Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors

Michel Bahuau, Dominique Vidaud, Robert Brian Jenkins, Ivan Bièche, David W. Kimmel, Brigitte Assouline, Justin S. Smith, Benjamin Alderete, Jean Michel Cayuela, Jean Paul Harpey, Bernard Caille, Michel Vidaud

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Abstract

Joint predisposition to malignant melanoma and nervous system tumors (NSTs) is a puzzle. Several melanoma susceptibility genes have been identified, including p16, a clustered tumor suppressor. However, the molecular bases of inherited proclivity to NSTs in the absence of a recognizable genetic syndrome are unknown. We analyzed two families with joint proneness to melanoma and NSTs in view of genetic linkage and identification of the causal molecular lesions. Highly informative linkage markers were used for segregation analyses of the predisposition alleles in the two pedigrees. Characterization of the molecular lesions required hemizygosity mapping based on microsatellite markers physically mapped to contigs of the 9p21 region and a Southern blot approach using several PCR- generated probes. Both families were found to be allelic and linked to p16 markers. In the family segregating the melanoma/NST syndrome, a large germ- line deletion ablated the whole p16, p19, and p15 gene cluster (or INK4 locus), whereas a more circumscribed molecular lesion disrupting pl 6 and p19 but leaving p15 unaltered segregated with the melanoma-astrocytoma syndrome (MIM 155755). Our results suggest that multiple cancer susceptibility in these two families ensues from contiguous tumor suppressor gene deletion. Indeed, known phenotypes associated with germ-line p16 mutations and an apparent correlation between the deletion span and tumor spectrum in the two families suggest a new model of cancer pathogenesis based on the inactivation of contiguous tumor suppressor genes, an alternative to the established pleiotropic effects of single-gene disruption.

Original languageEnglish (US)
Pages (from-to)2298-2303
Number of pages6
JournalCancer Research
Volume58
Issue number11
StatePublished - Jun 1 1998

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Nervous System Neoplasms
Germ Cells
Melanoma
Tumor Suppressor Genes
Neoplasms
Joints
Genetic Linkage
Germ-Line Mutation
Gene Deletion
Pedigree
Multigene Family
Southern Blotting
Microsatellite Repeats
Genes
Alleles
Phenotype
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Bahuau, M., Vidaud, D., Jenkins, R. B., Bièche, I., Kimmel, D. W., Assouline, B., ... Vidaud, M. (1998). Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. Cancer Research, 58(11), 2298-2303.

Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. / Bahuau, Michel; Vidaud, Dominique; Jenkins, Robert Brian; Bièche, Ivan; Kimmel, David W.; Assouline, Brigitte; Smith, Justin S.; Alderete, Benjamin; Cayuela, Jean Michel; Harpey, Jean Paul; Caille, Bernard; Vidaud, Michel.

In: Cancer Research, Vol. 58, No. 11, 01.06.1998, p. 2298-2303.

Research output: Contribution to journalArticle

Bahuau, M, Vidaud, D, Jenkins, RB, Bièche, I, Kimmel, DW, Assouline, B, Smith, JS, Alderete, B, Cayuela, JM, Harpey, JP, Caille, B & Vidaud, M 1998, 'Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors', Cancer Research, vol. 58, no. 11, pp. 2298-2303.
Bahuau M, Vidaud D, Jenkins RB, Bièche I, Kimmel DW, Assouline B et al. Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. Cancer Research. 1998 Jun 1;58(11):2298-2303.
Bahuau, Michel ; Vidaud, Dominique ; Jenkins, Robert Brian ; Bièche, Ivan ; Kimmel, David W. ; Assouline, Brigitte ; Smith, Justin S. ; Alderete, Benjamin ; Cayuela, Jean Michel ; Harpey, Jean Paul ; Caille, Bernard ; Vidaud, Michel. / Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. In: Cancer Research. 1998 ; Vol. 58, No. 11. pp. 2298-2303.
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abstract = "Joint predisposition to malignant melanoma and nervous system tumors (NSTs) is a puzzle. Several melanoma susceptibility genes have been identified, including p16, a clustered tumor suppressor. However, the molecular bases of inherited proclivity to NSTs in the absence of a recognizable genetic syndrome are unknown. We analyzed two families with joint proneness to melanoma and NSTs in view of genetic linkage and identification of the causal molecular lesions. Highly informative linkage markers were used for segregation analyses of the predisposition alleles in the two pedigrees. Characterization of the molecular lesions required hemizygosity mapping based on microsatellite markers physically mapped to contigs of the 9p21 region and a Southern blot approach using several PCR- generated probes. Both families were found to be allelic and linked to p16 markers. In the family segregating the melanoma/NST syndrome, a large germ- line deletion ablated the whole p16, p19, and p15 gene cluster (or INK4 locus), whereas a more circumscribed molecular lesion disrupting pl 6 and p19 but leaving p15 unaltered segregated with the melanoma-astrocytoma syndrome (MIM 155755). Our results suggest that multiple cancer susceptibility in these two families ensues from contiguous tumor suppressor gene deletion. Indeed, known phenotypes associated with germ-line p16 mutations and an apparent correlation between the deletion span and tumor spectrum in the two families suggest a new model of cancer pathogenesis based on the inactivation of contiguous tumor suppressor genes, an alternative to the established pleiotropic effects of single-gene disruption.",
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AU - Kimmel, David W.

AU - Assouline, Brigitte

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AU - Alderete, Benjamin

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