Gain of chromosome band 7q11 in papillary thyroid carcinomas of young patients is associated with exposure to low-dose irradiation

Abstract

The main consequence of the Chernobyl accident has been an increase in papillary thyroid carcinomas (PTCs) in those exposed to radioactive fallout as young children. Our aim was to identify genomic alterations that are associated with exposure to radiation. We used array comparative genomic hybridization to analyze a main (n = 52) and a validation cohort (n = 28) of PTC from patients aged <25 y at operation and matched for age at diagnosis and residency. Both cohorts consisted of patients exposed and not exposed to radioiodine fallout. The study showed association of a gain on chromosome 7 (7q11.22-11.23) with exposure (false discovery rate = 0.035). Thirty-nine percent of the exposed group showed the alteration; however, it was not found in a single case from the unexposed group. This was confirmed in the validation set. Because only a subgroup of cases in the exposed groups showed gain of 7q11.22-11.23, it is likely that different molecular subgroups and routes of radiation-induced carcinogenesis exist. The candidate gene CLIP2 was specifically overexpressed in the exposed cases. In addition, the expression of the genes PMS2L11, PMS2L3, and STAG3L3 correlated with gain of 7q11.22-11.23. An enrichment of Gene Ontology terms "DNA repair" (PMS2L3, PMS2L5), "response to DNA damage stimulus" (BAZ1B, PMS2L3, PMS2L5, RFC2), and "cell-cell adhesion" (CLDN3, CLDN4) was found. This study, using matched exposed and unexposed cohorts, provides insights into the radiation-related carcinogenesis of young-onset PTC and, with the exposure-specific gain of 7q11 and overexpression of the CLIP2 gene, radiation-specific molecular markers.FISH | post-Chernobyl

Integration of a radiation biomarker into modeling of thyroid carcinogenesis and post-Chernobyl risk assessment

“…They have joined the discovery cohort Genrisk-T with validation cohorts Genrisk-T plus and UkrAm (CTB tumors only) which were investigated in earlier exploratory studies related to the CLIP2 marker (14,15). All PTC cases are listed in Table.…”

“…The histological composition of more than 90% of all thyroid carcinoma from the Chernobyl studies pertains to papillary thyroid cancers (PTC). Genomic analysis of PTC samples stored in the Chernobyl tissue bank (CTB, ) revealed a DNA copy number gain on chromosome band 7q11.23 and mRNA overexpression of the CLIP2 gene related to radiation exposure (14). The samples came from the Genrisk-T cohort of patients which were exposed at very young age below 5 years.…”

Ionizing radiation biomarkers for potential use in epidemiological studies

“…However whether radiation induced tumours have a specific mutation profile remains to be established. As noted in Section 4.3.2, a recent study has identified a potential genetic signature of radiationinduced thyroid tumours [148]. In another study assessing the mutational pattern of a reporter gene in mouse fibroblasts upon fractionated IR exposure, a high proportion of T:A !…”

“…For example IQGAP1 CNA is associated with the invasiveness of thyroid cancer and may represent a novel prognostic marker and therapeutic target for this cancer [147]. In addition, a study conducted on young patients with papillary thyroid carcinoma exposed to an estimated average dose of 150 mGy after the Chernobyl accident showed an amplification of the region 7q11.22-11.23 in a subgroup of exposed patients, and could potentially represent a biomarker of exposure, although possibly limited to certain cases or dose ranges [148]. However whether the presence of specific CNAs reflects the tumour aetiology remains to be examined.…”

Follow-up studies on genome damage in children after Chernobyl nuclear power plant accident

“…Similarly, the greatest increase in the rate after irradiation was found for RET/PTC1 (Ushenkova et al 2015), exposure-specific gain of 7q11, and overexpression of the CLIP2 gene (Hess et al 2011).…”