We identified germline mutations in highly CM-associated genes (CDKN2A and CDK4) and low/medium-penetrance variants (MC1R and MITF) in patients with multiple primary CMs or individuals with one or more CM and a positive family history for CM or pancreatic cancer among first- or second-degree relatives.
To examine for the genetic basis of metastatic progression in cutaneous melanoma, we have compared loss of heterozygosity (LOH) of several selected chromosome regions that are implicated in the initiation and progression of melanoma, and alterations of the p16INK4a gene in 14 pairs of primary tumor and synchronous or asynchronous metastasis excised from the same patients.
Germ-line mutations in CDKN2A predispose to the familial atypical multiple-mole melanoma (FAMMM) syndrome but also have been seen in rare families in which only 1 or 2 individuals are affected by cutaneous malignant melanoma (CMM).
Retention of the CDKN2A locus was found in 10 (47%) tumours with deletions at one or both sides of CDKN2A, suggesting that loss of this gene is not involved in CMM-tumour initiation and that another tumour-suppressor gene involved in melanoma is located at 9p21.
Germline mutations within the CDKN2A gene, coding for the cyclin-dependent kinase inhibitor p16, have been detected by screening in 8% of Swedish families with an inheritance of cutaneous melanoma (FMM) and dysplastic nevus syndrome (DNS).
Mutations in the cyclin-dependent kinase inhibitor-2A (CDKN2A) gene have been associated with a number of malignancies, most notably cutaneous malignant melanoma (CMM).
Evidence for comorbid OM and CM exists in patients with strong phenotypic expression of atypical nevi and conjunctival melanoma, although CDKN2A mutations have not been documented in patients with OM.
It is known that the pRb pathway cell-cycle inhibitor p16(INK4A) plays a significant role in cutaneous melanoma and that alteration of p16(INK4A), which resides within the 9p21-22 locus that also contains p15(INK4B) and p14(ARF), may occur in up to one third of uveal melanomas.