Genomic Characterization of Papillary Thyroid Cancer Reveals Germline Mutations Associated With Congenital Hypothyroidism.

Purpose: Thyroid dyshormonogenesis, a form of congenital hypothyroidism, is characterized by defects in thyroid hormone synthesis genes, affecting both children and adults. However, the potential link between such genetic defects and the development of papillary thyroid cancer (PTC) remains unclear.

Methods: We conducted whole-exome sequencing on 100 (N = 100) tumor-normal paired and orphan tumor samples of PTC from Indian patients, characterizing both germline and somatic molecular alterations.

Results: We identified significant germline mutations in the DUOX2 gene (approximately 8.8%), commonly associated with congenital hypothyroidism and thyroid dyshormonogenesis, and found these mutations to correlate with poor prognosis in PTC. Additionally, hallmark somatic mutations were detected in genes such as BRAF (35.4%), KRAS (3.8%), HRAS (5.1%), and NRAS (17.7%), which are well-known drivers of PTC. Importantly, we identified a distinct molecular subtype termed independent of BRAF-RAS (iBR), characterized by nonhallmark alterations and associated with a higher recurrence rate and poorer recurrence-free survival in Indian patients with PTC, highlighting the clinical significance of these molecular insights in prognosis and treatment strategies.

Conclusion: Our analysis of PTC among Indians revealed novel genetic alterations and molecular subtypes. We identified a germline mutation in the DUOX2 gene, associated with congenital hypothyroidism, as a potential risk factor of PTC. Additionally, we characterized distinct molecular subtypes, BRAF-RAS driven and iBR driven, and their clinical implications. These findings provide valuable insights into the genetic landscape of thyroid cancer in Indian patients and offer potential avenues for targeted therapies.