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Principal Investigator: MARIA HAHN
Organization: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
Fiscal Year: 2024
Award: $779,408
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Each year, up to 50,000 patients in the United States receive unnecessary thyroidectomies. These unnecessary
thyroidectomies are due to difficulties in preoperatively distinguishing benign thyroid nodules from thyroid
cancers. In preliminary data, we developed an epigenetic test that shows promise to distinguish benign versus
malignant thyroid nodules. Here, we will rigorously test and validate the ability of our epigenetic biomarkers to
evaluate the biologic aggressiveness of thyroid nodules and determine whether the new epigenetic testing will
improve thyroid nodule management towards the eradication of unnecessary thyroidectomies. Current molecular
diagnostics for indeterminate thyroid nodules, while providing some improvement, have not eliminated the
unnecessary thyroidectomies. Current molecular diagnostics are based on molecular differences between
normal thyroid tissue and thyroid cancer. However, benign thyroid nodules can contain many molecular
alterations including gene fusions and mutations. As a result, over half of thyroid nodules with a significant cancer
risk according to the current molecular classifiers are found to be benign after thyroidectomy. In our published
preliminary data, we performed a genome-wide DNA methylation analysis of 109 surgically excised thyroid
nodules and adjacent benign tissue. We found that the DNA methylation pattern in benign nodules is different
from thyroid cancer and normal thyroid. Based on the DNA methylation pattern specific to benign nodules and
the DNA methylation pattern specific to thyroid cancer, we developed the Diagnostic DNA Methylation Signature
(DDMS) approach to distinguish between benign versus malignant nodules. In a retrospective pilot study
performed under 1R21CA223367, we developed DDMS further (DDMS-2). We tested the ability of the DDMS-2
assay to distinguish benign from malignant surgically excised thyroid nodules (n=121). In this Pilot study, DDMS-
2 had an estimated positive predictive value (PPV) of 96% and a negative predictive value (NPV) of 98%. Guided
by our preliminary data, we hypothesize that DDMS (i) can be successfully used for molecular thyroid cancer
diagnostics of pre-operative thyroid nodule aspirations; (ii) will have superior performance in comparison to
current thyroid cancer molecular testing and (iii) can affect physician decision-making towards elimination of
unnecessary thyroidectomies. We will accomplish our overall objective by pursuing the following specific aims:
Aim 1: To perform analytical validation of the DDMS-2 assay. Aim 2: To determine the DDMS-2 accuracy in a
prospective cohort obtained from 7 medical centers and containing 1450 thyroid nodule aspirations including
800 aspirations with indeterminate cytopathology. Aim 3: To compare the diagnostic accuracy between DDMS-
2 and two current thyroid cancer molecular diagnostic approaches and to evaluate how the knowledge of the
DDMS-2 results impacts clinical management of thyroid nodules. The development of a more accurate assay to
distinguish benign and malignant thyroid nodules will address current clinical limitations and reduce the number
of needless thyroidectomies and associated morbidities.
Terms: <Abscission><Accuracy of Diagnosis><Affect><Assay><Benign><Bilateral><Bioassay><Biological><Biological Assay><Biological Markers><Body Tissues><Calcium><Cancer Diagnostics><Cancers><Cellular Morphology><Classification><Clinical><Clinical Management><Clinical Trials><Cytology and Pathology><Cytopathology><DNA Methylation><Data><Decision Making><Development><Diagnostic><Diagnostic Method><Diagnostic Procedure><Diagnostic Specificity><Diagnostic Technique><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Evaluation><Excision><Extirpation><FNA><Failure><Fine Needle Aspirate><Fine needle aspiration biopsy><Fine-Needle Aspiration><Gene Alteration><Gene Expression><Gene Fusion><Gene Mutation><Genetic Alteration><Genetic Change><Genetic defect><Knowledge><Laboratories><Malignant><Malignant - descriptor><Malignant Neoplasms><Malignant Thyroid Gland Neoplasm><Malignant Tumor><Malignant Tumor of the Thyroid><Malignant Tumor of the Thyroid Gland><Malignant neoplasm of thyroid><Medical center><Molecular><Morbidity><Morbidity - disease rate><Mutation><Nodule><Operative Procedures><Operative Surgical Procedures><Papillary Thyroid Cancer><Papillary Thyroid Gland Cancer><Papillary thyroid carcinoma><Parathyroid><Parathyroid Head and Neck><Parathyroid gland><Pathologic><Patients><Performance><Physicians><Pilot Projects><Predictive Value><Prospective cohort><Publishing><Recurrent Laryngeal Nerve><Removal><Reproducibility><Research Specimen><Sensitivity and Specificity><Specialist><Specimen><Surgeon><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Systematics><Testing><Thyroid><Thyroid Cancer><Thyroid Gland><Thyroid Gland Hormone><Thyroid Gland Nodule><Thyroid Gland Papillary Carcinoma><Thyroid Head and Neck><Thyroid Hormones><Thyroid Nodule><Thyroidectomy><Tissues><Total Vocal Cord Paralysis><Tracheostomy><Tracheostomy procedure><United States><Validation><Vocal Cord Palsy><Vocal Cord Paralysis><Vocal Fold Palsy><aspirate><bio-markers><biologic><biologic marker><biomarker><cancer risk><cell morphology><clinical decision-making><developmental><diagnostic ability><diagnostic accuracy><diagnostic approach><diagnostic capability><diagnostic power><diagnostic strategy><diagnostic utility><diagnostic value><epigenetic biomarker><epigenetic marker><epigenetically><epigenomics><genome mutation><genome scale><genome-wide><genomewide><improved><inter-institutional><internal control><malignancy><methylation pattern><molecular diagnostics><neoplasm/cancer><pilot study><pilot trial><prospective><resection><surgery><ultrasound><validations>