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Characterization of a Germ-Line Deletion, Including the Entire INK4/ARF Locus, in a Melanoma-Neural System Tumor Family: Identification of ANRIL, an Antisense Noncoding RNA Whose Expression Coclusters with ARF

¹ Laboratoire de Génétique Moléculaire-Institut National de la Sante et de la Recherche Medicale U745, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris V; ² Département de Génétique, Hôpital de la Pitié-Salpêtrière, Paris, France; and ³ Laboratoire d'Oncogénétique-Institut National de la Sante et de la Recherche Medicale U735, Centre René Huguenin, St-Cloud, France

Requests for reprints: Ivan Bièche, Laboratoire de Génétique Moléculaire-Institut National de la Sante et de la Recherche Medicale U745, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris 5, 4 Avenue de l'Observatoire, 75006 Paris, France. Phone: 33-1-53-73-97-25; Fax: 33-1-44-07-17-54; E-mail: ivan.bieche{at}univ-paris5.fr.

We have previously detected a large germ-line deletion, which included the entire p15/CDKN2B-p16/CDKN2A-p14/ARF gene cluster, in the largest melanoma-neural system tumor (NST) syndrome family known to date by means of heterozygosity mapping based on microsatellite markers. Here, we used gene dose mapping with sequence-tagged site real-time PCR to locate the deletion end points, which were then precisely characterized by means of long-range PCR and nucleotide sequencing. The deletion was exactly 403,231 bp long and included the entire p15/CDKN2B, p16/CDKN2A, and p14/ARF genes. We then developed a simple and rapid assay to detect the junction fragment and to serve as a direct predictive DNA test for this large French family. We identified a new large antisense noncoding RNA (named ANRIL) within the 403-kb germ-line deletion, with a first exon located in the promoter of the p14/ARF gene and overlapping the two exons of p15/CDKN2B. Expression of ANRIL mainly coclustered with p14/ARF both in physiologic (various normal human tissues) and in pathologic conditions (human breast tumors). This study points to the existence of a new gene within the p15/CDKN2B-p16/CDKN2A-p14/ARF locus putatively involved in melanoma-NST syndrome families and in melanoma-prone families with no identified p16/CDKN2A mutations as well as in somatic tumors. [Cancer Res 2007;67(8):3963–9]

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