Abstract 1787: Prevention of skin cancer in xeroderma pigmentosum: A long-term study of fourteen patients
Authors: Lambert W Clark , Anderson Randal , Lambert Muriel W. 
Published: May 2015

Abstract
Xeroderma pigmentosum (XP) is a multigenic, recessively inherited precancerous disorder occurring in approximately 4 per million live births in the United States with higher rates in Japan, the Middle East, and regions of Latin America. Eight separate genetic subgroups, known as complementation groups, each due to a mutation in a separate gene and associated with a defect in a separate protein encoded by that gene are known at present, but the biology may be considerably more complex, with other genes not yet identified and other defective genes and proteins simultaneously involved. The seven known “classical” complementation groups, identified as XP-A to XP-G, are associated with defective nucleotide excision type DNA repair(NER) of adducts induced into the DNA of sun exposed cells by ultraviolet radiation in sunlight, whereas the eighth complementation group, designated the “variant” group, XP-V, is associated with defective DNA synthesis bypassing such adducts in a process known as “trans-lesion synthesis” (TLS); some of these patients have been shown to have a defective DNA polymerase, pol eta, which is primarily responsible for this TLS in normal human cells. Depending on the severity of the disease and the degree of sun protection, XP patients have historically been known to be markedly susceptible to skin and other cancers in sun-exposed areas, with hundreds or even thousands of such cancers developing early in life, often in early childhood. EXPERIMENTAL DESIGN AND METHODS: Over ten years ago we began to apply topical 5 fluorouracil (5-FU), 2 to 8 percent, once or twice per day for two to three weeks every three to six months, as tolerated, topically to sun exposed areas of children with XP, identified clinically and/or by cellular functional assays testing fibroblasts removed from these subjects and grown in culture. Topical 5-FU is known to sensitize normal immunity, producing focal inflammation at sites of developing skin cancers; such skin cancers, or their precursors, actinic keratoses, then tend not to arise at these sites. Some XP patients do not experience focal inflammation but are protected from development of skin cancer by a second mechanism. More recently we have alternatively applied imiquimod (IQ), 2 to 5 percent, topically to these same sites. IQ acts as an immune response modifier in a manner analogous to that of topical 5-FU. Fourteen patients have now been treated for over 5 years. RESULTS: Over 5 to nine years, the 14 patients have developed a total of 88 skin cancers, all non-melanoma skin cancers and all removed at early stages with minimal morbidity, even though DNA repair related, “unscheduled DNA synthesis” (UDS) was as low as two percent. Thousands of skin cancers were expected in this group without this intervention. Skin inflammation was also reduced. CONCLUSION: Skin cancer may be effectively prevented in XP patients using topical immune response modifiers such as topical 5-FU or IQ.
Citation Format: W Clark Lambert, Randal Anderson, Muriel W. Lambert. Prevention of skin cancer in xeroderma pigmentosum: A long-term study of fourteen patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1787. doi:10.1158/1538-7445.AM2014-1787