We are studying the molecular genetics of renal cell carcinoma, evaluating growth factor production by genitourinary tumors and participating in studies of adoptive immunotherapy in patients with advanced malignancies. By use of the molecular technique of restriction fragment length polymorphism analysis we have identified DNA sequence deletions in the short arm of chromosome 3 in sporadic renal cell carcinoma. The loss of alleles at loci on the short arm of chromosome 3 may indicate the presence of a renal carcinoma recessive oncogene at this location. We have also identified DNa sequence deletions at chromosome 11 and also at chromosome 13 at the retinoblastoma locus. We have demonstrated, also in collaboration with Berton Zbar, DNA sequence deletions in the short arm of chromosome 3 in kidney tumors and pheochromocytoma from patients with a familial form of renal cell carcinoma, Von Hippel-Lindau syndrome. We have demonstrated that chromosome 3s retained in the renal tumors of the proband were inherited from the affected parent which is consistent with our previous data suggesting that the RCC gene is located on chromosome 3p and that 3p allele loss represents the second step of a two-mutation process. DNA sequence deletions observed at other chromosomal loci (11 and/or 13) may be important in progression or metastasis. We have demonstrated loss of heterozygosity at loci on chromosome 11 and 17 in a related tumor, adrenocortical carcinoma. In study of the effect of tumor produced growth factors we have demonstrated by Northern blot analysis that human renal cell carcinoma has an increased expression of the transforming growth factors TGF-alpha and TGF-beta and that the tumor produces TGF-beta in a biologically inactive form. We have shown that TGF-beta inhibits the growth of renal cell carcinoma. These studies may provide a basis for the development of new therapeutic strategies for treatment of this malignancy as well as increase our understanding of how tumor produced factors effect immunologic response. We have evaluated patients with metastatic and locally advanced renal cell carcinoma as part of this protocol and in support of basic and clinical studies of tumor infiltrating lymphocytes.
