High frequency of loss of heterozygosity on chromosome region 9p21-p22 butlack of p16(INK4a)/p19(ARF) mutations in Greek patients with basal cell carcinoma of the skin

Basal cell carcinoma of the skin is the most common neoplasia in humans. Pr evious studies have shown the existence of allelic imbalance (loss of heter ozygosity and microsatellite instability) in BCC on several human chromosom es. Chromosome region 9p21-p22 harbors the CDKN2a/16(INK4a), p19(ARF), and p15(INK4b) tumor suppressor genes. To determine the contribution of these g enes to the development of basal cell carcinomas we looked for evidence of allelic imbalance in 67 sporadic basal cell carcinoma specimens from Greek patients and screened 28 of them presenting loss of heterozygosity at 9p21- p22 for germline mutations in p16(INK4a) and p19(ARF) genes. Chromosome reg ions 17q21 and 17p13 were also screened for allelic imbalance in all the 67 basal cell carcinoma specimens. Overall, 69% (46 of 67) of the specimens d isplayed loss of heterozygosity in at least one microsatellite marker, wher eas only six of the 67 (9%) exhibited microsatellite instability. For the 9 p21-p22 locus the overall frequency of loss of heterozygosity reached 55% ( 37 of 67) and is the highest reported. The overall frequency of loss of het erozygosity for the 17q21 locus is 34% (22 of 64) and for the 17p13 locus i s 11% (seven of 65). Two of the 28 loss of heterozygosity positive cases we re heterozygous for a previously described polymorphism, Ala148Thr, in exon 2 of the CDKN2a gene. This is the first demonstration of polymorphism in t he CDKN2a gene in human basal cell carcinomas. No sequence variation in exo n 1 beta of the p19(ARF) gene was found. Our results provide evidence of a significantly high occurrence of loss of heterozygosity for the 9p21-p22 lo cus; however, lack of p16(INK4a)/p19(ARF) mutation suggests that these gene s seem not to be implicated by mutational inactivation in the development o f basal cell carcinoma. Other(s), yet unidentified, tumor suppressor gene(s ) located in this locus may be related to this specific type of skin cancer .