Prognostic significance of allelic losses in primary melanoma

Abstract

Loss of genetic material, including loss of loci on chromosome arms 6q, 9p, and 10q, occurs frequently in cutaneous melanoma but infrequently in benign melanocytic nevi or other melanocytic lesions, suggesting that these genetic alterations are important in the development and progression of melanoma. To examine whether allelic loss is of prognostic importance in melanoma, disease-free survival was related to loss of heterozygosity on 6q, 9p and 10q in 83 individuals with sporadic primary cutaneous melanoma. Loss of chromosome arms 6q and 10q were each signi®cantly associated with a poorer clinical outcome (P=0.013 and P=0.001 respectively). In a subgroup of 41 subjects whose primary tumours were allelotyped, the fractional allelic loss (FAL) at 39 autosomal arms also signi®cantly correlated with disease-free survival (P=0.013), with an increase in FAL associated with a poorer outcome; this association remained signi®cant when controlled for tumour thickness (P=0.035). In addition, a greater proportion of cells were immunopositive for Ki67 antigen, p53 and p21 WAF1 protein in the primary melanomas than in the benign melanocytic nevi, however, only p53 overexpression was signi®cantly associated with improved survival (P=0.041).

Cellular senescence in naevi and immortalisation in melanoma: a role for p16?

“…Here, we also report the presence of giant cells, multinucleate cells and heterochromatic foci. From previous publications, naevi show very low expression of proliferative marker Ki67 (Healy et al, 1998), and naevus-cell cultures contain large and multinucleate cells and grow poorly (Gilchrest et al, 1986;Halaban et al, 1986) (reviewed Bennett and Medrano (2002) Figure 3A, top). Little reaction is visible.…”

PTEN/MMAC1 expression in melanoma resection specimens

“…As this tumour suppressor gene is located at chromosome 10q23.3 and melanomas frequently harbour deletions at chromosome 10q22-qter (Isshiki et al, 1993;Herbst et al, 1994;Walker et al, 1995;Healy et al, 1996Healy et al, , 1998 like carcinomas of the prostate (Trybus et al, 1996) and the kidney (Speicher et al, 1994), inactivation of PTEN/MMAC1 has been supposed to occur in melanomas. Actually, deletions and mutations of PTEN/MMAC1 have been found in 29 -43% of investigated melanoma cell lines (Guldberg et al, 1997;Tsao et al, 1998;.…”

“…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).…”

Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma

“…This is, to our knowledge, the ®rst demonstration of somatic mutations in the LKB1/STK11 gene, and our ®ndings substantiate the notion (Jenne et al, 1998;Hemminki et al, 1998) that LKB1/STK11 may be a tumour suppressor involved in the development of human cancer. The low mutation frequency, together with the previously observed low frequency of LOH at 19p in primary melanoma and benign melanocytic nevi (Healy et al, 1996), suggests that LKB1/STK11 may be a relatively rare target in malignant melanoma. It remains to be elucidated whether LKB1/STK11 is part of a molecular pathway with a central role in melanoma pathogenesis.…”