Screening of Germline Mutations in the CDKN2A and CDKN2B Genes in Swedish Families With Hereditary Cutaneous Melanoma

Platz, Anton; Hansson, Johan; Månsson‐Brahme, Eva; Lagerlöf, B.; Linder, Stig; Lundqvist, Elisabeth Åvall; Sevigny, P; Inganäs, M.; Ringborg, Ulrik

doi:10.1093/jnci/89.10.697

Cited by 142 publications

(97 citation statements)

References 17 publications

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“…33 More than 100 melanoma kindreds were sequenced for germline p16 mutations in Sweden and only 8% were found to carry mutation. 39 Thus it is likely that other, yet unidentified susceptibility genes are involved in melanoma. Similarly, it has been estimated that germline BRCA1 and BRCA2 mutations each account for some 11% of breast cancer in families with 3 or more affected relatives.…”

Section: Heritable Effectsmentioning

confidence: 99%

Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish family‐cancer database

Czene

Lichtenstein

Hemminki

2002

Intl Journal of Cancer

479

321

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The genetic and environmental components in 15 common cancers were estimated using the nationwide Swedish Family-Cancer Database. Tetrachoric correlations were used to describe similarity in cancer liability among family members. Structural equation modeling was used to derive estimates of the importance of genetic and environmental effects. Statistically significant estimates of proportion of cancer susceptibility, accounted for by genetic effects, were obtained for all studied cancers except for leukemia. The estimate was highest in thyroid cancer (53%), followed by tumors at endocrine glands (28%), testis (25%), breast (25%), cervix (22%), melanoma (21%), colon (13%), nervous system (12%), rectum (12%), non-Hodgkin lymphoma (10%), lung (8%), kidney (8%), urinary bladder (7%), stomach (1%) and leukemia (1%). The estimates of shared environmental effects ranged from 0% (cervix) to 15% (stomach). The childhood shared environmental effects were most important in testicular cancer (17%), stomach cancer (13%) and cervix in situ (13%). Our results indicate that environment has a principal causative role in cancer at all studied sites except for thyroid. The relatively large effect of heritability in cancer at some sites, on the other hand, indicates that even though susceptibility genes have been described at many cancer sites, they are likely to explain only part of the genetic effects.

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Section: Heritable Effectsmentioning

confidence: 99%

Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish family‐cancer database

Czene

Lichtenstein

Hemminki

2002

Intl Journal of Cancer

479

321

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“…The p16 INK4a tumour suppressor is clearly important in melanoma predisposition; almost one third of melanoma-associated germline mutations a ect the p16 INK4a speci®c exon 1a (FitzGerald et al, 1996;Harland et al, 1997;Holland et al, 1999;Hussussian et al, 1994;Kamb et al, 1994;Platz et al, 1997;Walker et al, 1995) and impair p16 INK4a function (Parry and Peters, 1996;Ranade et al, 1995;Reymond and Brent, 1995). The role of p14ARF in melanoma susceptibility is not as clear.…”

Section: Introductionmentioning

confidence: 99%

“…The role of p14ARF in melanoma susceptibility is not as clear. No germline mutations a ecting the p14ARF speci®c exon1b have been identi®ed (FitzGerald et al, 1996;Platz et al, 1997) and yet many INK4a/ARF exon 2 mutations alter both the p16 INK4a and p14ARF amino acid sequence (Holland et al, 1999). To determine the e ect of such mutations on p14ARF function the functional domains of this protein must be de®ned.…”

Section: Introductionmentioning

confidence: 99%

Two arginine rich domains in the p14ARF tumour suppressor mediate nucleolar localization

et al. 2000

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The INK4a/ARF locus encodes two distinct tumour suppressors, p16 INK4a and p14ARF, that regulate cell cycle progression via the pRB and p53 pathways, respectively. The ARF protein inhibits hdm2 activity, leading to the stabilization of the p53 tumour suppressor and cell cycle inhibition. The amino-terminal domain of human p14ARF and of the mouse homologue, p19ARF, is su cient for these e ects. This domain is also su cient for the nucleolar localization of the mouse ARF protein. In contrast, we show that the human ARF protein requires two arginine rich domains, one in the amino-and the other in the carboxy-terminus, for nucleolar targeting. The amino-terminal nucleolar-targeting domain of p14ARF is also important for ARF-hdm2 binding and cell cycle inhibition. The carboxy-terminal p14ARF nucleolar localization domain lies within the shared INK4a/ARF exon 2, and is mutated in a small number of melanoma-prone kindreds. The INK4a/ARF exon2-mutations could a ect the function of both the p16 INK4a and p14ARF tumour suppressors. Oncogene (2000) 19, 2978 ± 2985.

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“…2 The estimated frequency of p16 mutations in familial melanoma varies from 8 to 50%. [9][10][11] Some of this variability could reflect the different ways in which familial inheritance of melanoma is inferred. For example, in two studies a positive correlation was noted between the frequency of p16 mutation and the number of MM affected individuals within a given melanoma family.…”

Section: Introductionmentioning

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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Screening of Germline Mutations in the CDKN2A and CDKN2B Genes in Swedish Families With Hereditary Cutaneous Melanoma

Cited by 142 publications

References 17 publications

Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish family‐cancer database

Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish family‐cancer database

Two arginine rich domains in the p14ARF tumour suppressor mediate nucleolar localization

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

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