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Analysis of G 1 /S checkpoint regulators in metastatic melanoma
Author(s) -
Sauroja Ilari,
Smeds Johanna,
Vlaykova Tatyana,
Kumar Rajiv,
Talve Lauri,
HahkaKemppinen Marjo,
Punn Kari,
Jansèn Christer T.,
Hemminki Kari,
Pyrhönen Seppo
Publication year - 2000
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/1098-2264(200008)28:4<404::aid-gcc6>3.0.co;2-p
Subject(s) - melanoma , metastatic melanoma , cancer research , medicine
We have analyzed the expression of the CDKN1A (p21 CIP1 ), CDKN1B (p27 Kip1 ), TP53, RB1 and MDM2 proteins and tumor cell proliferation by immunohistochemical staining in 59 cases of metastatic melanoma. The genomic status of the CDKN 2 A ( INK 4‐ ARF , p 16/ p 14 ARF ), CDKN 2 B ( p 15) and CDKN 2 C ( p 18) genes was determined by PCR‐SSCP (single‐strand conformation polymorphism) in 46 of these cases. These results were correlated with various clinico‐pathological parameters, including the outcome of combined chemoimmunotherapy. We found positive correlations between the expression of CDKN1A and MDM2 ( r = 0.5063, P = 0.001), between the expression of CDKN1B and RB1 ( r = 0.5026, P = 0.001), and between RB1 expression and tumor cell proliferation (0.5564, P < 0.001). Two mutations in the CDKN 2 A ( p 16) gene were detected, including a novel base change AAC→ATC (Asn to Ile) at codon 71, that also changes the codon 85 of the alternative reading frame gene p 14 ARF from CAA to CAT (Gln to His). Homozygous deletion at exon 2 of the CDKN 2 A ( INK 4‐ ARF ) gene was detected in six cases. In seven cases, the 540C→G polymorphism in the 3′UTR of the CDKN 2 A ( p 16) gene was found in linkage disequilibrium with the 74C→A polymorphism in intron 1 of the CDKN 2 B gene ( P < 0.0001). These cases had significantly lower expression of the TP53 protein ( P = 0.0032). Both 540C→G and 580C→T polymorphisms in the 3′UTR of the CDKN 2 A ( p 16) gene were associated with significantly shorter progression time from primary to metastatic disease ( P = 0.0071). We conclude, that although none of the analyzed cell cycle regulators could be singled out as a major prognostic factor, G 1 /S checkpoint abnormalities remain one of the most significant factors in the development of malignant melanoma. Genes Chromosomes Cancer 28:404–414, 2000. © 2000 Wiley‐Liss, Inc.