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Biallelic Deletions in INK4 in Cutaneous Melanoma Are Common and Associated with Decreased Survival

Authors' Affiliation: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Karolinska University Hospital Solna, Stockholm, Sweden

Requests for reprints: Johan Hansson, Department of Oncology-Pathology, Cancer Center Karolinska, R8:03, Karolinska University Hospital Solna, S-171 76 Stockholm, Sweden. Phone: 46-8-5177-3640; Fax: 46-8-5177-4245; E-mail: johan.hansson{at}onkpat.ki.se.

Purpose: 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.

Experimental Design: 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.

Key Words: CDKN2A • CDKN2B • homozygous loss

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