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Somatic Mutations Detected by Mini- and Microsatellite DNA Markers Reveal Clonal Intratumor Heterogeneity in Gastrointestinal Cancers¹

Division for Clinical and Experimental Research [S. N., M. O.], Department of Pathology [B. B.], Central Haematology Laboratory [A. T.], Institute of Medical Oncology [M. F. F.], Inselspital, Ch-3010, Berne; Department of Surgery [F. N., S. B.], Tiefenauspital, University of Berne, Berne, Switzerland; and Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom [S. L. T.]

We investigated clonal intratumor heterogeneity by comparing different areas of each tumor in 20 gastrointestinal cancers from female patients (1 esophageal cancer, 5 stomach cancers, and 14 colorectal cancers). In all 19 cases informative for X-inactivation analysis with the M27ß and/or the phosphoglycerate kinase probes, the tumors were clonal. Separate areas from a given tumor showed identical X-inactivation patterns, providing evidence for its single-cell origin. Of 20 cancers, 11 showed p53 gene mutations (base pair insertions, point mutations, and one case of a base pair deletion) in exons 5–8. A particular p53 gene mutation was identical in all tumor areas investigated per case. The minisatellite probes detected loss of heterozygosity or new mutant alleles at 1p33, 1q21, 5q35, 17p13, or 18q21. In seven cases mutations at particular loci were restricted to one or two areas per tumor, while in another seven cases they were common to all tumor areas. Loss of heterozygosity or new alleles detected at the microsatellite loci D2S123, D3S1611, D5S107, D17S261, or D18S34 [(CA)_n repeats] were common to all tumor areas in 7 of 19 cases. In another seven cases, however, microsatellite mutations at these loci were restricted to one to three areas per tumor. Tracing clonal intratumor heterogeneity would permit one to study the hierarchy of mutational events in cancers where no premalignant lesions can be harvested. Most important, our study indicates that clonal intratumor heterogeneity might lead to sampling errors in the molecular diagnosis of cancer biopsy specimens when using mini- or microsatellite markers.

¹ Part of this work was presented as an abstract at the 1994 meeting of the American Association for Cancer Research, San Francisco, California and at the 1995 meeting of the American Society of Clinical Oncology in Los Angeles, California. This work was supported by Swiss National Foundation Grants 31-28744.90 (B. B.), 3100-037577.93 (M. F. F.), and 31-32524.91 (A. T.), the Swiss and the Bernese Cancer League as well as The Bernese Foundation for Clinical Cancer Research (S. N., Research Fellow), and the Medical Research Council of the United Kingdom (S. L. T.).

² To whom requests for reprints should be addressed.

Received 12/27/94. Accepted 5/ 3/95.

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