The fragile
histidine triad (FHIT) gene, located within chromosome arm 3p, is a potential target for testicular
tumorigenesis. In the present study, 62 primary testicular
germ cell tumors were analyzed for allelic imbalance (AI)
at 10 loci mapping to chromosome bands 3p14.1-21.1. Twenty-seven
tumors (44%) showed AI at one or more 3p loci. The chromosome 3 copy number was evaluated by fluorescence in situ hybridization with centromere and p-telomere probes onto interphase nuclei from 22 of the
tumors. Sixteen of these (73%) presented three or more signals of each probe in at least one-third of the nuclei. The combined fluorescence in situ hybridization and AI results indicated that
tumors with AI at all loci, in most cases (five of six), reflected an increased chromosome copy number, whereas
tumors presenting AI only at some loci reflected interstitial chromosomal changes. A smallest region of overlapping changes could be delineated from
tumors showing interstitial chromosomal changes (n = 16). The smallest region of overlapping changes was flanked by D3S1312 and D3S1234 and included parts of FHIT. In the second part of this study, expression analyses of FHIT were performed. Transcripts of aberrant lengths were found in 7 of 17 (41%) analyzed
tumors and were identified by sequencing as splice variants. Three different types of transcripts were found, and all lacked exon 3. Immunohistochemical staining showed reduced
Fhit protein expression, compared with normal testicular tissue, in 62% (40 of 65) of the testicular
germ cell tumors. Although we found a significant association between FHIT
mRNA alterations and AI (P = 0.006), altered
protein expression did not correlate with AI. The nonepithelial components of
teratomas showed strong association with reduced
Fhit protein compared with the epithelial component (P < 0.001). Interestingly, reduced Fhit expression seems to be associated with
metastasis in the patient at the time of diagnosis, although the association was not statistically significant.