DERMATOPATHOLOGY DOI 10.1111/j.1365-2133.2008.08575.x Malignant melanoma in patients with hereditary nonpolyposis colorectal cancer G. Ponti, L. Losi,* G. Pellacani, L. Wannesson,à A.M. Cesinaro,* T. Venesio,§ C. Petti§ and S. Seidenari  Department of Oncology and Haematology,*Department of Pathology and  Division of Dermatology, University of Modena and Reggio Emilia, 41100 Modena, Italy àOncology Institute of Southern Switzerland, Bellinzona, Switzerland §Unit of Pathology, IRCC-Institute for Cancer Research and Treatment, Candiolo-Torino, Italy Correspondence Giovanni Ponti. E-mail: ponti.giovanni@unimo.it Accepted for publication 11 February 2008 Key words familial melanoma syndrome, hereditary nonpolyposis colorectal cancer, malignant melanoma, mismatch repair genes, p16 Conflicts of interest None declared. Summary Background Malignant melanoma (MM) is the most aggressive skin cancer. Most MMs are sporadic, and in this setting an association with mismatch repair (MMR) gene mutations, typical of hereditary nonpolyposis colorectal cancer (HNPCC) tumours, has been proposed. Objectives To characterize clinically and ⁄ or by molecular biology the patients with MM belonging to a cohort of 60 kindreds with HNPCC. Methods Patients with HNPCC with a diagnosis of MM were studied by immuno- histochemistry (IHC) on tumour tissue using antibodies to MLH1, MSH2, p16, b-catenin and E-cadherin, and by direct sequencing of MMR genes on germline DNA, and BRAF and NRAS on somatic DNA extracted from MM. Results Nine cutaneous MMs were detected in the tumour spectrum of eight fami- lies with HNPCC. The median age at diagnosis was 46 years. In one HNPCC fam- ily the diagnosis of MM was made in two first-degree relatives fitting the clinical definition of familial melanoma. IHC and sequencing analysis showed an MSH2 mutation in one patient with MM. Conclusions Dermatological surveillance should be recommended to families in which MM is diagnosed in at least one member, especially at a young age. The combination of MMR gene mutations and abnormalities of p16 or other molecu- lar pathways is needed to induce melanocytic carcinogenesis in a familial setting as well as in sporadic MM. Genetic and familial factors are crucial in the development of cutaneous carcinogenesis. About 10% of malignant melanomas (MMs) develop in a familial setting, often associated with atypical or dysplastic naevi. 1 Features associated with familial MMs include the diagnosis of MM in two or more first-degree relatives, an early age at diagnosis, the association with multi- ple atypical naevi and the diagnosis of multiple MMs in the same individuals. 2 Clinical diagnosis of familial MM requires the onset of MM in at least two first-degree relatives or in three relatives inde- pendently of the degree. The tumour spectrum associated with familial MM includes pancreatic adenocarcinomas, ocular MM and neural system tumours (astrocytoma, medulloblastoma, glioblastoma multiforme, ependymoma, glioma, meningioma and acoustic neurilemmoma). 3 Molecular pathogenesis of familial MM is linked to germline CDKN2A mutations in about 25% of cases. This gene encodes for p16 and p14 proteins that regulate the cell cycle. 4 Other less relevant genes involved in the pathogenesis of familial MM are CDK4 genes and MC1R. 5,6 Somatic mutations have been detected in MAPK path- way genes as well as in the BRAF gene. In addition to the genetic conditions described above, fur- ther genetic disorders confer a high susceptibility to cutaneous MMs. Patients with the rare disease xeroderma pigmentosum have a defect in the DNA repair mechanism that is inherited in an autosomal recessive manner, and they develop numerous malignant skin tumours including MM within the first 20 years of life. 7 Other genetic disorders include Cowden syndrome linked to PTEN gene mutation, hereditary breast–ovarian cancer syndrome linked to BRCA2 germline mutations, Li-Fraumeni syndrome due to p53 mutations, MEN1 (multiple endocrine neoplasia type 1) syndrome and MAP (MYH-associated polyp- osis) syndrome caused by mutations of the base excision repair gene named MYH. 8 There is some evidence to include MM in the tumour spectrum of Lynch syndrome where the tumori- genesis is the result of mutations of mismatch repair (MMR) Ó 2008 The Authors 162 Journal Compilation Ó 2008 British Association of Dermatologists • British Journal of Dermatology 2008 159, pp162–168