Differential expression of p16INK4a and p16β transcripts in B-lymphoblastoid cells from members of hereditary melanoma families without CDKN2A exon mutations

Mutations in the CDKN2A (p16INK4a) tumour suppressor gene on chromosome 9p21 are associated with inherited predisposition to melanoma, yet some 9p-linking hereditary melanoma families show no mutations in this gene. Splicing of CDKN2A exons 2 and 3 to an alternative first exon produces a transcript (p16β) encoding a protein with cell cycle regulatory properties. We have analysed allele-specific expression levels of both the p16INK4a and p16β transcripts in B-lymphoblastoid cells from 18 members of hereditary melanoma kindreds including four unrelated control individuals. In 15 of the 18 individuals examined, steady-state levels of each transcript either originated equally from each parental chromosome, or one parental chromosome was dominant for both transcripts. However, in three affected members of two 9p-linking hereditary melanoma kindreds, without exonic CDKN2A mutations, this pattern of coordinate expression was disrupted. In these individuals there was underexpression of the p16β transcript, relative to the p16INK4a transcript, from the chromosome segregating with disease susceptibility. Loss of coordinate expression of the p16INK4a and p16β transcripts may be an alternative genetic basis for melanoma susceptibility in certain 9p-linking kindreds.