Sunlight and Cutaneous Malignant Melanoma: Evidence for and Against Causation

Koh, Howard K.; Kligler, Benjamin; Lew, Robert A.

doi:10.1111/php.1990.51.6.765

Cited by 102 publications

(55 citation statements)

References 95 publications

(58 reference statements)

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“…Heredity, target cell susceptibility, and excessive sunlight exposure are all believed to be factors in cutaneous malignant melanoma (44,45); however, a precise role for each of these factors in melanoma formation has not been established (45). CDKN2A, encoding the p16 gene product, is a strong candidate for a human melanoma susceptibility gene, based on pedigree analyses of families with hereditary melanomas (13,14,46), and genetic and biochemical studies of both hereditary and sporadic melanomas (16,17).…”

Section: Discussionmentioning

confidence: 99%

A CDKN2 -like polymorphism in Xiphophorus LG V is associated with UV-B-induced melanoma formation in platyfish–swordtail hybrids

Nairn

Kazianis

McEntire

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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The genetic basis of spontaneous melanoma formation in spotted dorsal (Sd) Xiphophorus platyfishswordtail hybrids has been studied for decades, and is adequately explained by a two-gene inheritance model involving a sex-linked oncogene, Xmrk, and an autosomal tumor suppressor, DIFF. The Xmrk oncogene encodes a receptor tyrosine kinase related to EGFR; the nature of the DIFF tumor suppressor gene is unknown. We analyzed the genetic basis of UV-B-induced melanoma formation in closely related, spotted side platyfish-swordtail hybrids, which carry a different sex-linked pigment pattern locus, Sp. We UV-irradiated spotted side Xiphophorus platyfish-swordtail backcross hybrids to induce melanomas at frequencies 6-fold higher than occur spontaneously in unirradiated control animals. To identify genetic determinants of melanoma susceptibility in this UVinducible Xiphophorus model, we genotyped individual animals from control and UV-irradiated experimental regimes using allozyme and DNA restriction fragment length polymorphisms and tested for joint segregation of genetic markers with pigmentation phenotype and UV-induced melanoma formation. Joint segregation results show linkage of a CDKN2-like DNA polymorphism with UV-B-induced melanoma formation in these hybrids. The CDKN2-like polymorphism maps to Xiphophorus linkage group V and exhibits recombination fractions with ES1 and MDH2 allozyme markers consistent with previous localization of the DIFF tumor suppressor locus. Our results indicate that the CDKN2-like sequence we have cloned and mapped is a candidate for the DIFF tumor suppressor gene.Genetic hybrids between species of the genus Xiphophorus (Teleostei: Poeciliidae) exhibit spontaneous melanoma formation in several different cross types and have been used for decades to investigate genetic factors contributing to melanoma formation (1). The most studied and best understood Xiphophorus hybrid melanoma is the spotted dorsal GordonKosswig platyfish-swordtail model (2-5), represented by genetic hybrids derived from crossing F 1 hybrids between the platyfish Xiphophorus maculatus Jp 163 A and the swordtail Xiphophorus helleri back to X. helleri. Melanoma formation in this tumor model is genetically controlled by inheritance of a sex-linked receptor tyrosine kinase gene (Xmrk), associated with the spotted dorsal (Sd) pigment pattern locus, and segregation of an autosomal locus in Xiphophorus linkage group (LG) V, variously referred to in the literature as DIFF, R DIFF , and R (3-6). The DIFF locus is believed to regulate macromelanophore pigment cell differentiation (4, 6), and behaves in the Gordon-Kosswig model as a classical tumor suppressor for which loss of species-specific alleles in pigmented backcross hybrids results in melanoma formation according to simple, Mendelian inheritance (1, 3-5).Elegant experiments have shown that Xmrk is a duplicated gene, which has adventitiously acquired the promoter from another gene (7,8). It has been postulated that expression of the oncogenic Xmrk gene duplicate is re...

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Section: Discussionmentioning

confidence: 99%

A CDKN2 -like polymorphism in Xiphophorus LG V is associated with UV-B-induced melanoma formation in platyfish–swordtail hybrids

Nairn

Kazianis

McEntire

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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“…The causal association between sun exposure and malignant melanoma is well-documented, but not fully consistent (Koh et al, 1990). In addition to risk factors such as UV exposure and certain individual characteristics, e.g.…”

Section: Melanoma Inductionmentioning

confidence: 99%

Interaction Between Chemicals and Melanin

Larsson

1993

Pigment Cell Research

261

182

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Various drugs and other chemicals, such as organic amines, metals, polycyclic aromatic hydrocarbons, etc., are bound to melanin and retained in pigmented tissues for long periods. The physiological significance of the binding is not evident, but it has been suggested that the melanin protects the pigmented cells and adjacent tissues by adsorbing potentially harmful substances, which then are slowly released in nontoxic concentrations. Long-term exposure, on the other hand, may build up high levels of noxious chemicals, stored on the melanin, which ultimately may cause degeneration in the melanin-containing cells, and secondary lesions in surrounding tissues. In the eye, e.g., and in the inner ear, the pigmented cells are located close to the receptor cells, and melanin binding may be an important factor in the development of some ocular and inner ear lesions. In the brain, neuromelanin is present in nerve cells in the extrapyramidal system, and the melanin affinity of certain neurotoxic agents may be involved in the development of parkinsonism, and possibly tardive dyskinesia. In recent years, various carcinogenic compounds have been found to accumulate selectively in the pigment cells of experimental animals, and there are many indications of a connection between the melanin affinity of these agents and the induction of malignant melanoma.

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“…It would be ill-advised, without additional experimental data, to conclude that the regular use of these agents will diminish the likelihood of acquiring this serious disease. Few studies have attempted to investigate this issue largely because the relationship between sunlight and melanoma is quite complex and has not been well worked out (19). Without more information about the photopathogenesis of the disorder, most studies that address this issue will be difficult to evaluate.…”

Section: Sunscreens and Melanomamentioning

confidence: 99%

“…Moreover, there are few experimental models for UV-induced melanoma development and for those that do exist, it is unclear how closely they correspond to the human situation (20). Epidemiologic studies in humans suggest that in melanoma, UV acts primarily as a tumor initiator, as brief intense exposure early in life is associated with an increased incidence of the disease (19). However, most animal models for melanoma growth and development require either repeated UV exposure or transplantation of already existing melanomas to a UV-irradiated skin site (20).…”

Section: Sunscreens and Melanomamentioning

confidence: 99%