Prevalence of minisatellite and microsatellite instability in radiation-induced post-Chernobyl pediatric thyroid carcinomas

Abstract

Exposure to ionizing radiation induces di erent forms of genomic instability in cultured cells and experimental animals. A higher rate of germline mutations at human hypervariable minisatellite loci was reported in children born from parents exposed to radiation after Chernobyl, implicating genome destabilization as a possible mechanism responsible for late radiation e ects in humans. To test if radiation-induced carcinogenesis in the thyroid gland may be associated with somatic minisatellite instability or microsatellite instability, we utilized a PCR-based approach to study normal and tumor DNA from 17 pediatric post-Chernobyl papillary thyroid carcinomas for mutations at three di erent minisatellite loci (D1S80, D17S30, ApoB), and 27 microsatellite loci of di-, tri-, or tetranucleotide repeats. Minisatellite instability was found in three (18%) tumors, with one of them exhibiting mutations in all three minisatellite loci, whereas two others showed mutations in one of two informative markers. By contrast, none of 20 sporadic thyroid cancers from patients with no history of radiation exposure was positive for minisatellite instability. Microsatellite analysis of post-Chernobyl tumors revealed a mutation in one (6%) tumor only at the locus of D10S1412, whereas all other 26 microsatellite markers showed identical patterns in each normal/tumor pair. Our results suggest that somatic cell microsatellite instability does not contribute to radiation-induced thyroid carcinogenesis. However, somatic minisatellite mutation events are present in a subset of radiationinduced, but not sporadic, thyroid cancers, suggesting that this type of genomic instability may play a role in radiation-induced tumorigenesis in the thyroid gland.

High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation

“…Moreover, a recent study suggested that p53 gene point mutations may play a pathogenic role in some radiation-induced well di erentiated thyroid cancers, explaining the aggressiveness of some of these tumors (Fogelfeld et al, 1996). In contrast with the data from Challeton et al (1995), in tumors arising in children after the Chernobyl accident Nikiforov et al (1996) observed ras point mutations in 1/1 follicular carcinoma and in 3/7 follicular adenomas, but not in the 33 papillary carcinomas studied. These authors concluded that ras does not appear to be important in the development of the Chernobyl papillary carcinomas.…”

Genome instability in secondary solid tumors developing after radiotherapy of bilateral retinoblastoma

“…The panel of TP53 mutations is uncommon TP53 status has been described in several series of radiation-induced sarcomas and carcinomas (Behrens et al, 2000;Brachman et al, 1991;Brat et al, 1999;De Benedetti et al, 1996;Fogelfeld et al, 1996;Gamble et al, 1999;Nakanishi et al, 1998;Nikiforov et al, 1996;Tada et al, 1997). In these series, the rates of mutations ranged from 0 to 100%, which makes any ®rm conclusion impossible.…”

p53 induced by ionizing radiation mediates DNA end-jointing activity, but not apoptosis of thryroid cells

“…First, they are aggressive cancers, almost all are of papillary type and often invade the neighboring tissues (Williams, 1994). Second, genetic analysis revealed a relatively high prevalence of ret/PTC (approximately 60%) (Fugazzola et al, 1995;Santoro et al, 1996), whereas very few point mutations of p53 and ras genes were detected (Nikiforov et al, 1996). These ®ndings suggest that thyroid tumors occurring around Chernobyl were caused by exposure to ionizing radiation known to cause double strand breaks of genomic DNA.…”