hTERT mRNA Splice Variant Analysis for Thyroid Tumor Classification

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Solution Overview

Problem

Current diagnostic methods for thyroid nodules are inadequate in distinguishing between malignant and non-malignant tumors, leading to unnecessary surgeries and potential undertreatment of cancer, as fine needle aspiration biopsies often yield indeterminate results.

Innovation Solution

A method involving the analysis of hTERT mRNA alternative splice variants, specifically the presence or absence of the β sequence, to determine if a thyroid tumor is malignant, using techniques such as RT-PCR and in situ hybridization to quantify the ratio of β-containing to β-lacking mRNA, allowing for more accurate classification and treatment decisions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If fine needle aspiration (FNA) biopsy is used to detect thyroid malignancy, then sensitivity in detecting malignancy is high, but diagnostic precision deteriorates because results are indeterminate or suspicious in 20-30% of cases

Engineering Contradiction:

Improvesensitivity in detecting malignancyVSAvoiddiagnostic precision

Core Design Contradiction:

ReliabilityVSMeasurement precision

Solution Approach 1:

The patent segments the hTERT mRNA into different splice variants (wild-type and alternative splice variants with deletions/insertions). By analyzing the specific patterns of these segmented mRNA variants rather than just overall hTERT expression, the method achieves better diagnostic precision while maintaining the sensitivity of detecting malignancy.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent changes the parameter being measured from overall hTERT mRNA expression levels to the specific splicing patterns and ratios of different hTERT mRNA variants. This parameter change allows differentiation between benign and malignant tumors that would otherwise appear indeterminate using conventional FNA biopsy methods.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If aggressive treatment such as total thyroidectomy is administered to patients with suspicious thyroid lesions, then potential malignancy is addressed, but unnecessary surgery is performed on patients with benign lesions

Engineering Contradiction:

Improvecancer detection reliabilityVSAvoidharm from unnecessary surgery

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent performs preliminary molecular analysis of hTERT mRNA splice variants on fine needle aspiration samples before committing patients to aggressive surgery. This preliminary action provides additional diagnostic information that helps distinguish malignant from benign lesions, allowing clinicians to avoid unnecessary total thyroidectomies in patients with benign conditions while ensuring appropriate treatment for malignant cases.

Inventive Principle:

Principle #10Preliminary action

3Ease of manufacture

If conventional cytological analysis is used for thyroid nodule diagnosis, then the diagnostic process is simple and inexpensive, but the ability to distinguish malignant from benign tumors deteriorates

Engineering Contradiction:

Improvediagnostic process simplicityVSAvoidtumor classification accuracy

Core Design Contradiction:

Ease of manufactureVSMeasurement precision

Solution Approach 1:

The patent uses universal molecular biology techniques (RT-PCR, in situ hybridization) that can be performed in standard laboratory settings to analyze hTERT mRNA splice variants. These multi-functional methods provide both quantitative and qualitative information about tumor nature, enhancing classification accuracy while remaining relatively simple and cost-effective compared to more complex molecular profiling approaches.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This approach provides a rapid, inexpensive, and accurate means to differentiate between malignant and benign thyroid tumors, preventing unnecessary surgeries and ensuring appropriate treatment, including the option for a single operation for malignant tumors.

Implementation Method 1

RT-PCR

Methodology Applied

Scientific EffectReverse transcription:

Implementation Method 2

PCR

Methodology Applied

Scientific EffectPolymerase chain reaction:

Implementation Method 3

in situ hybridization

Methodology Applied

Scientific EffectHybridization:

Data Source

PatentUS10774389B2Alternative splice variant patterns of human telomerase reverse transcriptase (hTERT) in thyroid tumors to distinguish benign from malignant

Publication Date: 2020.09.15 JOHNS HOPKINS UNIVERSITY

AI summary

This invention relates, e.g., to a method for determining if a thyroid tumor in a subject is malignant, comprising determining in a sample from the subject the amount of TERT (telomerase reverse transcriptase) mRNA which lacks the β sequence and the amount of TERT mRNA in the sample which comprises the β sequence, wherein a preponderance (e.g., at least about 55%) of TERT mRNA in the sample which comprises the β sequence indicates that the tumor is malignant, and wherein a preponderance of TERT mRNA which lacks the β sequence indicates that the tumor is not malignant.