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Modulation of Pro-Epidermal Growth Factor, Pro-Transforming Growth Factor and Epidermal Growth Factor Receptor Gene Expression in Human Renal Carcinomas¹

Molecular Oncology Laboratory, Department of Medicine III, University of Munich Medical School Grosshadern, 8 Munich-70, West Germany [P. E. P., S. B., J. B.]; Institute for Clinical Hematology, GSF, 8 Munich-70, West Germany [P. E. P.]; and Department of Urology, Technical University Medical School, 8 Munich-80, West Germany [R. H., G. J.]

We have analyzed the expression of the genes for the precursors of epidermal growth factor (pro-EGF) and transforming growth factor (proTGF-) as well as for the EGF receptor in tissue specimens of a large number of adult patients with renal cell carcinoma. Since normal kidney tissue was available from the same patients we could directly compare the expression of these genes in tumors with that in adjacent normal renal tissue. Our experiments reveal underexpression of the proEGF gene in all tumors analyzed (21 of 21) and overexpression of the genes for proTGF- (33 of 33 analyzed) and EGF receptor (22 of 23 analyzed) in tumor samples, when compared with normal kidney tissue. The expression of the proTGF- gene appeared to depend on grade and differentiation of the tumor, since well differentiated tumors (grade 1) expressed more proTGF- mRNA than the adjacent normal tissue but significantly less than poorly differentiated tumors (grade 2 or 3), which are the most aggressive ones. In none of these tissue specimens did we find, by Southern analysis, amplification of the proTGF- or EGF receptor gene. Therefore, overexpression of these genes must be due to another effect, perhaps an alteration of their mRNA turnover. Although the EGF receptor gene (c-erbB1) is overexpressed in nearly all carcinomas analyzed, there was no linear coexpression with the proTGF- gene. In contrast, transcription of the proEGF gene was completely turned off in tumor tissue. Although we have found by restriction fragment length polymorphism analysis, in one of three tumor samples, evidence for a somatic mutation within the proEGF gene, we do not know yet, due to the limited number of Southern analyses, whether this somatic mutation is causally involved in the decrease of proEGF mRNA expression and, hence, is representative of renal cell carcinoma. To our knowledge, this is the first observation on primary tumor tissue in humans that upon malignant transformation the gene for a polypeptide growth factor gene is underexpressed.

¹ This work was supported in part by a grant from the W. Sander Foundation (85.028.2) (to P. E. P.), a predoctoral fellowship from the University of Munich (to S. B.), and a postdoctoral fellowship from the Boehringer-Ingelheim Foundation (to J. B.).

² To whom requests for reprints should be addressed, at Molecular Oncology Laboratory, Department of Medicine III, University of Munich Medical School Grosshadern, 15 Marchioninistrasse, 8 Munich-70, FRG.

³ Present address: Millipore Co., Frankfurt/Main, FRG.

⁴ Present address: Department of Urology, Technical University of Aachen Medical School, Aachen, FRG.

Received 1/12/90.

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