Affiliation of authors: Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden.
Correspondence to: Kari Hemminki, M.D., Ph.D., Karolinska Institute, Department of Biosciences at Novum, 141 57 Huddinge, Sweden.
Berwick and Vineis (1) recently summarized results from human studies on DNA repair and cancer susceptibility markers. They carefully discussed the aspects relating to technical validity, such as reproducibility, sample size, and selection of control subjects. However, the primary question about the biologic relevance of the assay systems used was discussed in only a few sentences. Of the 64 tabulated studies, three reported DNA polymorphisms, two reported cultured fibroblast assays, two reported kinetics from skin biopsies in situ, and the remaining 57 were different types of lymphocyte assays. The lymphocyte assays have been carried out to make inferences about DNA repair functions in other organs in situ. Circulating lymphocytes are dormant cells and any functional tests on them require extensive in vitro manipulation. The relevance of the tests remains to be established, in spite of the large number of times that they have been used. A relevant repair test measures removal of specific DNA damage in the target organ, when it has been demonstrated that DNA repair is the only means of damage removal (i.e., the adduct is chemically stable and no appreciable cell death and replication takes place). The two cited studies using kinetic tests on skin biopsies do fulfill the criterion of biologic relevance.
Recently, a repair test was developed by measuring the removal of specific UV radiation (UVR)-induced DNA damage in human skin in situ (2). The method was based on the 32P-postlabeling technique in which two cyclobutane pyrimidine dimers, T = T and T = C, and two 6-4 photoproducts, TT and TC, were quantified based on external standards. Many of the findings challenge results from earlier, published in vitro assays. Repair kinetics of dimers and 6-4 photoproducts encompassed fast and slow components, probably relating to repair of transcribed and nontranscribed sequences, respectively (3). Dimers were removed considerably more slowly than 6-4 photoproducts, with 50% removal times of approximately 15 and 5 hours, respectively; dimers at TT sites were repaired slower than those at TC sites (3). A 20-fold interindividual variation in repair rates was observed. Because we have applied this test to relatively small numbers of case subjects and matched control subjects, we need to refrain from making general conclusions. However, age does not cause a decline in repair of UVR damage in situ, in contrast to results from the host-mediated assay (4). As evidence of further contradictions, basal cell carcinoma patients have not displayed lower rates of DNA repair (5), and melanoma patients appear to repair DNA damage like healthy matched control subjects (6). The most recent development is a postlabeling assay for excreted urinary photoproducts, informative of the total-body UV damage (7).
Valid DNA repair tests will also be exceedingly valuable to analyze the functional effects of DNA repair gene polymorphisms, which is currently a popular research area. Here we concur with Berwick and Vineis who state, in reference to the bewildering literature on attempts to match metabolic genotypes to risk of any cancers: "It is not clear that conducting these studies without concomitant studies of expression and/or function will be fruitful." Conducting DNA repair tests in the relevant human organs will be fruitful and relevant.
REFERENCES
1
Berwick M, Vineis P. Markers of DNA repair and susceptibility to cancer in humans: an epidemiologic review. J Natl Cancer Inst 2000;92:87497.
2 Bykov VJ, Jansen CT, Hemminki K. High levels of dipyrimidine dimers are induced in human skin by solar-simulating UV radiation. Cancer Epidemiol Biomarkers Prev 1998;7:199202.[Abstract]
3
Bykov VJ, Sheehan JM, Hemminki K, Young AR. In situ repair of cyclobutane pyrimidine dimers and 6-4 photoproducts in human skin exposed to solar simulating radiation. J Invest Dermatol 1999;112:32631.
4 Xu G, Snellman E, Bykov VJ, Jansen CT, Hemminki K. Effect of age on the formation and repair of UV photoproducts in human skin in situ. Mutat Res 2000;459:195202.[Medline]
5
Xu G, Snellman E, Jansen CT, Hemminki K. Levels and repair of cyclobutane pyrimidine dimers and 6-4 photoproducts in skin of sporadic basal cell carcinoma patients. J Invest Dermatol 2000;115:959.
6
Xu G, Snellman E, Bykov VJ, Jansen CT, Hemminki K. Cutaneous malignant melanoma patients have normal repair kinetics of ultraviolet-induced DNA damage in skin in situ.J Invest Dermatol 2000;114:62831.
7 Hemminki K, Xu G, Le Curieux F. Ultraviolet radiation-induced photoproducts in human skin DNA as biomarkers of damage and its repair. IARC Sci Publ. No. 154. In press 2000.
This article has been cited by other articles in HighWire Press-hosted journals:
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |