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[Cancer Research 60, 6864-6867, December 15, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

CDKN2A Germ-line Mutations in Individuals with Multiple Cutaneous Melanomas1

Jamileh Hashemi2, Anton Platz2, Takayuki Ueno, Ulrika Stierner, Ulrik Ringborg and Johan Hansson3

Radiumhemmet, Department of Oncology-Pathology, Karolinska Hospital, S-171 76 Stockholm, Sweden [J. Has., A. P., T. U., U. R., J. Han.], and Department of Oncology, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden [U. S.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
Germ-line CDKN2A mutations are present in some kindreds with hereditary cutaneous melanoma, and in Sweden a founder mutation with an extra arginine in codon 113 (113insR) has been identified. We screened 80 individuals with at least two primary cutaneous melanomas, who were identified mainly by a search of a regional cancer registry, for germ-line CDKN2A mutations. In nine patients, CDKN2A alterations that may contribute to melanoma predisposition were detected. In six individuals with a family history of melanoma, the 113insR founder mutation was present. One patient, who also had a family history of melanoma, had a 24-bp deletion that included codons 62–69. An in vitro binding assay established that the resulting mutant p16 protein was unable to bind cyclin-dependent kinase 4 and cyclin-dependent kinase 6. Two patients without a family history of melanoma had CDKN2A alterations: (a) one had a mutation in the 5' noncoding sequence (-14C/T); and (b) the other had an insertion of an extra T in codon 28, which results in a stop signal in codon 43. The median age at diagnosis of the first melanoma was significantly lower, the number of primary melanomas was significantly higher, and the presence of a family history of melanoma was significantly more common in patients with CDKN2A mutations than in those without germ-line mutations. The proportion of CDKN2A mutation carriers was significantly higher among patients treated for three or more primary melanomas compared with those with two tumors only. We conclude that mutation screening of individuals with multiple primary melanomas is a useful strategy to identify new melanoma kindreds with CDKN2A germ-line mutations.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
Approximately 10% of cutaneous melanomas occur in families with hereditary predisposition (1, 2, 3) . In a proportion of melanoma kindreds, germ-line CDKN2A mutations have been identified (4 , 5) . The major part of the p16 protein, the CDKN2A gene product, consists of four ankyrin repeat motifs, which are of importance for binding to CDKs4 : CDK4 and CDK6. The CDK4 and CDK6 proteins are activated by association with cyclin D and phosphorylate the retinoblastoma protein, leading to dissociation of the E2F class of transcription factors, which are required for the entry of the cell into S phase. Binding of the p16 protein to the CDK4/CDK6 proteins inhibits their association with cyclin D and thereby serves as a negative regulatory component in the G1-S-phase checkpoint control. The relation between the structure and function of the p16 protein has been analyzed in detail (6) .

In several Swedish kindreds, an identical germ-line mutation consisting of an extra arginine base in codon 113 (113insR) in exon 2 of CDKN2A has been found (7 , 8) . Haplotype analysis has shown that this unique alteration is an ancient Swedish founder mutation.5

In approximately 5% of melanoma patients, more than one primary melanoma is diagnosed (9 , 10) . In some cases, the occurrence of multiple primary melanomas may have a genetic background and may be associated with a family history of melanoma (1 , 11) . It has been reported that germ-line CDKN2A mutations can be identified in individuals with multiple cutaneous melanomas (12) . Identification of individuals with a genetic predisposition to develop multiple primary melanomas is of considerable value not only for these patients but also for all additional family members who may have inherited the trait and can be offered participation in preventive clinical programs.

We have investigated the frequency of germ-line CDKN2A mutations in Swedish patients with multiple cutaneous melanomas followed in Stockholm and Gothenburg. Genomic DNA prepared from blood samples was used for PCR of CDKN2A exons 1 and 2. Mutational analysis was then carried out using SSCP analysis combined with nucleotide sequencing. A novel CDKN2A mutation was functionally characterized by an in vitro binding assay.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Patients.
Patients who had been treated for two or more histologically verified cutaneous melanomas and were still alive were identified in the Regional Cancer Registry of the Stockholm-Gotland area in Sweden. The search included both invasive and in situ melanomas. All patients with multiple cutaneous melanomas who attended the outpatient clinic at the Department of Oncology at the Sahlgrenska University Hospital (Gothenburg, Sweden) were also asked if they were willing to participate in the study. After obtaining informed consent, venous blood was obtained from each patient. Of 79 patients identified in Stockholm, 73 agreed to participate, and all 7 patients identified in Gothenburg were willing to give blood. Thus, a total of 80 patients, 73 from Stockholm and 7 from Gothenburg, participated in the study. The six patients who declined to take part in the study did not differ significantly from the participating patients with respect to the number of primary melanomas, sex, or age. All diagnoses of melanoma were verified by specialized pathologists at both centers as part of the clinical program for melanoma care. Each patient was questioned regarding family history of melanoma. Diagnoses of cutaneous melanoma in blood relatives were confirmed by histopathology reports. The investigation was approved by the Ethical Review Committee of the Karolinska Institute.

DNA Extraction, PCR Amplification, and SSCP and Nucleotide Sequence Analysis.
DNA was extracted from whole blood using the Qiagen Blood and Cell Culture DNA system (Qiagen GmbH, Hilden, Germany). CDKN2A exons 1 and 2 were amplified using the primer pairs AP161/AP162 and AP163/AP164, respectively (Table 1)Citation . The exon 1 amplification protocol consisted of 30 cycles, with temperature steps at 94°C, 63°C, and 72°C for 30 s each, and the exon 2 protocol consisted of 30 cycles with temperature steps at 94°C, 60°C, and 72°C for 30 s each. The amplified products were cleaved into two pieces at single SmaI sites to obtain smaller fragments for optimal resolution on SSCP. Sequencing primers were AP1613 and AP1614 for exon 1 and AP167, AP168, AP161B, and AP162B for exon 2 (Table 1)Citation .


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  		Table 1 Primers used for PCR of CDKN2A exons and nucleotide sequencing

 
The PCR products were labeled with 32P by direct incorporation of [{alpha}-32P]dCTP. The SSCP analyses were carried out as described by Mashiyama et al. (13) and performed both in the presence of 5% glycerol at 18°C and in the absence of glycerol at 5°C. Nucleotide sequencing was performed with the dideoxy chain termination method using fluorescence-labeled dCTP and an automatic sequencer (Applied Biosystems, Foster City, CA). Sequencing of both strands was carried out.

In Vitro Mutagenesis of the CDKN2AcDNA.
The wild-type CDKN2A and CDK4 cDNAs in pcDNA3 and Bluescript II SK vectors (14, 15, 16) were a gift from Dr. G. Peters (Imperial Cancer Research Fund, London, United Kingdom) and Dr. D. H. Beach (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY), whereas CDK2 and CDK6 cDNAs in Bluescript II SK vectors were gifts from Dr. Å. Borg (University Hospital Lund, Lund, Sweden). To construct a CDKN2A cDNA containing the codon 62–69 24-bp deletion, we used the PCR-based overlap extension approach of Ho et al. (17) , as shown in Fig. 1Citation . Direct sequencing of both strands of the recloned plasmid DNA was performed, which confirmed that it contained only the desired deletion and otherwise had the wild-type CDKN2A sequence (data not shown).



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  		Fig. 1. PCR-based overlap extension to construct the codon 62–69 24-bp deletion CDKN2A mutant. The 24-bp deletion is shown in bold. Primers 1 and 2 (sequences shown in italic) were designed so that their 3' ends hybridize to template sequence on one side of the 24-bp deletion, and the 5' ends are complementary to the template sequence on the other side of the deletion (shown with dashed lines).

 
In Vitro Binding Assay.
[35S]Methionine-labeled wild-type and mutant p16 proteins and human CDK4, CDK6, and CDK2 proteins were synthesized by coupled transcription/translation of plasmid DNA in rabbit reticulocyte lysates using the TNT Quick Coupled Transcription/Translation systems (Promega). These proteins were then used in a coimmunoprecipitation assay using p16 (C-20) and CDK4 polyclonal rabbit antihuman antibodies (Santa Cruz Biotechnology and PharMingen), as described previously (18) .


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
Blood samples from 80 individuals with multiple cutaneous melanomas were analyzed in the present study. Patients were identified mainly by a search of the Stockholm-Gotland Regional Cancer Registry and thus constitute a representative sample of Swedish patients with multiple primary melanomas. Patient characteristics are shown in Table 2Citation . The gender distribution was equal, and the median age at diagnosis was only slightly lower than that of the majority of melanoma patients in Sweden. A large proportion of patients showed clinically dysplastic nevi, which is consistent with previous reports of multiple primary melanomas (12 , 19) . The majority of patients had been diagnosed with two primary melanomas; only 12 patients had been treated for three tumors, 4 patients had been treated for four melanomas, 2 patients had been treated for five tumors, and 1 patient had been operated on for six primary melanomas. In 15 patients, at least one additional family member with cutaneous melanoma was identified. These individuals belonged to 13 separate kindreds with hereditary melanoma; thus, two kindreds were represented with two individuals each in this patient material.


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  		Table 2 Characteristics of 80 patients with multiple cutaneous melanomas analyzed for germ-line CDKN2A mutations

 
In nine patients, germ-line CDKN2A mutations of known or possible functional significance were found (Table 3)Citation . Six of these individuals carried the 113insR founder mutation in exon 2 of CDKN2A, which was previously recognized independently among melanoma families from the Stockholm area (8) and from southern Sweden (7) . The 113insR mutation results in functional impairment of the protein product (16) and segregates with melanoma in affected families (8 , 18) .


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  		Table 3 Germ-line CDKN2A alterations in individuals with multiple cutaneous melanomas

 
One of the patients had a previously unreported exon 1 alteration consisting of an insertion of an extra T base residue in codon 28. This change results in a shift of the reading frame and a stop signal in codon 43, yielding a protein product with an altered sequence from the middle part of the first ankyrin repeat, which is terminated at a point corresponding to the end of this repeat. The resulting protein will thus contain only the first part of the first of four ankyrin repeats that make up the main part of the wild-type p16 protein and is most likely to be nonfunctional.

One individual had a previously unreported 24-bp deletion including codons 62–69 of CDKN2A exon 2. The 24-bp deletion is located within a conserved residue of exon 2, and the resulting protein lacks eight amino acids in the end of the second and the beginning of the third ankyrin repeat. NH2-terminal deletion studies have demonstrated that this region plays an important role in protein function (20) . Functional analysis of the 24-bp deletion by an in vitro binding assay showed that it has functional consequences. As shown in Fig. 2Citation , antibody against p16 immunoprecipitated wild-type p16, mutant p16, and the complex of wild-type p16 and either CDK4 or CDK6 but not CDK2. In contrast, neither CDK4, CDK6, nor CDK2 was coprecipitated with mutant p16 by the p16 antibody. The CDK binding assay was repeated at 42°C, giving results identical to those obtained when the assay was carried out at 30°C (data not shown). A 19-bp deletion in the same region of exon 2 has been recognized among a collection of endogamous melanoma families from the Netherlands, resulting in a frameshift and a truncated protein product (21) , and a 14-bp deletion in this region has also been reported in a tumor of the esophagus (22) , further supporting the role of deletions in this region of the CDKN2A gene for development of malignant tumors.



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  		Fig. 2. Binding of wild-type and 24-bp deletion mutant p16 to CDK proteins. Wild-type p16, 24-bp deletion mutant p16, and wild-type CDK4, CDK6, and CDK2 proteins were synthesized by in vitro translation in the presence of [35S]methionine. p16 and complexes of p16 and CDKs were precipitated with a polyclonal antibody to p16. In the far right lane, CDK4 was precipitated by polyclonal antibody to CDK4. The immunocomplexes were analyzed by SDS-PAGE, and the labeled products were visualized by autoradiography. The 24-bp deletion mutant showed no binding to CDK4 or CDK6, in contrast to wild-type p16 protein.

 
Finally, one individual had a single C/T nucleotide change at position -14 in the noncoding 5'-UTR. It is not yet known whether this mutation has any functional significance. However, it does not seem to be a common polymorphism because this change has not been registered in any of the approximately 300 other individual blood samples we have screened for changes in CDKN2A. It has recently been demonstrated that germ-line mutations in the 5'-UTR may have functional effects and predispose carriers to melanoma (23 , 24) . Mutational screening of the 5'-UTR of CDKN2A in affected individuals from 59 Canadian melanoma-prone families and in 38 individuals with multiple primary melanomas detected a -34G/T base shift in members of 4 of the families and in 2 individuals with multiple primary melanomas (23) . This single nucleotide change, which has also been observed in British kindreds with hereditary melanoma (24) , creates an additional potential AUG codon in position -35, and investigations of in vitro translation of plasmid constructs suggest that the alternative translation initiation may result in a nonfunctional truncated protein product (23) . At present, however, there is no evidence that the -14C/T base change affects translation or the structure of the resulting p16 protein.

In the present patient series, the yield of CDKN2A germ-line mutation carriers was higher in patients with three or more primary melanomas (6 of 16 patients, 32%), compared to patients with two primary melanomas only (3 of 61 patients, 5%; {chi}2 exact test, P < 0.001). The clinical characteristics of patients with germ-line CDKN2A mutations are summarized in Table 4Citation . The median age at diagnosis of the first primary melanoma was 42 years in these patients, which was significantly lower than a median age of 54 years in patients without mutations (P = 0.023; Table 2Citation ). The number of primary melanomas in germ-line CDKN2A mutation carriers was significantly higher than that in patients with wild-type CDKN2A genes (P = 0.025; Table 2Citation ). All 9 patients with germ-line CDKN2A mutations and 58 (82%) of the patients without mutations had dysplastic nevi.


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  		Table 4 Characteristics of patients with germ-line CDKN2A alterations of possible functional significance

 
Investigation of the family histories of our patients revealed that the patient with the 24-bp exon 2 deletion belongs to a family with several cases of melanoma, and the six individuals with the 113insR mutations are all members of families with proposed hereditary melanoma predisposition. Two melanoma kindreds with this founder mutation were represented by two patients each in the present study (Table 4)Citation . Thus, altogether, 9 of 80 (11%) individuals with multiple primary tumors had germ-line mutations in CDKN2A, and 7 of these individuals belong to families with hereditary predisposition for the disease. A family history of melanoma was also present in some patients with wild-type CDKN2A genes, but the proportion of patients with verified melanoma heredity (7 of 9 patients) was significantly higher among CDKN2A mutation carriers than among patients without germ-line mutations (8 of 71 patients; P < 0.001; Table 2Citation )

We conclude that screening for germ-line mutations among individuals with multiple primary melanomas (in particular, individuals with more than two primary tumors) thus identifies families who may have a hereditary predisposition for the development of cutaneous melanoma. Members of such families may benefit from preventive clinical programs aimed at reducing melanoma risk.


   ACKNOWLEDGMENTS
 
We thank Elisabet Lundin for excellent technical assistance, Lena Westerberg for collecting blood samples, and Bo Nilsson for aid with statistical analyses.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by grants from the Cancer Society in Stockholm, the Gustaf V Jubilee Fund, the Swedish Cancer Society, and the Research Funds of the Karolinska Institute. Back

2 J. Has. and A. P. contributed equally to this work. Back

3 To whom requests for reprints should be addressed, at Radiumhemmet, Department of Oncology-Pathology, Karolinska Hospital, S-171 76 Stockholm, Sweden. Phone: 46-8-51773640, Fax: 46-8-51776290; E-mail: Johan.Hansson{at}onkpat.ki.se Back

4 The abbreviations used are: CDK, cyclin-dependent kinase; SSCP, single-strand conformational polymorphism; UTR, untranslated region. Back

5 J. Hashemi, P. Bendahl, T. Sandberg, A. Platz, S. Linder, U. Stierner, H. Olsson, C. Ingvar, J. Hansson, and Å. Borg. Haplotype analysis and age estimation of the 113insR CDKN2A founder mutation in Swedish melanoma families, in press. Back

Received 4/10/00. Accepted 10/26/00.


   REFERENCES
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 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

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