Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma

• Published in: British journal of cancer Vol. 90; no. 2; pp. 503 - 509
• Main Authors: SOUFIR, N, LACAPERE, J. J, BOUSCARAT, F, BACCARD, M, LANTERNIER, G, SAÏAG, P, LEBBE, C, BASSET-SEGUIN, N, CRICKX, B, CAVE, H, GRANDCHAMP, B, BERTRAND, G, MATICHARD, E, MEZIANI, R, MIREBEAU, D, DESCAMPS, V, GERARD, B, ARCHIMBAUD, A, OLLIVAUD, L
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 26.01.2004
• Subjects: Adolescent; Adult; Age of Onset; Aged; Biological and medical sciences; Cancer research; Cell cycle; Chromosome aberrations; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Dermatology; DNA Mutational Analysis; DNA, Neoplasm; Female; Genes; Genetic Predisposition to Disease; Genetics and Genomics; Germ-Line Mutation; Humans; Kinases; Male; Medical genetics; Medical research; Medical sciences; Melanoma; Melanoma - genetics; Melanoma - pathology; Middle Aged; Mutation; Patients; Pedigree; Polymerase Chain Reaction; Proteins; Risk Factors; Skin cancer; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Tumor Suppressor Protein p14ARF - genetics; Tumors of the skin and soft tissue. Premalignant lesions; France; Human; INK4a-ARF; melanoma genetics; Malignant tumor; germline mutation; CDKN2 gene; Genetic disease; Cdk4; Malignant melanoma; Predisposition; Deletion; Genetics; Tumor suppressor gene
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6601503

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.