Radiation-related genomic profile of papillary thyroid carcinoma after the Chernobyl accident

Abstract

The 1986 Chernobyl nuclear power plant accident increased papillary thyroid carcinoma (PTC) incidence in surrounding regions, particularly for radioactive iodine (131I)–exposed children. We analyzed genomic, transcriptomic, and epigenomic characteristics of 440 PTCs from Ukraine (from 359 individuals with estimated childhood 131I exposure and 81 unexposed children born after 1986). PTCs displayed radiation dose–dependent enrichment of fusion drivers, nearly all in the mitogen-activated protein kinase pathway, and increases in small deletions and simple/balanced structural variants that were clonal and bore hallmarks of nonhomologous end-joining repair. Radiation-related genomic alterations were more pronounced for individuals who were younger at exposure. Transcriptomic and epigenomic features were strongly associated with driver events but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth after environmental radiation exposure.

Major Oncogenic Drivers and Their Clinicopathological Correlations in Sporadic Childhood Papillary Thyroid Carcinoma in Belarus

“…Non-exposed pediatric groups of PTC patients from Ukraine had 16.9% (10/59) and 5.1% (3/59) of cases with RET/PTC1 and RET/PTC3, respectively [18,19]. This prevalence does not differ statistically significantly from those in our sporadic childhood series for either oncogene (p = 0.563 and 0.069, respectively).…”

“…In sporadic PTC, BRAF V600E was absent among eight non-exposed children from Ukraine aged ≤ 15 years [10]. The 31.2% (10/32) prevalence was found in a recent study of non-exposed PTC patients from Ukraine aged less than 18 years in Ukraine [19], and a similar prevalence of 25.9% (7/27) was reported in children and adolescents aged 5-19 years in an independent study [20]. For comparison, in a group of adult patients with sporadic PTC aged 47 ± 9.7 years from Russia, BRAF V600E was found in 61.8% (47/76) of cases [21].…”

“…Three studies of radiation-related pediatric Ukrainian PTCs diagnosed at the end of the 1990s and during the first decade of the 2000s in Ukraine also reported the null prevalence of RAS mutations [8,17,18] (0/15, 0/26 and 0/16, respectively, Supplementary Table S5, Figure 6-RAS). The two latter studies also reported the 7.4% (2/27) and 3.1% (1/32), respectively, prevalence of NRAS codon 61 mutations in young patients from Ukraine not exposed to radiation [18,19].…”

“…Rearrangement in Pediatric/Young Adult PTC Patients ETV6/NTRK3 in pediatric PTC was determined previously in a few works (Supplementary Table S5, Figure 6-ETV6/NTRK3). In patients from Ukraine exposed to Chernobyl radiation, this fusion gene was found in 11.5% (12/104), and in 6.8% (4/59) of non-exposed cases [18,19]. Young-exposed PTC patients from the UkrAm cohort (mean age 22.7 years) displayed the prevalence of 14.5% (9/62) [31].…”

“…In the same work, however, no AKAP9/BRAF rearrangements were found among 64 PTCs diagnosed after the 9-12 years long period of latency. The prevalence of 0% (0/16) [19] and 3.8% (1/26) [20] was reported in radiationrelated pediatric PTCs from Ukraine. These two studies also did not find AKAP9/BRAF in 32 and 27 sporadic pediatric PTCs from Ukraine, respectively.…”