High frequency of ultraviolet mutations at the INK4a-ARF locus in squamous cell carcinomas from psoralen-plus-ultraviolet-A-treated psoriasis patients.
Squamous cell carcinomas in psoralen-plus-ultraviolet A (PUVA) treated patients frequently exhibit p53 tumor suppressor genes and Ha-ras protooncogenes that are mutated at dipyrimidine sites and carry the ultraviolet fingerprint (i.e., C-to-T or CC-to-TT transitions). To further broaden the knowledge of genetic mutations in PUVA-associated skin cancer, we used DNA sequencing analysis to study the mutational spectrum of the INK4a-ARF locus in 26 squamous cell carcinomas from 11 long-term PUVA-treated psoriasis patients and classified the mutations by origin (ultraviolet, ultraviolet and/or PUVA, or other). Nineteen INK4a-ARF missense/nonsense mutations were found in exons 1alpha, 1beta, and 2 in 11 of 26 squamous cell carcinomas (42%) from seven of 11 patients (64%). Eleven mutations (58%) were of the ultraviolet type; three (16%) were of the ultraviolet and/or PUVA type (i.e., C-to-T transitions at dipyrimidine sites opposite a 5'TpG sequence, a potential psoralen binding site); and five (26%) were of other type. Interestingly, 10 of 11 patients (91%) showed intron polymorphism C500G at the 3' untranslated region of exon 3. These data indicate that (i) INK4a-ARF mutations frequently occur in PUVA-associated squamous cell carcinomas; (ii) ultraviolet B radiation is the major cause of these mutations; and (iii) PUVA itself may play no direct role in development of most INK4a-ARF mutations.
Kreimer-Erlacher
Heidemarie
H
Department of Dermatology, Karl-Franzens University, Graz, Austria.
Seidl
Hannes
H
Bäck
Barbara
B
Cerroni
Lorenzo
L
Kerl
Helmut
H
Wolf
Peter
P
D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D016172:DNA Fingerprinting; D004252:DNA Mutational Analysis; D005260:Female; D005363:Ficusin / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000528:radiation effects; D011701:PUVA Therapy / Q000009:adverse effects*; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000009:adverse effects; D018807:Polymorphism, Single-Stranded Conformational; D011565:Psoriasis / Q000188:drug therapy / Q000532:radiotherapy*; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics
D019941:Cyclin-Dependent Kinase Inhibitor p16; D017319:Photosensitizing Agents; D025803:Tumor Suppressor Protein p14ARF; D005363:Ficusin