Faculty Bibliography

BACKGROUND AND AIMS/OBJECTIVE:Overexpression of p53 protein in malignancies induces an immune response in some cancer patients. We investigated whether production of serum antibodies against p53 (p53-Ab) is associated with pathohistological parameters of colorectal carcinoma and whether p53-Ab can serve as a tumor marker during cancer treatment. PATIENTS AND METHODS/METHODS:Serum samples from 220 colorectal cancer patients during surgery and adjuvant chemotherapy and 42 healthy controls were tested for the presence of p53-Ab by ELISA. Expression of p53 protein in tumors was determined using mouse anti-human p53-Ab. RESULTS:Serum p53-Ab were detected in 18% of patients while all controls were negative. A strong correlation between p53-Ab production and p53 protein expression was observed: 70% of p53-Ab positive cases had tumors positive for p53 vs. 52% of p53-Ab negative cases. There was also a significant predominance of p53-Ab positive cases in Dukes' stages B and C over stage A. Although surgery alone reduced p53-Ab levels, decreases in p53-Ab titer became significant midterm through chemotherapy compared to both pre- and postoperative values and remained decreased until the completion of treatment. CONCLUSION/CONCLUSIONS:The presence of p53-Ab in sera of patients with colorectal cancer indicates tumors in more advanced histopathologic stages (Dukes' B, C). Due to low sensitivity (18%) p53-Ab are not recommendable as a preoperative marker for colorectal cancer. However, due to high specificity (100%), their monitoring after surgery and adjuvant chemotherapy has potential for early diagnosis of tumor relapse in p53-Ab positive cases.

Biallelic inactivation of the von Hippel-Lindau tumor suppressor gene (VHL) is linked to the development of hereditary (VHL-associated) and sporadic clear-cell renal carcinomas as well as other abnormalities. The VHL gene product, pVHL, is part of an E3 ubiquitin ligase complex that targets the alpha subunits of the heterodimeric transcription factor HIF (hypoxia-inducible factor) for degradation in the presence of oxygen. Here we report that a HIF2alpha variant lacking both of its two prolyl hydroxylation/pVHL-binding sites prevents tumor inhibition by pVHL in a DNA-binding dependent manner. Conversely, downregulation of HIF2alpha with short hairpin RNAs is sufficient to suppress tumor formation by pVHL-defective renal carcinoma cells. These results establish that tumor suppression by pVHL is linked to regulation of HIF target genes.

Oligonucleotide arrays that detect single nucleotide polymorphisms were used to generate genome-wide loss of heterozygosity (LOH) maps from laser capture microdissected paraffin-embedded samples using as little as 5 ng of DNA. The allele detection rate from such samples was comparable with that obtained with standard amounts of DNA prepared from frozen tissues. A novel informatics platform, dChipSNP, was used to automate the definition of statistically valid regions of LOH, assign LOH genotypes to prostate cancer samples, and organize by hierarchical clustering prostate cancers based on the pattern of LOH. This organizational strategy revealed apparently distinct genetic subsets of prostate cancer.

Inactivation of the von Hippel-Lindau tumor suppressor gene is linked to the development of hereditary (VHL Disease-associated) and sporadic clear cell carcinoma of the kidney. The VHL gene product, pVHL, targets the heterodimeric transcription factor HIF for polyubiquitination, and restoration of pVHL function in VHL(-/-) renal carcinoma cells suppresses their ability to form tumors in nude mice. Here we show that tumor suppression by pVHL can be overridden by a HIF variant that escapes pVHL control. These studies prove that HIF is a critical downstream target of pVHL and establish that activation of HIF target genes can promote tumorigenesis in vivo.

The study was so designed as to determine the effect of low to medium daily doses of methimazole (10-20 mg per day) on the number and function of different types of immunocompetent cells in peripheral blood of patients with Graves' disease administered methimazole for the treatment of hyperthyroidism. The study included 127 patients with Graves' disease divided into three groups: group I of 29 thyrotoxic patients before the beginning of treatment; group II of 73 euthyroid patients under antithyroid treatment; and group III of 25 patients who remained euthyroid 8 weeks after therapy discontinuation. In group I, the proportion of CD4+ cells, proportion and number of granulocytes, and their ingestion and microbicidity as well as monocyte phagocytic activity and ingestion were decreased. The mentioned alterations were concluded to most likely be the consequence of the underlying autoimmune process. In group II, the proportion and number of CD8+ cells were increased, while the natural killer cell activity was impaired. Granulocyte microbicidity was suppressed as compared to group I, while the granulocyte phagocytic activity was impaired as compared to normal values. Compared to normal, monocyte microbicidity and phagocytic activity were also suppressed. Monocyte ingestion was suppressed as compared to groups I and III, regardless of the patients' thyroid hormone status. Study results strongly support the hypothesis of a direct immunosuppressive effect of methimazole in patients with Graves' disease rather than the theory favoring concomitant immunomodulation due to thyroid hormone decrease.