We have analyzed the expression of the genes for the precursors of
epidermal growth factor (
pro-EGF) and
transforming growth factor alpha (proTGF-alpha) 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-alpha (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-alpha gene appeared to depend on grade and differentiation of the
tumor, since well differentiated
tumors (grade 1) expressed more proTGF-alpha
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-alpha 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-alpha 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.