Abstract
For many years, ARF has languished in the shadow of INK4a, a famous and well-characterized tumor suppressor gene. The INK4a/ ARF locus at chromo-some 9p21 is a frequent target for loss-of-function alterations in human cancers, including melanoma. Despite sharing largely overlapping DNA sequences, the INK4a/ARF locus encodes two completely distinct proteins [p16INK4a, which regulates Rb, and p14ARF (or p19Arf in mice), which regulates p53]. This is made possible through the use of two separate first exons (1α for INK4a and 1β for ARF) that splice into common second and third exons in different reading frames. Not surprisingly, mutation/deletion at the INK4a/ARF locus often affects both proteins. Numerous studies have also reported germline and somatic deletions in melanoma that inactivate only INK4a. This had not been the case for ARF, leading many to assume that INK4a is the critical melanoma susceptibility gene at the INK4a/ ARF locus, and to question the role of ARF. However, recently a few patients from melanoma prone families have been discovered that harbor ARF-specific germline mutations consisting of deletions, insertions or missense mutations within exon 1β, thereby resurrecting arguments concerning the possible importance of ARF in human melanomagenesis (reviewed by Saporita et al., 2007). In a new study Polsky and colleagues (Freedberg et al., 2008) have employed a systematic evaluation of a wide array of ARF alterations in metastatic melanoma to elevate ARF to its proper status as a bone fide melanoma susceptibility gene.