Characterization of ligurian melanoma families and risk of occurrence of other neoplasia

Ghiorzo, Paola; Ciotti, Paola; Mantelli, Michela; Heouaine, Abdelhamid; Queirolo, Paola; Rainero, Maria Luisa; Ferrari, Carlo; Santi, Pier Luigi; Marchi, R. De; Farris, Alessandro; Ajmar, Franco; Bruzzi, Paolo; Bianchi‐Scarrǎ, Giovanna

doi:10.1002/(sici)1097-0215(19991112)83:4<441::aid-ijc2>3.0.co;2-r

Cited by 79 publications

(74 citation statements)

References 23 publications

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“…In our families, evidence for the presence of tumours additional to melanoma indicates a high heterogeneity, as already observed in melanoma families of various geographical origins (Ghiorzo et al, 1999). In studies aimed at investigating whether familial susceptibility to melanoma increases the risk of other tumours, increased risks of pancreatic and breast carcinomas have been found in CDKN2A mutation carriers Borg et al, 2000).…”

Section: Discussionsupporting

confidence: 76%

“…The N71S, alike to P48T, retained CDKbinding activity but behaved as partially impaired in the cell proliferation assay (Ruas et al, 1999). Italian melanoma families commonly have a small number of affected relatives and the likelihood that these families represent clustering of sporadic cases is minor because of the low melanoma incidence in the Italian population (Ghiorzo et al, 1999). In our series of 15 Italian melanoma families, 25% of families with 2 affected relatives and 50% of families with 3 or more affected relatives had identifiable melanoma specific CDKN2A mutations.…”

Section: Discussionmentioning

confidence: 99%

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CDKN2A and CDK4 mutation analysis in Italian melanoma-prone families: functional characterization of a novel CDKN2A germ line mutation

et al. 2001

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Summary Physical interaction between CDKN2A/p16 and CDK4 proteins regulates the cell cycle progression through the G1 phase and dysfunction of these proteins by gene mutation is implicated in genetic predisposition to melanoma. We analysed 15 Italian melanoma families for germ line mutations in the coding region of the CDKN2A gene and exon 2 of the CDK4 gene. One novel disease-associated mutation (P48T), 3 known pathological mutations (R24P, G101W and N71S) and 2 common polymorphisms (A148T and Nt500 G>C) were identified in the CDKN2A gene. In a family harbouring the R24P mutation, an intronic variant (IVS1, +37 G>C) of uncertain significance was detected in a noncarrier melanoma case. The overall incidence of CDKN2A mutations was 33.3%, but this percentage was higher in families with 3 or more melanoma cases (50%) than in those with only 2 affected relatives (25%). Noteworthy, functional analysis established that the novel mutated protein, while being impaired in cell growth and inhibition assays, retains some in vitro binding to CDK4/6. No variant in the p16-binding region of CDK4 was identified in our families. Our results, obtained in a heterogeneous group of families, support the view that inactivating mutations of CDKN2A contribute to melanoma susceptibility more than activating mutations of CDK4 and that other genetic factors must be responsible for melanoma clustering in a high proportion of families. In addition, they indicate the need for a combination of functional assays to determine the pathogenetic nature of new CDKN2A mutations.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

CDKN2A and CDK4 mutation analysis in Italian melanoma-prone families: functional characterization of a novel CDKN2A germ line mutation

et al. 2001

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“…In other populations, founder mutations in the p16 gene were reported on several occasions. 16,23,[29][30][31][32] Examination of a greater number of melanoma families, extension of analysis to non-coding regions of the p16 gene and screening for large rearrangements involving the p16 gene, will further clarify the role of p16 mutations in familial melanoma in Jews. The possibility of presence of germline mutations in another gene, CDK4, which have been reported in a few melanoma pedigrees 11,33 should be also investigated.…”

Section: Discussionmentioning

confidence: 99%

Two p16 (CDKN2A) germline mutations in 30 Israeli melanoma families

et al. 2000

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Germline mutations in the p16 (CDKN2A) tumour suppressor gene have been linked to inherited predisposition to malignant melanoma (MM). Variable frequencies of p16 germline mutations were reported in different collections of melanoma families but it can be as high as 50%. Here we describe the results of p16 mutation screening in 30 melanoma kindreds in Israel. The entire coding region of the p16 gene, including exons 1, 2 and 3, flanking exon/intron junctions, and a portion of the 3' untranslated (UTR) region of the gene were examined by single-stranded conformation polymorphism (SSCP) analysis and direct sequencing. Two p16 germline mutations were identified: G101W, which has been previously observed in a number of melanoma kindreds, and G122V, a novel missense mutation. Thus, the frequency of mutations identified in this collection of Israeli families was 7%. Functional analysis indicated that the novel G122V variant retained some capacity to interact with cyclin dependent kinases (CDKs) in vitro, yet it was significantly impaired in its ability to cause a G1 cell cycle arrest in human diploid fibroblasts. This partial loss of function is consistent with the predicted impact of G122V substitution on the 3-dimensional structure of the p16 protein.

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“…At the same time, Whelan et al (1995) reported a CDKN2A mutation in a kindred with three cases of pancreatic cancer and two cases of melanoma, and suggested that CDKN2A may underlie susceptibility to the familial cancer syndrome comprising these tumour types. Several other groups have since reported the occurrence of pancreatic cancer in mutation-positive melanoma families (Gruis et al, 1995;Borg et al, 1996Borg et al, , 2000Ciotti et al, 1996;Moskaluk et al, 1998;Soufir et al, 1998;Ghiorzo et al, 1999;Liu et al, 1999;Goldstein et al, 2000;Lal et al, 2000a, b;Lynch et al, 2002). There have also been suggestions of an increased risk of breast, prostate, colon and lung cancers, but these are the most common of all cancers and therefore their occurrence in melanoma families may be because of chance.…”

Section: Cdkn2amentioning

confidence: 99%