To identify novel tumor suppressor genes involved in ovarian carcinogenesis, we generated four down-regulated suppression subtraction cDNA libraries from two early-stage (stage I/II) and two late-stage (stage III) primary ovarian tumors, each subtracted against cDNAs derived from normal ovarian epithelial cell brushings. Approximately 600-700 distinct clones were sequenced from each library. Comparison of down-regulated clones obtained from early- and late-stage tumors revealed genes that were unique to each library which suggested tumor-specific differences. We found 45 down-regulated genes that were common in all four libraries. We also identified several genes, the role of which in tumor development has yet to be elucidated, in addition to several under expressed genes, the potential role of which in carcinogenesis has been described previously (Bagnoli et al., Oncogene, 19: 4754-4763, 2000; Yu et al., Proc. Natl. Acad. Sci. USA, 96: 214-219, 1999; Mok et al., Oncogene, 12: 1895-1901, 1996). The differential expression of a subset of these genes was confirmed by semiquantitative reverse transcription-PCR using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as control in a panel of 15 stage I and 15 stage III tumors of mixed histological subtypes. Chromosomal sorting of library sequences revealed that several of the genes mapped to known regions of deletion in ovarian cancer. Loss of heterozygosity (LOH) analysis revealed multiple genomic regions with a high frequency of loss in both early- and late-stage tumors. To determine whether loss of expression of some of the genes corresponds to loss of an allele by LOH, we used a microsatellite marker for one of the novel genes on 8q and have shown that loss of expression of this novel gene correlates with loss of an allele by LOH. In conclusion, our analysis has identified down-regulated genes, which map to known as well as novel regions of deletions and may represent potential candidate tumor suppressor genes involved in ovarian cancer.
In the United States, ovarian cancer is the fourth most common cause of cancer-related deaths among women. The most important prognostic factor for this cancer is tumor stage, or extent of disease at diagnosis. Although women with low-stage tumors have a relatively good prognosis, most women diagnosed with late-stage disease eventually succumb to their cancer. In an attempt to understand early events in ovarian carcinogenesis, and to explore steps in its progression, we have applied multiple molecular genetic techniques to the analysis of 21 early-stage (stage I/II) and 17 advanced-stage (stage III/IV) ovarian tumors. These techniques included expression profiling with cDNA microarrays containing approximately 18,000 expressed sequences, and comparative genomic hybridization to address the chromosomal locations of copy number gains as well as losses. Results from the analysis indicate that early-stage ovarian cancers exhibit profound alterations in gene expression, many of which are similar to those identified in late-stage tumors. However, differences observed at the genomic level suggest differences between the early- and late-stage tumors and provide support for a progression model for ovarian cancer development.
Objective: The purpose of colonoscopic polypectomy is cancer prevention. Multiple or large adenomas require intensive follow up but solitary or smaller lesions are considered safer and less frequent examinations are necessary. The aim of this study was to test if these principles are supported in practice. Method: Individuals with polyps but no family history of colorectal cancer (CRC), where pathology and endoscopy reports could be cross‐referenced to confirm size, number and histological classification were included. Cases of colorectal cancer were identified from records of repeat examinations. Follow‐up interval and number of subsequent examinations was determined. A control population of individuals with a normal initial colonoscopy were also studied. Results: In total 0.05% of individuals with a normal initial colonoscopy developed CRC. The cancer incidence following numerous or large polyps was not significantly higher than the controls although on average more examinations were performed (see table). Individuals with a single small adenoma did not appear to have increased risk of cancer with fewer colonoscopies, but there were significantly higher numbers of cancers where intermediate sized polyps had been identified. Conclusion: Risk of cancer is reduced in large or numerous polyps by frequent examinations. Intermediate sized polyps appear to need more intensive follow‐up protocols than small single adenomas for effective cancer prevention. First exam result Number Follow up (months) Number of exams Metachronous cancers Normal 4935 88.7 (1–201) 1.2 24 (0.05%) Single (< 5 mm) 74 64.3 (7–148) 1.3 1 (1.4%) χ 2 = 1.1 P = 0.29 Between 5 and 10 mm 73 73.4 (6–165) 1.5 3 (4.1%) χ 2 = 17.61 P < 0.0001 > 3 mm 27 68.1 (6–152) 2.5 0 (0%) χ 2 = 0.13 P = 0.72 Larger than 10 mm 114 73.7 (3–170) 2.9 1 (0.9%) χ 2 = 0.35 P = 0.56
Three young infants who had severe gastroenteritis developed radiological and histological features of renal tubular necrosis. Characteristically the excretion urogram showed renal enlargement with prolonged and heavy opacification of the renal parenchyma and a pronounced increase in density of the pyramids. Subsequent radiological studies showed extensive papillary necrosis. Though these infants are now apparently fit, renal damage has occurred and this may eventually give rise to features indistinguishable from chronic pyelonephritis.
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