Prognostic significance of homozygous deletions and multiple duplications at the CDKN2A (p16INK4a)/ARF (p14ARF) locus in urinary bladder cancer.
OBJECTIVE
The 9p21 locus is a major target in the pathogenesis of human urinary bladder cancer. This locus harbours the CDKN2A/ARF tumour suppressor gene, which encodes two cell-cycle regulatory proteins: p16INK4a and p14ARF. We studied how homozygous deletions and multiple duplications at this locus affect prognosis and survival in patients with bladder cancer.


METHODS
Real-time quantitative polymerase chain reaction (QPCR), based on simultaneous amplification of ARF and a reference gene, glyceraldehyde-3-phosphate dehydrogenase, was used to measure homozygous deletions and multiple duplications in a population-based material consisting of 478 patients with urinary bladder cancer. Results from real-time QPCR were compared with clinico-pathological parameters and survival curves were generated using the Kaplan-Meier method.


RESULTS
Real-time QPCR analysis showed 71 (15%) homozygous deletions and 8 (2%) multiple duplications. We were unable to find any association between either stage or grade and urinary neoplasms with homozygous deletions. However, although there were only a limited number of patients with multiple duplications, 7/8 of them had highly malignant tumours (G2b-G4 or > or = T1; p = 0.02).


CONCLUSIONS
Urinary bladder cancers constitute a spectrum of neoplasms with varying clinical manifestations. We were unable to establish a prognostic relevance for patients with tumours harbouring homozygous deletions at the CDKN2A/ARF locus. However, our data did indicate that patients with multiple duplications at the CDKN2A/ARF locus had poor survival. This suggests that multiple duplications, in combination with other genetic changes, have cooperative effects which have a negative outcome on urinary bladder cancer prognosis.
Berggren de Verdier
Petra J
PJ
Clinical Center Epidemiology, Department of Oncology-Pathology, Karolinska University Hospital, Stockholm, Sweden.
Kumar
Rajiv
R
Adolfsson
Jan
J
Larsson
Per
P
Norming
Ulf
U
Onelöv
Erik
E
Wijkström
Hans
H
Steineck
Gunnar
G
Hemminki
Kari
K
D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D015331:Cohort Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D017353:Gene Deletion; D020440:Gene Duplication; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF