Biallelic deletions in INK4 in cutaneous melanoma are common and associated with decreased survival.
OBJECTIVE
Both the retinoblastoma and p53 pathways are often genetically altered in human cancers and their complex regulation is in part mediated by the three gene products p16, p14(ARF), and p15 of the INK4 locus on chromosome 9p21. Partial or complete biallelic deletions of the INK4 locus have been recognized in a variety of malignant tumors, including malignant melanoma. We have in the present study measured the frequency of INK4 deletions in a large number of melanoma metastases and determined their association with clinicopathologic variables and survival data.


METHODS
Quantitative real-time PCR, as well as fluorescence-based fragment analysis, has been used to perform measurements of the relative allelic concentrations of the INK4 genes in 112 human melanoma tumor samples from 86 patients.


RESULTS
Thirty-eight of 86 melanoma patients (44%) had metastases with biallelic losses in INK4. Ten of 20 patients with multiple metastases showed similar deletion patterns in all analyzed tumors. There was no significant association between any of the clinicopathologic variables and loss of INK4. However, loss of INK4 had an adverse effect on median survival from time of diagnosis. Patients with tumors with diploid INK4 had a median survival of 142 months, whereas those with monoallelic or biallelic loss in INK4 had a median survival of only 47 months (P = 0.006).


CONCLUSIONS
Our results point to homozygous deletions in the INK4 region as being one of the most common genetic alterations in malignant cutaneous melanoma. INK4 deletions are associated with an adverse prognosis.
Grafström
Eva
E
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Karolinska University Hospital Solna, Stockholm, Sweden.
Egyházi
Suzanne
S
Ringborg
Ulrik
U
Hansson
Johan
J
Platz
Anton
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000704:Analysis of Variance; D018797:Cell Cycle Proteins / Q000235:genetics; D016009:Chi-Square Distribution; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D006720:Homozygote; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016133:Polymerase Chain Reaction / Q000379:methods; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D016019:Survival Analysis; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins