Independent Clonal Origin in Early‐Stage Bilateral Papillary Thyroid Cancer: Evidence From Nuclear and Mitochondrial Genome Analysis

ABSTRACT Papillary thyroid cancer (PTC) often presents as anatomically distinct foci in bilateral lobes. However, it remains controversial whether these foci arise independently from distinct malignant progenitor cells or result from the dissemination of the primary lesion. Fifteen pairs of bilateral PTC at Stage I were enrolled, and sequencing was performed using a 437‐cancer‐gene panel (Geneseeq). The entire mitochondrial DNA (mtDNA) was also sequenced and analyzed. The genetic alterations and molecular profiles were comprehensively analyzed and compared between the paired bilateral tumors. Fourty‐eight mutations were detected in the nuclear genome, all of which were somatic and heteroplasmic. Among these, BRAF V600E mutation was predominant (25/30, 83.3%). In mtDNA, three mutations (10963A‐C, 13193T‐C, 13341 C‐G) were identified as novel, seven heteroplasmic mutations were detected including six somatic mutations. Discordant genetic alterations were observed between the paired tumors in 86.7% (13/15) of bilateral PTC cases. Our results reveal that the majority of early‐stage bilateral PTCs develop from independent malignant clones harboring different genetic backgrounds, which provides insights into the pathogenesis of bilateral PTCs and supports individualized clinical decision‐making.