Using genomics to invesIgate radiaIon-related thyroid cancer following the Chernobyl accident in 1986
Following the Chernobyl nuclear power plant accident in Ukraine in 1986, increased childhood exposure to radioactive iodine (131I), which occurred primarily through consumption of contaminated food sources, has been consistently associated with increased risk of developing papillary thyroid carcinoma (PTC). In a landscape analysis of fresh-frozen tumor tissues from the Chernobyl Tissue Bank, we conducted a genomic landscape analysis of 440 cases of PTC that provided new insights into radiation-associated molecular characteristics of PTC occurring after the accident, specifically, an increase in DNA double-strand breaks with increasing radiation dose (Morton et al.,Science 2021). Here, we expand that study with additional detailed clinical data to identify molecular and clinical predictors of the occurrence of LNM with the aim of disentangling the independent effects of patient, clinical, and molecular characteristics. We then conducted a comprehensive genomic landscape analysis of 47 LNMs with patient-matched primary PTCs to investigate the specific genomic alterations occurring in LNM. PTC with fusion drivers had substantially higher rates of LNM than those with mutation drivers (56% versus 30%, P=2.2×10-6), whereas P>1.0×10-4 for all other patient, clinical, and molecular characteristics, including radiation dose (P=0.31). We further observed striking heterogeneity by driver gene (P=4.2×10-20), with the highest rate of LNM occurrence among PTC with RET (73%) and other RTK (64%) fusion drivers but much lower LNM rates among PTC with fusion drivers in other genes (10%) or mutations in BRAF (37%), RAS (7%), or other genes (7%).
Molecular profiling of the LNM revealed 100% concordance of the driver gene and no novel driver mutations compared with the matched primary tumor, as well as a highly concordant mutational spectrum (mean=48% of simple somatic variants and 97% of structural variants were shared between primary PTC and LNM). Transcriptome analysis revealed 17 differentially expressed genes in LNM compared to primary PTC with P<1.0×10-4. Most notably, we observed overexpression in LNM of HOXC10 (P=6.4×10-23) and 8 other genes located in the 12q13 HOXC locus, which has previously been linked to regulation of cell proliferation, migration in cancer progression, and promotion of TGF-beta signaling. Our findings provide insights into the molecular processes underlying the development of metastatic PTC and underscore the critical role of the driver mutation in PTC metastasis. To better understand the biological underpinnings of metastatic PTC, further investigation of the altered expression of HOXC locus and its role in disrupting activity of TGF-beta is indicated.