Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds

Abstract

Germline mutations within the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and one of its targets, the cyclin dependent kinase 4 (CDK4) gene, have been identi®ed in a proportion of melanoma kindreds. In the case of CDK4, only one speci®c mutation, resulting in the substitution of a cysteine for an arginine at codon 24 (R24C), has been found to be associated with melanoma. We have previously reported the identi®cation of germline CDKN2A mutations in 7/18 Australian melanoma kindreds and the absence of the R24C CDK4 mutation in 21 families lacking evidence of a CDKN2A mutation. The current study represents an expansion of these eorts and includes a total of 48 melanoma families from Australia. All of these families have now been screened for mutations within CDKN2A and CDK4, as well as for mutations within the CDKN2A homolog and 9p21 neighbor, the CDKN2B gene, and the alternative exon 1 (E1b) of CDKN2A. Families lacking CDKN2A mutations, but positive for a polymorphism(s) within this gene, were further evaluated to determine if their disease was associated with transcriptional silencing of one CDKN2A allele. Overall, CDKN2A mutations were detected in 3/30 (10%) of the new kindreds. Two of these mutations have been observed previously: a 24 bp duplication at the 5' end of the gene and a G to C transversion in exon 2 resulting in an M53I substitution. A novel G to A transition in exon 2, resulting in a D108N substitution was also detected. Combined with our previous ®ndings, we have now detected germline CDKN2A mutations in 10/48 (21%) of our melanoma kindreds. In none of the`CDKN2A-negative' families was melanoma found to segregate with either an untranscribed CDKN2A allele, an R24C CDK4 mutation, a CDKN2B mutation, or an E1b mutation. The last three observations suggest that these other cell cycle control genes (or alternative gene products) are either not involved at all, or to any great extent, in melanoma predisposition.Keywords: CDKN2A; CDKN2B; CDK4; melanoma; familial; mutation The CDKN2A (or p16) gene is located on chromosome 9p21 within a region that has been found to be frequently deleted in sporadic melanomas (Fountain et al

Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma

“…The functional significance of this in-frame insertion is uncertain as it occurs outside of the ankyrin domains. However, it is noteworthy that it segregates with melanoma in four melanoma kindreds (two in Australia, one in the UK, and one in the United States) (Walker et al, 1995;Flores et al, 1997;Harland et al, 1997). In our case, the mutation is present in the unaffected mother of the proband, but unfortunately the other two melanoma-affected members (the grandmother and her mother) could not be tested because they are deceased.…”

Familial melanoma, pancreatic cancer and germline CDKN2A mutations

“…The distribution of pancreatic cancer in these families differed significantly (p=0.02); the frequency of pancreatic cancer varied from > 30% in p.G101W, p.P75fs, p.R112_L113insR, and p.V126D families to <10% in p.R24P and p.M53I families (figure 1). Fargnoli et al, 1998;MacKie et al, 1998;Soufir et al, 1998;Holland et al, 1999;Newton-Bishop et al, 1999;Della Torre et al, 2001;Mantelli et al, 2002;Lynch et al, 2002 1α c.78insG Fitzgerald et al, 1996;Flores et al, 1997;MacKie et al, 1998;Monzon et al, 1998;Soufir et al, 1998;Holland et al, 1999; Gruis et al, 1995aGruis et al, , 1995bHolland et al, 1999;Goldstein et al, 2000;Vasen et Hussussian et al, 1994;Whelan et al, 1995;Soufir et al, 1998;Ghiorzo et al, 1999;Holland et al, 1999; Codon numbering for the mutations is taken from table 1. Insertions, deletions, and frameshift mutations are shown at the codon in which the mutation.…”

Targeted Therapy for Cutaneous Melanoma: Beyond BRAF...

“…44 Mutations in CDK4 are the second most common germline mutation found in familial melanoma. [41][42][43] These mutations affect the residue in the CDK4 protein that mediates the binding of P16 INK4A , thus blocking this interaction from occurring, and reinforcing the significance of loss of P16 INK4A function in melanoma.…”

“…41 The most common causes (~40%) of familial melanoma are the presence of agermline loss-of-function mutations or deletions of the CDKN2A gene. [41][42][43] Due to alternative splicing mechanisms two cell cycle regulators (P16 INK4A and P14 ARF ) are encoded by this CDKN2A. Most functional studies in melanoma have focused on P16 INK4A , as some mutations in CDKN2A detected in patients do not affect the function of P14 ARF .…”