Gene-Environment Interactions in the Development of Skin Cancer

Karl T. Kelsey, Ph.D.
Harvard School of Public Health
NIEHS Grant P30ES00002

Background: The incidence of non-melanoma skin cancer (NMSC) has been increasing at an alarming rate over the past 50 years. This trend indicates that NMSC is increasingly becoming a public health problem. NMSC primarily results from exposure to UV radiation from the sun; however, there are other factors involved such as ionizing radiation, arsenic exposure, tendency to burn, and DNA repair capacity.

Recent studies have shown that a single nucleotide base difference, or polymorphism, in the code for a specific gene may alter DNA repair capability. Further research has identified three polymorphisms of the gene, known as XRCC1. The polymorphism results in a substitution at the 399th amino acid of the protein. The arg399gly polymorphism has been associated with cancers of the head and neck, breast, lung, bladder, stomach, and the colorectal region. The role of the gly399gly XRCC1 is unclear because in some studies it has had a protective effect, increased risk in some studies, and shown no association in others. To address this inconsistency, these investigators performed a case-control study of NMSC.

Advance: NMSC cases were derived from a survey of all newly diagnosed cases of NMSC in New Hampshire. Environmental exposure history was obtained through a questionnaire which included information on sunburn and exposure to therapeutic ionizing radiation. In summary, the data show that the homozygous gln399gln XRCC1 variant is associated with lower risk of NMSC and suggests that the etiology of sunburn-related squamous cell carcinoma may be significantly different by XRCC1 genotype.

Implication: This study of a classic skin cancer model, provides new insights into the role of the XRCC1 399 polymorphism and may help to explain the conflicting results relating this polymorphism to various types of cancer. The function of the polymorphism is likely to vary by disease, ethnicity, and geography. Additional laboratory-based and larger population-based studies are needed to confirm these findings both in skin cancer and other environmentally-induced cancers.

Citation: Nelson HH, Kelsey KT, Mott LA, Karagas MR. The XRCC1 Arg399Gln polymorphism, sunburn, and non-melanoma skin cancer:evidence of gene-environment interaction.Cancer Res. 2002 Jan 1;62(1):152-5.