Cyclin D3 immunoreactivity in follicular lymphoma is independent of the t(6;14)(p21.1;q32.3) translocation or cyclin D3 gene amplification and is correlated with histologic grade and Ki-67 labeling index.
An abnormal expression of cyclin D3, a key regulator of the cell cycle, has been documented in a variety of human malignancies, and the cyclin D3 gene, mapping to 6p21, may be deregulated in plasma cell myeloma and non-Hodgkin's lymphoma as a result of the t(6;14)(p21.1;q32.3) translocation and/or gene amplification. In the current study, we for the first time investigated by immunohistochemistry and fluorescence in situ hybridization (FISH) the prevalence of cyclin D3 abnormalities in follicular lymphomas (FLs), comparing the results with traditional clinicopathologic characteristics, p27 and skp2 immunoreactivity (IR) and Ki-67 labeling index (LI). Cyclin D3, skp2 and Ki-67 IR significantly increased from grade I to grade III FL (p = 0.0003, p = 0.0001 and p < 0.0001, respectively), while p27 IR was significantly (p < 0.0001) more prevalent in low-grade tumors. Cyclin D3 IR was directly correlated with the Ki-67 LI (p < 0.0001) and inversely correlated with p27 IR (p = 0.050). None of the 13 cases analyzed by FISH showed the t(6;14) translocation, but in 2 (15.3%) grade I FLs 3 cyclin D3 signals were detected. Cohybridization with probes specific for the centromeric region and the long arm of the chromosome 6 indicated trisomy in one case and a pattern highly suggestive for the presence of an isochromosome 6p in the other case. Our data suggest that the t(6;14) translocation may be extremely uncommon in FL and that a deregulated expression of cyclin D3, possibly due to epigenetic mechanisms, may be involved in the pathogenesis of high-grade tumors.
Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy. giancarlo.pruneri@ieo.it
Giancarlo
G
Pruneri
Stefano
S
Valentini
Sonia
S
Fabris
Barbara
B
Del Curto
Daniele
D
Laszlo
Francesco
F
Bertolini
Giovanni
G
Martinelli
Pietro
P
Leocata
Giuseppe
G
Viale
Antonino
A
Neri
D000328:Adult; D000368:Aged; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D056743:Cyclin D3; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D019394:Ki-67 Antigen / Q000378:metabolism*; D008224:Lymphoma, Follicular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic / Q000502:physiology*; D014314:Trisomy; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
C534696:CCND3 protein, human; D018797:Cell Cycle Proteins; D056743:Cyclin D3; D016213:Cyclins; D019394:Ki-67 Antigen; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27