Differentiated thyroid cancer (DTC) affects thousands of lives worldwide every year. Typically, DTC is a treatable disease with a good prognosis. Yet, some patients are subjected to partial or total thyroidectomy and radioiodine therapy to prevent local disease recurrence and metastasis. Unfortunately, thyroidectomy and/or radioiodine therapy often worsen(s) the quality of life and might be unnecessary in indolent DTC cases. This clinical setting highlights the unmet need for a precise molecular diagnosis of DTC, which should dictate appropriate therapy. Here we propose a differential multi-omics model approach to distinguish normal gland from thyroid tumor and to indicate potential metastatic diseases in papillary thyroid cancer (PTC), a sub-class of DTC. Based on PTC patient samples, our data suggest that elevated nuclear and mitochondrial DNA mutational burden, intratumor heterogeneity, shortened telomere length, and altered metabolic profile reflect the potential for metastatic disease. Specifically, normal and tumor thyroid tissues from these patients had a distinct yet well-defined metabolic profile with high levels of anabolic metabolites and/or other metabolites associated with the energy maintenance of tumor cells. Altogether, this work indicates that a differential and integrated multi-omics approach might improve DTC management, perhaps preventing unnecessary thyroid gland removal and/or radioiodine therapy. Well-designed, prospective translational clinical trials will ultimately show the value of this targeted molecular approach.

E.W. is a founder of Vescor Therapeutics, has stock in Forma Therapeutics, and receives research funding from Deciphera. RP and WA are founders and equity stockholders of PhageNova Bio and MBrace Therapeutics. RP is a paid consultant for PhageNova Bio and serves as its Chief Scientific Officer. RP serves as Chief Scientific Officer and a Board Member, and WA is a Member of the Scientific Advisory Board at MBrace Therapeutics. RP and WA receive research support from PhageNova Bio and MBrace Therapeutics. These arrangements are managed in accordance with the established institutional conflict of interest policy of Rutgers, The State University of New Jersey. Neither PhageNova nor MBrace participated in the present work.

Acknowledgments: This work was supported by R01 CA243547 to EW, ECL, and SG; Robert Wood Johnson Foundation (Project number #73711). The Biospecimen Repository and Histopathology Service Shared Resource from the Cancer Institute of New Jersey provided all the specimens and associated services (P30CA072720-5919); Biometrics Shared Resource (P30CA072720-5918); Metabolomics Shared Resource (P30CA072720-5923), Bioinformatics Shared Resources (P30CA072720-5917).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Study approval: All patients consented to submit their samples to this protocol in writing. All tissue samples were acquired by partial or total thyroid dissection per the approved protocol (CINJ 001724 Pro20170001082) and Institutional Review Board (IRB) approval at Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present work are contained in the manuscript