Advancing Education, Research, and Quality of Care for the Head and Neck oncology patient.
Introduction: Papillary thyroid cancers (PTC) are typically indolent, with a 98% 5-year survival rate. In contrast, poorly differentiated (PDTC) and anaplastic (ATC) have a poorer prognosis. It is well established that ATC may dedifferentiate from a long-standing PTC, accumulating somatic single nucleotide variants (SNVs) in various cancer driver genes. We used optical genome mapping (OGM) to examine the somatic structural variants (SV) in histological samples of ATC and PDTC subtypes and compared them to those seen in PTC tumor samples. When compard to next-generation or whole genome DNA sequencing, OGM detects SV that often remain undetected. Our study aims were further to assess the molecular basis of clinically aggressive thyroid cancers.
Methods: We obtained fresh frozen thyroid cancer specimens and matched whole blood samples from patients consented under an IRB-approved protocol. The tumors included five ATCs, two PDTCs, and nine tall cell variants (TCV). These were matched with 13 classic PTC samples. We applied OGM to the tumor samples and matched blood to identify somatic structural and DNA copy number variants, including insertions, deletions, inversions, duplications, and chromosomal translocations. Identified SV and gene fusions were cross-referenced with the Catalogue of Somatic Mutations in Cancer (COSMIC) database, which contains data on genes implicated in cancer development. Wilcoxon rank sum tests were used to compare counts of variants in comparison groups of interest.
Results: Ten of 16 (63%) patients in the clinically aggressive TC group were female, and the average age was 61.87 ± 18.09 years at the time of diagnosis. Seven of 13 (53.8%) patients in the classic PTC group were female and had an average age of 61.6 ± 18.9 years. The total number of SV was greater in patients with ATC vs. PTC (p = 0.042). Additionally, the number of inter-chromosomal translocations was greater in ATC than in PTC (p = 0.034). Differences among the other samples and SV types were insignificant. The affected COSMIC genes for ATC and PDTC samples included NFIB, CDKN2A, AFF4, SRGAP3, CDK12, ERBB2, IKZF3, PTPRD, JAZF1, CHD2, and PDE4DIP. These gene mutations were not observed in classic PTC samples. In addition, an ETV6-NTRK3 gene fusion was seen in one PDTC sample. No deletions or fusions of COSMIC genes were identified in TCV specimens.
Conclusions: ATC samples harbor more somatic structural variants and inter-chromosomal translocations than PTC. These SVs affect a variety of cancer driver and tumor suppressor genes, consistent with previous studies examining somatic SNVs. Additionally, the significantly increased number of structural variants in ATC versus PTC suggests that loss of genome integrity mechanisms may promote the transformation of thyroid cancers. By using OGM, we were able to gain additional insight into the process.