Differential expression of p16^INK4a and p16β transcripts in B-lymphoblastoid cells from members of hereditary melanoma families without CDKN2A exon mutations

Abstract

Mutations in the CDKN2A (p16^INK4a) 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 p16^INK4a 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 p16^INK4a transcript, from the chromosome segregating with disease susceptibility. Loss of coordinate expression of the p16^INK4a and p16β transcripts may be an alternative genetic basis for melanoma susceptibility in certain 9p-linking kindreds.