High frequency of loss of heterozygosity in imprinted, compared with nonimprinted, genomic regions in follicular thyroid carcinomas and atypical adenomas.
BACKGROUND
Many mammalian genes that are imprinted regulate cell growth, differentiation, and apoptosis. Because imprinting silences one of the two alleles, resulting in functional haploinsufficiency, we hypothesized that loss of heterozygosity (LOH) at an imprinted locus may result in the deletion of the only functional copy of an imprinted tumor suppressor gene.


OBJECTIVE
The goal of this study was to specifically address this hypothesis that in thyroid neoplasias loss of imprinted loci becomes enriched during oncogenesis.


METHODS
In total, thyroid tissue was obtained from 72 patients with thyroid neoplasias comprising 34 follicular thyroid carcinomas (FTCs) and 38 follicular adenomas. We performed PCR-based LOH analysis of DNA from paired normal-tumor samples using 18 markers mapped to imprinted regions (IR) and 13 markers in nonimprinted regions (NIR).


RESULTS
Overall LOH frequencies for the IR markers were 26% for the adenomas and 38% for the carcinomas. In the NIR, the overall LOH frequency was 23 and 26% for adenomas and FTCs, respectively. The difference in LOH frequencies between IR and NIR was statistically significant only for the carcinomas (P = 0.001), although there was a similar trend for the atypical adenomas (ATY, P = 0.06).


CONCLUSIONS
Our observations suggest that IRs are more prone to genomic instability in FTCs. The fact that the ATY trended toward differential IR/NIR LOH, similar to FTC, may suggest that loss of IR might be instrumental in the adenoma-carcinoma sequence in thyroid carcinogenesis and that ATY could be an important intermediate in this pathway.
Sarquis
Marta S
MS
Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA.
Weber
Frank
F
Shen
Lei
L
Broelsch
Christoph E
CE
Jhiang
Sissy M
SM
Zedenius
Jan
J
Frilling
Andrea
A
Eng
Charis
C
D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D018265:Carcinoma, Papillary, Follicular / Q000235:genetics* / Q000473:pathology; D002875:Chromosomes / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D018392:Genomic Imprinting; D005838:Genotype; D006801:Humans; D019656:Loss of Heterozygosity / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
D005819:Genetic Markers