© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 19, 1492-1493,
October 3, 2001
© 2001 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Biomarker Risk Assessment and Bladder Cancer Detection in a Cohort Exposed to Benzidine
Correspondence to: George P. Hemstreet III, M.D., Ph.D., 1009 Outabounds Dr., Edmond, OK 73034 (e-mail: gphemstreet{at}hotmail.com).
The comments by Dr. Nersesyan regarding cytogenetic biomarkers focus on a number of frequently underappreciated issues related to biomarker research. However, a central theme of the comments and our published work (1) is biomarker specificity and sensitivity. Potential biomarkers for bladder cancer, including chromosomal aberrations, and a meta-analysis of the more frequently used biomarkers have recently been reviewed (2,3). Currently, there are numerous promising biomarkers, but few have undergone phase II or III validation studies. In one phase II study, Halling et al. (4) compared cytology and fluorescence in situ hybridization (FISH) for the detection of genetic ploidy in urothelial carcinomas and reported that FISH had a sensitivity of 81% and a specificity of 96%. Similarly, Vysis Inc. (Downers Grove, IL) received U.S. Food and Drug Administration (FDA) approval to market FISH in a bladder cancer biomarker profile for detecting aneuploidy of chromosomes 3, 7, and 17 and loss of chromosome 9p21 and reported a sensitivity of 73.5%–75% and a specificity of 93% (package insert). The acceptance of FISH for chromosomal analysis and other tests depends on multiple parameters that relate primarily to the population studied, specificity, sensitivity, assay reliability, and cost [see references in (1)].
Most biomarkers for bladder cancer are evaluated initially in symptomatic patients and, thus, their performance for risk assessment, screening, and validation in asymptomatic patients remains to be determined. Although there are also encouraging clinical results with other biomarkers since the initiation of our study of Chinese workers in 1989 [see references in (1)], some markers, such as G-actin, that had shown great promise in earlier studies functioned poorly in later studies for as yet unknown reasons. This finding highlights the complexity of biomarker selection and evaluation. The two other biomarkers we focused on in our study (1), p300 and DNA ploidy, have both stood the test of time, are approved by the FDA, and are commercially available in a number of boutique laboratories with accessible reagents.
Cytogenetic biomarkers are the result of inherited susceptibility factors and exposures and should be clearly distinguished from inherited genetic factors (5). Of interest, the markers with high specificity and sensitivity appear to be associated with gross chromosomal aberrations or high-level phenotypic biomarkers, rather than point mutations. This observation is highly relevant to the mechanisms of bladder carcinogenesis, which may be elucidated by quantitative fluorescence image analysis. For example, because bladder cancers and most other solid tumors are heterogeneous, fluorescence imaging may assist in linking protein expression profiles to functional genomics by quantifying proteins expressed at the single cell level (proteomics).
Specificity is not only dependent on the methods but also on the cell type analyzed. Most clinicians consider atypical Pap cytology a major confounding report because of the poor specificity of the test. In our study (1), the inclusion of atypical Pap results reduced the specificity of the biomarker profile. For this reason, biomarkers can be used to subclassify atypical cells, which, once again, stresses the importance of linking the cytologic, genetic, or phenotypic biomarkers to quantitative biophysical cytochemistry. In a subset of patients from our study of Chinese workers, Li evaluated peripheral blood lymphocytes and cytogenetic studies to detect bladder cancer and found the test to be tedious and, in general, lacking specificity (Li G: unpublished observation). However, these studies served to illustrate the differential susceptibility of a target organ to genetic damage and the relevance of studying functional genomics and proteomics in the context of a defined organ ecosystem.
In reference to benzo[a]pyrenes, they are currently under intense investigations as human carcinogens (6). The 20%–25% cancer rate cited in our study (1) referred to occupational exposure overall and is the number frequently quoted (7).
REFERENCES
1
Hemstreet GP 3rd, Yin S, Ma Z, Bonner RB, Bi W, Rao JY, et al. Biomarker risk assessment and bladder cancer detection in a cohort exposed to benzidine. J Natl Cancer Inst 2001;93:427–36.
2 Cordon-Cardo C, Cote RJ, Sauter G. Genetic and molecular markers of urothelial premalignancy and malignancy. Scand J Urol Nephrol Suppl 2000;205:82–93.
3 Lotan Y, Roehrborn CG. Sensitivity and specificity of commonly available bladder tumor markers versus cytology: results of a comprehensive literature review and meta-analysis. J Urol 2001;165–6.
4 Halling KC, King W, Sokolova IA, Meyer RG, Burkhardt HM, Halling AC, et al. A comparison of cytology and fluorescence in situ hybridization for the detection of urothelial carcinoma. J Urol 2000;164:1768–75.[CrossRef][Web of Science][Medline]
5 U.S. National Research Council. Subcommittee on biological markers in urinary toxicology. Biologic markers in urinary toxicology. Washington (DC): National Academy Press; 1995.
6 Kazerouni N, Sinha R, Hsu CH, Greenberg A, Rothman N. Analysis of 200 food items for benzo[a]pyrene and estimation of its intake in an epidemiologic study. Food Chem Toxicol 2001;39:423–36.[CrossRef][Web of Science][Medline]
7 Vineis P, Pirastu R. Aromatic amines and cancer. Cancer Causes Control 1997;8:346–55.[CrossRef][Web of Science][Medline]
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