(31) KYU LN, KANAMARU H, YOSHIDA O: Assessment of the response of human bladder cancer cell lines to radiation using colony formation assay and [3H]thymidine incorporation assay. Hinyokika Kiyo 34:32-36, 1988

(35) HILDEBRAND-ZANKI SU, KERN DH: In vitro assays for new drug screening: Comparison of a thymidine incorporation assay with the human tumor colony-forming assay. Int J Cell Cloning 5:421^31, 1987

(32) KANAMARU H, HASHIMURA T, KAKEHI Y, ET AL: In vitro chemosensitivity

(36) WITTES RE, ADRIANZA ME, PARSONS R, ET AL: Compilation of phase II

test by human tumor colony forming assay. Hinyokika Kiyo 34:19171921,1988 (33) KERN DH, WEISENTHAL LM: Highly specific prediction of antineoplastic drug resistance with an in vitro assay utilizing suprapharmacologic drug exposures. J Natl Cancer Inst 82:582-588, 1990

results with single anti-neoplastic agents. Cancer Treat Sympos 4:12-35. 1985 (37) UNGERLEIDER RS, FRIEDMAN MA: Sex. trials, and datatapes. J Natl Cancer Inst 83:16-17. 1991

(34) SONDAK VK, BERTELSEN CA, TANIGAWA N, ET AL: Clinical correlations

vanced ovarian cancer: An overview of randomized clinical trials. Br Med J 303:884-893, 1991 (39) IFFY L: Randomized clinical trials. N Engl J Med 325:1513-1516, 1991

with chemosensitivities measured in a rapid thymidine incorporation assay. Cancer Res 44:1725-1728, 1984

Sandra R. Wolman, Gloria H. Heppner* A recurrent theme in recent cancer research is that genetic changes accompany, and presumably drive, the development of a neoplasm and its ensuing progression to an increasingly malignant phenotype. These changes fall broadly into two categories: those which add new potential to the behavioral repertoire of cancer cells and those which remove a regulatory influence, allowing cells to exhibit behavior that would otherwise be restrained. This latter group of changes is attributed to the loss of "suppressor genes," a designation which presupposes that cells are potentially cancerous but are somehow prevented from acting upon that potential. The primary function of suppressor genes may, in fact, be the regulation of normal cellular behavior that is restricted to certain tissues or stages of development. The existence of suppressor function is inferred by gene loss in tumors. Suppressor genes are detected by screening for loss of heterozygosity (LOH) at specific chromosomal loci. In this issue of the Journal, Chen and associates (/) describe LOH, ranging in frequency from 21% "to 51%, at six regions in the genome of primary human breast cancers. The background frequency of LOH in this series, as determined by the loss of some "randomly selected" sites, is 4%. Findings by others in retinoblastoma, Wilms' tumor, colon cancer, and other tumors implicate suppressor genes as major factors in many types of neoplasms (2,5), including breast cancer (4). Another recurrent theme in cancer research, both recent and not so recent, is the variability or heterogeneity of the neoplastic phenotype. Heterogeneity is evident among histologically similar cancers from different patients (intertumor heterogeneity) and among different cells of the same cancer at a single time (intratumor heterogeneity), as well as at different points in time (progression). The mechanisms underlying neoplastic heterogeneity are many; they include classical Vol. 84, No. 7, April 1, 1992

genetic (5), adaptive (6), and (micro-) environmentally determined events (5,7). Both themes — heterogeneity and genetic loss — appear in the report of Chen and co-workers (/), specifically in relation to LOH in breast cancer. Chen et al. analyze the frequency and distribution of LOH at multiple alleles within a series of primary breast cancers and lymph node metastases. Their results should be considered in the context of a rapidly growing literature on the same topic. For example, although 98 tumors might suffice with highly informative probes, many of the probes cited here are expected to be informative in one third or fewer of the cases. Furthermore, in their brief report, it is not possible to discern, case by case, the association of LOH in primary cancers with clinical or pathological characteristics, with intratumor heterogeneity, or with LOH in metastases. It would be fascinating to know whether intratumor heterogeneity for LOH in a primary cancer is recapitulated in its metastases or, indeed, whether such heterogeneity occurs in metastases at all. What is the relationship between LOH in primary cancers and the incidence of metastases? Are there informative primary tumors without LOH that have metastasized? Is there an association between LOH and clinical stage? The limited clinical and pathologic descriptions presented compromise the biological significance of the molecular data. The relevance of intratumor heterogeneity in terms of LOH should only be evaluated in relation to data on the percentage of cancer cells per individual tumor sample. This variable can influence the detection of LOH, particularly if LOH is present in only a minor subpopulation. Simulation experiments, in which -cancer samples with LOH at different loci are deliberately contaminated with varying amounts and types of adjacent normal tissues, could perhaps aid in setting the technical limitations of the analyses. Additional insight might also be gained if LOH heterogeneity were associated with other evidence of intratumor heterogeneity — for example, of morphology, tumor grade, or estrogen receptor expression.

Received February 25, 1992; accepted February 27, 1992 S. R. Wolman, M.D., Department of Pathology, Wayne State University School of Medicine, Detroit, Mich. G. H. Heppner, Ph.D., The Breast Cancer Program, Meyer L. Prentis Comprehensive Cancer Center of Metropolitan Detroit. *Correspondence to: G. H. Heppner, Ph.D., Michigan Cancer Foundation, 110 East Warren Ave., Detroit, MI 48201.

EDITORIALS 469

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Genetic Heterogeneity in Breast Cancer

(38) ADVANCED OVARIAN CANCER TRIALISTS GROUP: Chemotherapy in ad-

ability one might expect for a single locus in a relatively small series of patients. In addition, several authors have commented on the complexity and variable location of losses from l i p (10,11). For example, Larsson et al. (9) found no losses at the region probed in the Chen study and 21 % loss at the nearby INS locus (also 1 lpl5.5). Intratumor heterogeneity for LOH now appears as a possible addition to the long list of characteristics that are heterogeneous in their distribution within neoplasms. The fundamental issue in understanding the biological meaning of LOH heterogeneity will depend on whether it is shown to be selective in tumor evolution or is simply a passive byproduct of other mechanisms such as genetic instability.

References (/) CHEN L, KURISU W, LJUNG B-M, ET AL: Heterogeneity for allelic loss in human breast cancer. J Natl Cancer Inst 84:506-510, 1992 (2) SAGER R: Tumor suppressor genes: The puzzle and the promise. Science 246:1406-1412,1989 (3) WEINBERG RA: Tumor suppressor genes. Science 254:1138-1146, 1991 (4) WOLMAN SR, DAWSON PJ: Genetic events in breast cancer and their clinical correlates. Crit Rev Oncog 2:277-291, 1991 (5) NOWELL PC: The clonal evolution of tumor cell populations. Science 194:23-28, 1976 (6) FARBER E, RUBIN H: Cellular adaptation in the origin and development of cancer. Cancer Res 51:2751-2761, 1991 (7) HEPPNER GH: Tumor heterogeneity. Cancer Res 44:2259-2265, 1984 (8) VOGELSTEIN B, FEARON ER, KERN SE, ET AL: Allelotype of colorectal carcinomas. Science 244:207-211, 1989 (9) LARSSON C, BYSTROM C, SKOOG L, ET AL: Genomic alterations in human breast carcinomas. Genes Chromosom Cancer 2:191-197, 1990 (10) DEVILEE P, VAN DEN BROEK M, KUIPERS-DUKSHOORN N, ET AL: At least four different chromosomal regions are involved in loss of heterozygosity in human breast carcinoma. Genomics 5:554—560, 1989 (11) MACKAY J, ELDER PA, PORTEOUS DJ, ET AL: Partial deletion of chromosome 1 lp in breast cancer correlates with size of primary tumour and oestrogen receptor level. BrJ Cancer 58:710-714, 1988 (12) THEILLET C, LIDEREAU R, ESCOT C, ET AL: LOSS of a c-H-ras-1 allele and aggressive human primary breast carcinomas. Cancer Res 46:4776-4781, 1986

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scientist's home institution or by a European gran ing agency For American awardees. the host institution must be affiliated with the EORTC. Documentation The following documents are required, in English, from all applicants: • Completed application form. • Description of the research to be undertaken, nc to exceed three typewritten pages. • Letter of invitation from the prospective host. • Agreement to release the applicant from the home institution for the duration of the exchangeship • Assurance of intention to return to the home institution at the end of the exchangeship.

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The data of Chen et al. (/) in Table 4 of their report, showing heterogeneous distribution of partial LOH, are most intriguing when compared with the data on total LOH shown in their Table 3. The percentage of cases with partial loss appears inversely correlated with that for total loss: For probes 17p, 3p, 22q, and lq the percentages of informative cases with partial loss are 14%, 14%, 33%, and 43%, whereas for the same probes the total losses are 51%, 46%, 38%, and 26%, respectively. If one assumes that partial loss precedes total loss, then these data suggest an ordered sequence in which 17p and 3p losses tend to precede 22q and lq losses. This interpretation contrasts with the authors' comment that "the aberrations may be acquired in variable sequence." Another thought-provoking observation in this report is the background LOH of 4%, which is far lower than that reported in colon cancer (8). However, studies of breast cancer exhibit inconsistency in the criteria for establishing a baseline for that background. One group derived a baseline mean of 13% LOH from averaging all loci examined (9), whereas others have assumed biological significance for tumors with LOH greater than 20% (10). The background loci described by Chen et al. have been reported as regions with "complete or near-complete absence of LOH" (70). Is it possible that these low-loss regions are protected from LOH, rather than neutral as implied? Alternatively, if the baseline is truly lower than for other common cancers, might this situation reflect relative genetic stability in breast tumors, many of which are slowly growing and poorly mitotic? In contrast to others, Chen et al. did not find significant LOH at l i p . Although they suggest that their cases may represent early disease, this is not borne out by the 43% incidence of lymph node metastases in their patient population. The low frequency of LOH (two of 35 informative cases) in this study, compared with seven of 37 (10), 14 of 65 {11), and 14 of 51 (12) at the same locus, is not outside the realm of statistical vari-

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Genetic heterogeneity in breast cancer.

(31) KYU LN, KANAMARU H, YOSHIDA O: Assessment of the response of human bladder cancer cell lines to radiation using colony formation assay and [3H]th...
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