Methods, treatment, and compositions for characterizing thyroid nodule
Inventors
HAHN, MARIA A. • Yim, John H. • Fong, Yuman • Li, Arthur X. • Wu, Xiwei
Assignees
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Publication Number
US-12391993-B2
Publication Date
2025-08-19
Expiration Date
Abstract
The current disclosure provides, inter alia, method of determining benign nodules from thyroid cancer in a subject that is found to have a thyroid nodule, method of treating thyroid cancer in a subject detected to have thyroid cancer by the method of the current disclosure, compositions for determining benign nodules from thyroid cancer in a subject, and kits including reagents and composition for determining benign nodules from thyroid cancer in a subject.
Core Innovation
The invention relates to measuring decreased DNA methylation levels, relative to a control, at papillary thyroid carcinoma DNA methylation sites in an isolated DNA obtained from a thyroid nodule from a human subject. The papillary thyroid carcinoma DNA methylation sites are defined with respect to reference human genome assembly hg19 as chromosome 10 position 112259015, chromosome 12 position 56115043, and chromosome 15 position 85402496.
The invention further relates to measuring methylation by bisulfite conversion and detecting the presence of uracil in the reacted thyroid nodule DNA. Measuring methylation levels also comprises amplifying DNA by contacting the DNA with a primer complementary to a sequence at or within 1000 nucleotides of the chromosomal positions to produce amplicons for measuring methylation levels.
The measured decreased DNA methylation levels at the specified papillary thyroid carcinoma DNA methylation sites are used to treat papillary thyroid cancer in a subject in need thereof. The method comprises administering cabozantinib-S-malate, doxorubicin hydrochloride, lenvatinib mesylate, sorafenib tosylate, vandetanib, or a combination of two or more thereof to the subject having the decreased DNA methylation levels at the papillary thyroid carcinoma DNA methylation sites.
Claims Coverage
The independent claims cover three core inventive areas: treating papillary thyroid cancer based on decreased DNA methylation at specified hg19 papillary thyroid carcinoma sites, measuring decreased DNA methylation at those sites by amplification using primers near the defined coordinates, and measuring decreased DNA methylation by bisulfite conversion followed by uracil detection. The inventive set is anchored to the same three hg19 sites and includes comparison to a control.
Treating papillary thyroid cancer based on decreased methylation at hg19-defined carcinoma sites
Measuring decreased DNA methylation levels, relative to a control, at papillary thyroid carcinoma DNA methylation sites in an isolated DNA obtained from a thyroid nodule from the subject, where the sites comprise hg19 chromosome 10 position 112259015, chromosome 12 position 56115043, and chromosome 15 position 85402496, and administering cabozantinib-S-malate, doxorubicin hydrochloride, lenvatinib mesylate, sorafenib tosylate, vandetanib, or a combination of two or more thereof to treat the papillary thyroid cancer.
Measuring decreased methylation at hg19-defined papillary thyroid carcinoma sites by amplification
Measuring decreased DNA methylation levels, relative to a control, at papillary thyroid carcinoma DNA methylation sites in isolated DNA obtained from a thyroid nodule from a human subject, where the sites comprise hg19 chromosome 10 position 112259015, chromosome 12 position 56115043, and chromosome 15 position 85402496, and measuring methylation levels comprises amplifying DNA by contacting the DNA with a primer complementary to a sequence at or within 1000 nucleotides of the chromosomal positions to produce amplicons for measuring methylation levels.
Measuring decreased methylation at hg19-defined papillary thyroid carcinoma sites by bisulfite conversion and uracil detection
Contacting isolated DNA with a bisulfite salt to form a reacted thyroid nodule DNA, and measuring decreased DNA methylation levels, relative to a control, at papillary thyroid carcinoma DNA methylation sites by detecting the presence of uracil in the reacted thyroid nodule DNA, where the sites comprise hg19 chromosome 10 position 112259015, chromosome 12 position 56115043, and chromosome 15 position 85402496.
Across the independent claims, the patent claim coverage is centered on measuring decreased DNA methylation levels relative to a control at a defined three-site hg19 set, with methylation measurement implemented by amplification with primers near those sites and by bisulfite conversion followed by detecting uracil. One independent claim ties the measured decreased methylation levels to administering specified anticancer agents to treat papillary thyroid cancer.
Stated Advantages
Provides a basis for treating papillary thyroid cancer in a subject having decreased DNA methylation levels at defined papillary thyroid carcinoma DNA methylation sites.
Reports high diagnostic separation between benign versus cancer nodules and performance metrics including specificity, sensitivity, positive predictive value, and negative predictive value.
Uses methylation alteration scores and a Composite Cancer Risk Score to generate and present a treatment plan.
Documented Applications
Diagnose thyroid nodules by detecting methylation alterations at papillary thyroid carcinoma DNA methylation sites, including distinguishing benign versus cancer nodules.
Treat papillary thyroid cancer by administering cabozantinib-S-malate, doxorubicin hydrochloride, lenvatinib mesylate, sorafenib tosylate, vandetanib, or combinations, based on decreased DNA methylation levels at the specified carcinoma methylation sites.
Generate and present a treatment plan using methylation alteration scores and a Composite Cancer Risk Score.
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