1. ¹Laboratoire de Biochimie Hormonale et Génétique, Hôpital Bichat-Claude Bernard, 46 rue henri Huchard, Paris 75018, France
2. ²Inserm U 410 Faculté Bichat-Claude Bernard, Paris 75018, France
3. ³Laboratoire de Biochimie-Génétique, Hôpital Robert Debré, Paris 75018, France
4. ⁴Dermatology Department, Hôpital Bichat-Claude Bernard, Paris 75018, France
5. ⁵Dermatology Department, Hôpital Saint-Louis, Paris 75010, France
6. ⁶Dermatology Department, Hôpital Percy, Clamart 92140, France
7. ⁷Dermatology Department, Hôpital Ambroise Paré, 92 Boulogne Billancourt, France

Correspondence: N Soufir, E-mail: nadem.soufir@bch.ap-hop-paris.fr

Received 15 May 2003; Revised 30 September 2003; Accepted 22 October 2003.

Abstract

Germline anomalies of the INK4a-ARF and Cdk4 genes were sought in a series of 89 patients suspected of having a genetic predisposition to melanoma. Patients were selected based on the following criteria: (a) familial melanoma (23 cases), (b) multiple primary melanoma (MPM; 18 cases), (c) melanoma and additional unrelated cancers (13 cases), (d) age at diagnosis less than 25 years (21 cases), and (e) nonphoto-induced melanoma (NPIM; 14 cases). Mutations of INK4a-ARF and Cdk4 were characterised by automated sequencing, and germline deletions of INK4a-ARF were also examined by real-time quantitative PCR. Seven germline changes of INK4a-ARF, five of which were novel, were found in seven patients (8%). Four were very likely to be pathogenic mutations and were found in three high-risk melanoma families and in a patient who had a pancreatic carcinoma in addition to melanoma. Three variants of uncertain significance were detected in one MPM patient, one patient <25 years, and one NPIM patient. No germline deletion of INK4a-ARF was found in 71 patients, and no Cdk4 mutation was observed in the 89 patients. This study confirms that INK4a-ARF mutations are infrequent outside stringent familial criteria, and that germline INK4a-ARF deletions are rarely involved in genetic predisposition to melanoma.