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The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma.

Lesueur F, de Lichy M, Barrois M, Durand G, Bombled J, Avril MF, Chompret A, Boitier F, Lenoir GM, French Familial Melanoma Study GroupBressac-de Paillerets B, Baccard M, Bachollet B, Berthet P, Bonadona V, Bonnetblanc JM, Caron O, Chevrant-Breton J, Cuny JF, Dalle S, Delaunay M, Demange L, De Quatrebarbes J, Doré JF, Frénay M, Fricker JP, Gauthier-Villars M, Gesta P, Giraud S, Gorry P, Grange F, Green A, Huiart L, Janin N, Joly P, Kérob D, Lasset C, Leroux D, Limacher JM, Longy M, Mansard S, Marrou K, Martin-Denavit T, Mateus C, Maubec E, Olivier-Faivre L, Orlandini V, Pujol P, Sassolas B, Stoppa-Lyonnet D, Thomas L, Vabres P, Venat L, Wierzbicka E, Zattara H - Br. J. Cancer (2008)

Bottom Line: All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive.Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility.In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene.

View Article: PubMed Central - PubMed

Affiliation: Groupe Mélanome, Institut Gustave Roussy, FRE2939 CNRS-Université Paris-Sud, Villejuif, France.

ABSTRACT
Mutations in two genes encoding cell cycle regulatory proteins have been shown to cause familial cutaneous malignant melanoma (CMM). About 20% of melanoma-prone families bear a point mutation in the CDKN2A locus at 9p21, which encodes two unrelated proteins, p16(INK4a) and p14(ARF). Rare mutations in CDK4 have also been linked to the disease. Although the CDKN2A gene has been shown to be the major melanoma predisposing gene, there remains a significant proportion of melanoma kindreds linked to 9p21 in which germline mutations of CDKN2A have not been identified through direct exon sequencing. The purpose of this study was to assess the contribution of large rearrangements in CDKN2A to the disease in melanoma-prone families using multiplex ligation-dependent probe amplification. We examined 214 patients from independent pedigrees with at least two CMM cases. All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive. Among the remaining 167 negative patients, one carried a novel genomic deletion of CDKN2A exon 2. Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility. In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene.

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Family tree of patient carrying the CDKN2A exon 2 deletion.
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fig2: Family tree of patient carrying the CDKN2A exon 2 deletion.

Mentions: The patient carrying this novel deletion of CDKN2A presented with dysplastic nevus syndrome and developed five primary melanomas between 45 and 51 years of age. He was the index case of a melanoma-prone family of three affected members: his father had a confirmed diagnosis of melanoma at the age of 50, and his sister was also reported to have had melanoma, but no pathological report was available for her (Figure 2). We were unable to investigate the co-segregation of the genomic deletion with melanoma in this pedigree because of unavailability of biological material for the index case's relatives. In addition, the patient's uncle died of pancreatic cancer, a cancer that had been associated with CDKN2A germline mutations (Goldstein et al, 1995; Goldstein et al, 2006), and three other family members died of cancer, but no clinical details were reported to the clinician (Figure 2).


The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma.

Lesueur F, de Lichy M, Barrois M, Durand G, Bombled J, Avril MF, Chompret A, Boitier F, Lenoir GM, French Familial Melanoma Study GroupBressac-de Paillerets B, Baccard M, Bachollet B, Berthet P, Bonadona V, Bonnetblanc JM, Caron O, Chevrant-Breton J, Cuny JF, Dalle S, Delaunay M, Demange L, De Quatrebarbes J, Doré JF, Frénay M, Fricker JP, Gauthier-Villars M, Gesta P, Giraud S, Gorry P, Grange F, Green A, Huiart L, Janin N, Joly P, Kérob D, Lasset C, Leroux D, Limacher JM, Longy M, Mansard S, Marrou K, Martin-Denavit T, Mateus C, Maubec E, Olivier-Faivre L, Orlandini V, Pujol P, Sassolas B, Stoppa-Lyonnet D, Thomas L, Vabres P, Venat L, Wierzbicka E, Zattara H - Br. J. Cancer (2008)

Family tree of patient carrying the CDKN2A exon 2 deletion.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2480975&req=5

fig2: Family tree of patient carrying the CDKN2A exon 2 deletion.
Mentions: The patient carrying this novel deletion of CDKN2A presented with dysplastic nevus syndrome and developed five primary melanomas between 45 and 51 years of age. He was the index case of a melanoma-prone family of three affected members: his father had a confirmed diagnosis of melanoma at the age of 50, and his sister was also reported to have had melanoma, but no pathological report was available for her (Figure 2). We were unable to investigate the co-segregation of the genomic deletion with melanoma in this pedigree because of unavailability of biological material for the index case's relatives. In addition, the patient's uncle died of pancreatic cancer, a cancer that had been associated with CDKN2A germline mutations (Goldstein et al, 1995; Goldstein et al, 2006), and three other family members died of cancer, but no clinical details were reported to the clinician (Figure 2).

Bottom Line: All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive.Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility.In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene.

View Article: PubMed Central - PubMed

Affiliation: Groupe Mélanome, Institut Gustave Roussy, FRE2939 CNRS-Université Paris-Sud, Villejuif, France.

ABSTRACT
Mutations in two genes encoding cell cycle regulatory proteins have been shown to cause familial cutaneous malignant melanoma (CMM). About 20% of melanoma-prone families bear a point mutation in the CDKN2A locus at 9p21, which encodes two unrelated proteins, p16(INK4a) and p14(ARF). Rare mutations in CDK4 have also been linked to the disease. Although the CDKN2A gene has been shown to be the major melanoma predisposing gene, there remains a significant proportion of melanoma kindreds linked to 9p21 in which germline mutations of CDKN2A have not been identified through direct exon sequencing. The purpose of this study was to assess the contribution of large rearrangements in CDKN2A to the disease in melanoma-prone families using multiplex ligation-dependent probe amplification. We examined 214 patients from independent pedigrees with at least two CMM cases. All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive. Among the remaining 167 negative patients, one carried a novel genomic deletion of CDKN2A exon 2. Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility. In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene.

Show MeSH
Related in: MedlinePlus