The relationship between skin color and skin cancer is well established: the less melanin in one’s skin the greater the risk for developing skin cancer.,This review is in two parts.,First, we summarize the current understanding of the cutaneous pigmentary system and trace melanin from its synthesis in the pigment cell melanosomes through its transfer to keratinocytes.,We also present new methods for reducing melanin content in hyper-pigmented areas of skin such as solar lentigenes, melasma, and post-inflammatory hyperpigmentation.,Second, we present evidence that at least one mechanism for the development of metastatic melanoma and other solid tumors is fusion and hybridization of leucocytes such as macrophages with primary tumor cells.,In this scenario, hybrid cells express both the chemotactic motility of the leucocyte and the de-regulated cell division of the tumor cell, causing the cells to migrate a deadly journey to lymph nodes, distant organs, and tissues.
Xeroderma pigmentosum (XP) is a rare, autosomal recessive disorder of DNA repair characterized by sun sensitivity and ultraviolet (UV) induced skin and mucous membrane cancers.,Described in 1874 by Moriz Kaposi in Vienna, nearly 100 years later James Cleaver in San Francisco reported defective DNA repair in XP cells.,This eventually provided the basis for a mechanistic link between sun exposure, DNA damage, somatic mutations and skin cancer.,XP cells were found to have defects in 7 of the proteins of the nucleotide excision repair pathway and in DNA polymerase eta.,XP cells are hypersensitive to killing by UV and XP cancers have characteristic “UV signature” mutations.,Clinical studies at NIH found a nearly 10,000-fold increase in skin cancer in XP patients under age 20 years demonstrating the substantial importance of DNA repair in cancer prevention in the general population.,About 25 % of XP patients have progressive neurological degeneration with progressive loss of neurons, probably from DNA damage induced by oxidative metabolism which kills non-dividing cells in the nervous system.,Interestingly, patients with another disorder, trichothiodystrophy have defects in some of the same genes as XP but they have primary developmental abnormalities without an increase in skin cancer.