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Germ-Line Deletion Involving the INK4 Locus in Familial Proneness to Melanoma and Nervous System Tumors¹

Laboratoire de Génétique Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques de l'Université Paris V, 75006 Paris, France [M. B., D. V., I. B., B. As., M. V.]; Division of Laboratory Genetics [R. B. J., J. S. S., B. Al.] and Department of Neurology [D. W. K.], Mayo Clinic, Rochester, Minnesota 55905; Laboratoire d'Hématologie Moléculaire, INSERM U 462, Institut d'Hématologie, Hôpital Saint-Louis, 75475 Paris Cedex 10, France [J-M. C.]; and Service de Pédiatrie et Génétique Médicale, Groupe Hospitalier Pitié-Salpêtrière, 75651 Paris Cedex 13, France [J-P. H., B. C.]

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 p16 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.

¹ Supported by the Association pour la Recherche contre le Cancer, the French Ministère de l'Enseignement Supérieur et de la Recherche and by a grant from the Fondation pour la Recherche Médicale (to M. B.).

² M. B. and D. V. contributed equally to this work.

³ To whom requests for reprints should be addressed, at Laboratoire de Génétique Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques de l'Université Paris V, 4 Avenue de l'Observatoire, 75006 Paris, France. Phone: 33-1-43-29-76-08; Fax: 33-1-44-07-17-54; E-mail: mvidaud@teaser.fr.

Received 2/20/98. Accepted 4/15/98.

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