Genetics of melanoma

Abstract

Melanoma may cluster in families with 'family cancer syndromes' in which there is a predisposition to a variety of different tumours. Other families seem vulnerable to melanoma alone. In the majority of these families, the propensity to melanoma is associated with the presence of abnormal melanocytic naevi, the so-called atypical mole syndrome (AMS) phenotype. However, in a smaller number of families, individuals are susceptible to melanoma but have normal naevi. There appears, therefore, to be clinical (and probably genetic) heterogeneity. Segregation analysis does not support a predisposition by single dominant gene as an explanation for the AMS/melanoma syndrome. To date, a single gene which is clearly important for susceptibility to melanoma has not been identified. Karyotypic studies of melanoma tumours have pointed to chromosomes 1, 6, 7, 9 and 10 as possible sites for melanoma related genes. Loss of heterozygosity studies have suggested that chromosome 9 may carry a tumour suppressor gene important in familial disease, and linkage studies appear to confirm this. It is not yet clear, however, what percentage of familial melanoma is attributable to this gene. A more longstanding suggestion that a gene on chromosome 1 may be important has not been confirmed, but a chromosome/gene may be responsible for susceptibility in a small subset of melanoma families. Even within AMS families, there is a lack of concordance between the AMS phenotype and susceptibility to melanoma. This might be explained either by the effects of modifying genes, or the environment.

KLF6 Gene and Early Melanoma Development in a Collagen I-Rich Extracellular Environment

“…Melanoma is the most aggressive and deadly form of skin cancer (1). Melanoma results from accumulating genetic alterations that lead to gene deregulation, cancer development, and tumor progression (1).…”

“…Melanoma results from accumulating genetic alterations that lead to gene deregulation, cancer development, and tumor progression (1). Some genetic alterations remove or deregulate proteins that are involved in signaling from the extracellular matrix to enable cancer development (2).…”

“…Some genetic alterations remove or deregulate proteins that are involved in signaling from the extracellular matrix to enable cancer development (2). Loss of all or part of chromosome 10 is observed in 30%-60% of nonfamilial melanomas (1,(3)(4)(5). Discrete regions of chromosome 10 at 10q23 and 10p15 that were identified previously as potential sites of cancer suppressor genes in melanoma (3) led to the identification of PTEN tumor suppressor gene at 10q23 (6)(7)(8).…”

PTEN/MMAC1 expression in melanoma resection specimens

“…Genomic regions that exhibit losses of heterozygosity (LOH) and therefore suggest the presence of tumour suppressor genes in sporadic melanomas, have been identified, among others, at chromosomes 6q22-27 (Albino et al, 1994) and 11q22-23 (Robertson et al, 1999). Moreover, LOHs at chromosome 10 occur in 30 -60% of both early-and advanced-stage tumours (Newton, 1994;Bastian et al, 1998) and are an indicator of a poor clinical prognosis (Healy et al, 1998). Segmental deletions were cytogenetically localized to 10q (Richmond et al, 1986;Parmiter et al, 1988;Isshiki et al, 1993;Indsto et al, 1998) and subsequently narrowed by studies of LOH to 10q22-qter (Isshiki et al, 1993;Herbst et al, 1994;Walker et al, 1995;Healy et al, 1996).…”

Mutation testing in melanoma families: INK4A, CDK4 and INK4D

“…Rare families exist in which there appears to be a predisposition to cutaneous melanoma (Clark et al, 1978;Newton, 1994). In some families, there is an apparent susceptibility to other tumours, particularly to pancreatic (Lynch and Fusaro, 1991) and other gastrointestinal cancers ), but in most families the susceptibility appears to be to melanoma alone.…”