DIFFERENTIAL EXPRESSION OF P16(INK4A) AND P16-BETA TRANSCRIPTS IN B-LYMPHOBLASTOID CELLS FROM MEMBERS OF HEREDITARY MELANOMA FAMILIES WITHOUT CDKN2A EXON MUTATIONS

Mutations in the CDKN2A (p16(INK4a)) tumour suppressor gene on chromos ome 9p21 are associated with inherited predisposition to melanoma, yet some 9p-linking hereditary melanoma families show no mutations in thi s gene. Splicing of CDKN2A exons 2 and 3 to an alternative first exon produces a transcript (p16 beta) encoding a protein with cell cycle re gulatory properties. We have analysed allele-specific expression level s of both the p16(INK4a) and p16 beta transcripts in B-lymphoblastoid cells from 18 members of hereditary melanoma kindreds including four u nrelated control individuals. In 15 of the 18 individuals examined, st eady-state levels of each transcript either originated equally from ea ch parental chromosome, or one parental chromosome was dominant for bo th transcripts. However, in three affected members of two 9p-linking h ereditary melanoma kindreds, without exonic CDKN2A mutations, this pat tern of coordinate expression was disrupted. In these individuals ther e was underexpression of the p16 beta transcript, relative to the p16( INK4a) transcript, from the chromosome segregating with disease suscep tibility, Loss of coordinate expression of the p16(INK4a) and p16 beta transcripts may be an alternative genetic basis for melanoma suscepti bility in certain 9p-linking kindreds.