Loss of expression of the metastasis suppressor gene KiSS1 during melanomaprogression and its association with LOH of chromosome 6q16.3-q23

KiSS1 is a putative melanoma metastasis suppressor gene, the expression of which may be regulated by another gene(s) mapping to chromosome 6q16.3-q23. To additionally elucidate the role of KiSS1 in the progression of human me lanoma in vivo, we examined KiSS1 mRNA expression in 51 melanocytic tumors with various stages of progression by in situ hybridization. We also examin ed a correlation between loss of KiSS1 mRNA expression and loss of heterozy gosity (LOH) of 6q16.3-q23 in 27 melanoma metastases. All of the four nevoc ellular nevi and eight primary melanomas < 4 mm in thickness showed KiSS1 m RNA expression, whereas only 50% (6 of 12) of primary melanomas > 4 mm in t hickness expressed KiSS1. Loss of KiSS1 mRNA was equally frequent in metast ases; 44% (12 of 27) of tumors lost KiSS1 expression. LOH of 6q16.3-q23 was observed in 52% (14 of 27) of metastases. There was a strong association b etween LOH and loss of KiSS1 expression (P = 0.03); nine metastases with LO H of 6q16.3-q23 lost KiSS1 expression, whereas 10 tumors with no LOH showed positive KiSS1 mRNA expression. The findings in this study show, for the f irst time, KiSS1 downregulation during the progression of melanoma in vivo and strongly suggest that inactivation of a tumor suppressor gene(s) mappin g to 6q16.3-q23 by deletion or mutation coupled with LOH may lead to the do wn-regulation of KiSS1.