targeted therapies.