Thymic epithelial tumors can develop along two different pathogenetic pathways

Abstract

To investigate genetic abnormalities associated with the development of thymic epithelial tumors, we performed microsatellite analysis of 26 thymomas belonging to three different World Health Organization types (A, B3, and C) using 48 repeats. The most frequent aberration seen was loss of heterozygosity (LOH) in the region 6q23.3-25.3 detected in 11 tumors (45.8% of informative cases). Further consistent LOHs were detected in regions 3p22-24.2, 3p14.2 (FHIT gene locus), 5q21 (APC), 6p21, 6q21-22.1, 7p21-22, 8q11.21-23, 13q14 (RB), and 17p13.1 (p53). Microsatellite instability was extremely rare, occurring in one type B3 thymoma only, although, at 12.5% of the analyzed loci. Comparing the allelotypes of the analyzed thymomas, we were able to identify two pathogenetic pathways these tumors develop along, characterized by the 6q23.3-25.3 and 5q21 LOHs, respectively. The APC aberration on 5q21 showed significant associations with LOH in the 3p22-24.2, 13q14, and 17p13.1 regions. Interestingly, type A thymomas presented with consistent LOH in the region 6q23.3-25.5 only, they did not reveal any aberrations in the APC, RB, and p53 gene loci or regions 3p22-24.2 and 8q11.21-23. The absence of these aberrations might be the reason for the well-known benign behavior of type A thymomas as compared to types B3 and C tumors.

Figure 1.

Chromosomal regions showing frequent allelic imbalance. The frequency of allelic imbalance found in chromosomal regions showing more than two aberrations was plotted in the diagram. Filled bars, LOH; open bars, amplifications of genomic DNA.

Figure 2.

LOH in the retinoblastoma gene locus as detected using the D13S153 microsatellite and confirmatory CGH for chromosome 13 in case no. 4550. A: DNA samples from normal and tumor tissues were amplified for the D13S153 (black) microsatellite in a PCR. The 224-bp allele of the D13S153 microsatellite showed signal strength decrease by 49% (arrow). B: Confirmatory CGH profile of chromosome 13 from the same tumor is shown on the right. The cut-off values for losses (0.80) and gains (1.25) are depicted as red and green lines, respectively.

Figure 3.

Pattern of genetic aberrations in thymic epithelial tumors. Microsatellite analysis results for 10 chromosomal regions harboring at least three allelic imbalances are displayed. Patients showing at least one aberration are listed in the first left column. Status of each locus is indicated: black, LOH; horizontal stripes, retention of heterozygosity; falling stripes, no amplificate; vertical stripes, homozygosity; and white, genomic amplification.

Figure 4.

Increasing RAI frequency with higher stage of disease. Stage I thymomas showed the lowest RAI frequency values with mean of 4.1% and SD of 4.2%. Increasing RAI values were observed in later stages: stage II, 8 ± 4.7%; stage III, 16 ± 14.8%; and stage IV, 15.2 ± 10%. However, only the RAI frequency difference between stages I and IV was statistically significant (Mann-Whitney U test, P = 0.027).