A germline deletion of p14ARF but not CDKN2A in a melanoma-neural system tumour syndrome family

Abstract

The melanoma-astrocytoma syndrome is characterized by a dual predisposition to melanoma and neural system tumours, commonly astrocytoma. Germline deletions of the region on 9p21 containing the CDKN2A and CDKN2B genes and CDKN2A exon 1beta have been reported in kindreds, implicating contiguous tumour suppressor gene deletion as a cause of this syndrome. We describe a family characterized by multiple melanoma and neural cell tumours segregating with a germline deletion of the p14(ARF)-specific exon 1beta of the CDKN2A gene. This deletion does not affect the coding or minimal promoter sequences of either the CDKN2A or CDKN2B genes. Our results are consistent with either: (i) loss of p14(ARF) function being the critical abnormality associated with this syndrome, rather than contiguous loss of both the CDKN2A and CDKN2B genes as suggested previously; or (ii) disruption of expression of p16 by mechanisms as yet unknown.

Search for germline alterations in CDKN2A/ARF and CDK4 of 42 Jewish melanoma families with or without neural system tumours

“…In another melanoma family with NST (mainly astrocytoma), deletion was found in the CDKN2A/ARF exon 1b. The deletion, leading to loss of ARF function, did not affect the coding region of p16 protein (Randerson-Moor et al, 2001). Finally, a splice site substitution mutation trimming CDKN2A exon 2 and severely affecting both p16INK4A and p14ARF was described in a family with melanomas, neurofibromas and multiple dysplastic nevi (Petronzelli et al, 2001).…”

“…Constitutional CDKN2A locus alterations, somatic point mutations and deletions at CDKN2A were identified in NST (Ueki et al, 1996;Bostrom et al, 2001;Ghimenti et al, 2003). Evidence was presented that deletion in ARF may be the underlying cause in the development of melanoma and NST (Randerson-Moor et al, 2001). …”

“…CDKN2A/ARF deletion detection Since CDKN2A/ARF deletions were previously identified in melanoma-NST families (Bahuau et al, 1998, Randerson-Moor et al, 2001, deletions were sought only in this subset of families (n ¼ 24). Deletion genotyping was performed using the D9S1748 microsatellite marker located adjacent to CDKN2A exon 1b.…”

Measurement of Relative Copy Number of CDKN2A/ARF and CDKN2B in Bladder Cancer by Real-Time Quantitative PCR and Multiplex Ligation-Dependent Probe Amplification

“…15 A germline deletion of p14 ARF but not CDKN2A exon 1␣ has been reported in a melanomaneural system syndrome family. 35 Similarly, deletion of exon 1␤ has been detected in a sporadic melanoma patient 36 in two melanoma cell lines 37 and three acute lymphocytic leukemia samples. 38 The rare detection of p14 ARF -specific deletions in tumor samples could be due to technical difficulties, since homozygous deletions are difficult to detect by conventional PCR due to the presence of contaminating normal cells.…”

“…This has not been reported in TCC though some melanoma cell lines have been identified with exon-1␤ deletion alone 37 and germline deletions have been recorded in cases of familial melanoma. 35,55 No p14 ARFspecific deletions were identified in TCC cell lines but the number studied was too small to ensure detection of rare events. To our knowledge, such deletions have not been reported in other adult sporadic tumors though there have been relatively few comprehensive homozygous deletion analyses reported to date.…”