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Tumor and normal tissues from 55 patients with papillary serous carcinoma of the peritoneum (PSCP) were analyzed. Polymerase chain reaction amplification of tandem repeat polymorphism was used to screen for loss of heterozygosity (LOH). We mapped 22 oligonucleotide primers to chromosomes 1p, 3p, 6q, 7q, 9p, 11p, 17p, 17q, and Xq. Germline BRCA1 mutation status of 43 patients was determined previously. High frequencies (> 30%) of LOH in PSCP were observed on 6q, 9p, 17p, 17q, and Xq. Compared with allelic loss of serous epithelial ovarian carcinoma (SEOC), the frequency of LOH was significantly lower in PSCP on 1p, 7q, 11p, 17p, and 17q. Of 43 cases screened for germline BRCA1 mutations, 9 cases were identified with mutations. The frequencies of LOH were not significantly different among the BRCA1-related and BRCA1-unrelated PSCP cases. The high LOH rate identified on 6q, 9p, 17p, 17q, and Xq in PSCP suggests that candidate tumor suppressor genes residing in these regions may be important for the development of the tumor. Compared with allelic loss of SEOC, PSCP exhibits a significantly lower frequency of LOH on chromosomes 1p36, 7q31.3, 11p15.1, 17p13.1, and 17q21. An increase in susceptibility to the acquisition of allelic loss in BRCA1-related PSCP cannot be identified.

Objective: The ras genes are a well-studied family of proto-oncogenes whose involvement in many cancers has been delineated. However, K-ras mutations have not previously been examined in papillary serous carcinoma of the peritoneum (PSCP), a tumor which resembles serous epithelial ovarian carcinoma (SEOC) both in histology and epidemiology. In this study we examine the role of the K-ras oncogene in PSCP compared to SEOC., Methods: Using single-strand conformational polymorphism analysis and cycle sequencing protocols, we evaluated our collection of 51 cases of PSCP for K-ras mutations and compared these findings with the experience in SEOC. We then examined 5 cases of PSCP for activation of ras proteins and MAP kinase to evaluate the potential involvement of the ras pathway in PSCP tumorigenesis., Results: We found only one K-ras mutation in our 51 cases (2%) of PSCP compared to three mutations in 46 cases (6.5%) of high-grade, late-stage SEOC. This was not significantly different (P > 0.10). In the single PSCP case with a K-ras mutation, the mutation was found in only one of five tumor sites tested. All four mutations involved a single nucleotide alteration in codon 12 (GGT to GTT, Gly to Val). To evaluate the ras pathway in PSCP, we used the known activated ras binding domain on Raf-1 to perform an assay to test for activated ras. We identified ras activation in 4 of 5 PSCP cases tested and, to confirm that the activation was functional, we tested and found similar activation of MAP kinase, a downstream mediator for K-ras expression., Conclusions: K-ras mutations occur at low rates in both PSCP and high-grade, late-stage SEOC, and therefore K-ras mutations are not involved in the development of these two diseases. Finding the mutation in only one of multiple tumor sites in the PSCP case supports growing evidence for a multifocal origin of PSCP. Our findings of ras activation in four of five cases of PSCP suggest that ras activation by mechanisms other than genetic mutation is important for PSCP tumorigenesis., (Copyright 2000 Academic Press.)

To define regions of deletion on chromosome 6q in papillary serous carcinoma of the peritoneum (PSCP), we analyzed 103 tumor tissues from 53 patients by using 11 polymorphic microsatellite markers spanning loci from 6q23 to 6q27. Allelic losses on 6q were observed in 42 of 53 (79.2%) cases. We identified 3 distinct regions with a high percentage (>40%) of loss of heterozygosity. The first region is located at 6q23-24 and defined by D6S311 (15 of 35 informative cases, 42.9%). Detailed deletion mapping of chromosome 6q23-24 in these tumor samples identified a novel 9 cM minimal deletion region flanked by D6S250 and ESR. The second one is located at 6q25.1-25.2 and defined by D6S448 (17 of 36 informative cases, 47.2%). A second minimal deletion region of 4 cM was flanked by D6S420 and D6S442. The third region is located at 6q27 and defined by D6S297 (9 of 19 informative cases, 47.4%). Comparing these results with our cases of advanced staged invasive serous epithelial ovarian carcinoma (SEOC), we observed that allelic losses at D6S311 (6q23) and D6S149 (6q27) were significantly higher for PSCP than for SEOC. The pattern of allelic loss at each tumor site within an individual patient was also studied. A total of 36 cases displayed allelic loss for at least 1 of multiple tumor sites, and 35 of these patients exhibited nonidentical patterns of allelic loss at various tumor sites of the same patient. Furthermore, an alternating pattern of allelic loss in the same patient was identified in 3 of 53 patients studied. These results show that allelic losses on 6q are very frequent in PSCP, and we show 2 discrete minimal deletion regions on 6q, suggesting the existence of at least 2 tumor suppressor genes within 6q that may be involved in the pathogenesis of PSCP. In addition, the finding of different patterns of allelic loss at different tumor sites within the same patient indicate a mutifocal origin in some PSCP cases. These results provide strong evidence to support our previous reports that PSCP is a multifocal disease entity.

Papillary serous carcinoma of the peritoneum (PSCP) is believed to develop de novo from the peritoneal lining of the pelvis and abdomen. Although it is histologically indistinguishable from serous ovarian carcinoma, PSCP exhibits minimal or absent ovarian involvement and may even develop in a woman years after prophylactic oophorectomy. We have shown previously that patients with germ-line BRCA1 mutations who develop PSCP are more likely to have disease originating from multiple peritoneal sites compared with patients with wild-type BRCA1. In this study, we tested the hypothesis that BRCA1-related PSCP has a unique molecular pathogenesis. DNA was extracted from normal tissue and multiple tumor sites in patients with PSCP. BRCA1 and p53 gene mutations were screened for using single-strand conformation polymorphism. Loss of heterozygosity was determined at the BRCA1 and p53 loci. Immunohistochemical analyses of p53, epidermal growth factor receptor, erbB-2, erbB-3, erbB-4, and Bcl-2 expression were performed. We detected germ-line BRCA1 mutations in 11 (26%) of 43 PSCP patients. BRCA1 mutation carriers had a higher overall incidence of p53 mutations (89% versus 47%; P = 0.052), were more likely to exhibit multifocal or null p53 mutations (63% versus 7%; P = 0.014), and were less likely to exhibit erbB-2 overexpression (P = 0.013) than wild-type BRCA1 case subjects. We propose that the unique molecular pathogenesis of BRCA1-related PSCP may affect the ability of current methods to reliably prevent or detect this disease prior to metastasis.

Objective: The Wilms' tumor (WT1) gene product is consistently detectable in both normal ovarian germinal epithelium and human mesothelium. Ovarian carcinomas frequently exhibit alterations in WT1 function. Papillary serous carcinoma of the peritoneum (PSCP) is believed to develop de novo from the peritoneal lining (mesothelium) of the pelvis and abdomen. The purpose of this study was to determine if genetic alterations of the WT1 gene are associated with the development of PSCP., Methods: Normal and tumor tissue specimens were retrieved from patients with stage III and IV PSCP (n = 38) and serous epithelial ovarian carcinoma (n = 38). Immunohistochemistry was performed using the anti-WT1 (C-19) antibody. Loss of heterozygosity (LOH) was performed at the WT1 locus. Clinical data were obtained and correlated with molecular findings., Results: Loss of normal WT1 expression was detected in 18 (51%) of 35 PSCP specimens and 18 (53%) of 34 ovarian carcinoma specimens. Six (27%) of 22 PSCP specimens and 3 (13%) of 24 ovarian carcinoma specimens had LOH at the WT1 locus (P = 0.27). Normal WT1 gene expression was maintained in 86% of tumors exhibiting LOH. Genetic alterations of the WT1 gene were not predictive of survival, nor were they associated with other clinical or molecular factors., Conclusions: Genetic alterations of the WT1 gene are associated with the development of PSCP. The loss of normal WT1 gene expression is a common event in both PSCP and advanced ovarian carcinoma, likely resulting from down-regulation by other regulatory factors-not from inactivating gene mutation and subsequent allelic loss., (Copyright 2000 Academic Press.)

Objective: To compare BRCA1 mutations in papillary serous carcinoma of the peritoneum and papillary serous ovarian carcinoma., Methods: Germline DNA from 17 consecutive patients with peritoneal carcinoma was screened for mutations in the BRCA1 gene using single-strand conformation polymorphism analysis. Shifted DNA bands were sequenced. Patients with germline BRCA1 mutations were screened for allelic loss in tumor DNA at the BRCA1 locus., Results: Two of the 17 patients (11%, 95% confidence interval 0.07, 0.37) exhibited the 185 delAG germline BRCA1 mutation described in the Ashkenazi Jewish population. The family history of one patient was notable for a mother and five aunts with breast or ovarian cancer. The other patient had a personal history of breast cancer. Both patients exhibited allelic loss of the normal BRCA1 allele in their tumor. A third patient was found to have a previously undescribed exon 11 single base pair substitution at nucleotide 1239 (CAG to CAC) resulting in a missense mutation (Gln to His). The patient had no family or personal history of breast or ovarian cancer, and her tumor did not exhibit loss of heterozygosity., Conclusion: Germline BRCA1 mutations occur in papillary serous carcinoma of the peritoneum with a frequency comparable to the BRCA1 mutation rate in ovarian cancer. Although the penetrance is unknown, peritoneal carcinoma should be considered a malignancy expressed in the familial breast ovarian cancer syndrome.

We extend the evaluation of allelic loss patterns on chromosome 17 to papillary serous carcinoma of the peritoneum (PSCP) which is histologically identical to papillary serous ovarian carcinoma (PSOC). DNA was obtained from 11 archival cases of PSCP, with 1-11 tumor sites per case. Using ten loci spanning chromosome 17, loss of heterozygosity (LOH) was identified in all 11 cases (100%). Furthermore, 75-100% of informative cases exhibited LOH at the loci p53, D17S1322 (intragenic to the tumor suppressor gene BRCA1), D17S1327 and MPO. PSCP cases exhibit a higher rate of LOH at most loci when compared with PSOC. Alternating allelic loss at different tumor sites was identified in three cases supporting a multifocal origin of PSCP. Microsatellite instability (MI) is an uncommon event which was identified in four cases. These data implicate chromosome 17 as a potential location of genetic events important in the pathogenesis of PSCP as well as ovarian cancer.

Background: Papillary serous carcinoma of the peritoneum (PSCP) diffusely involves peritoneal surfaces, while it spares or only superficially involves the ovaries. PSCP is histologically indistinguishable from serous epithelial ovarian carcinoma, and it may develop years after oophorectomy. The molecular pathogenesis of PSCP remains unresolved, although preliminary data suggest a multifocal origin in some cases. Patients with germline BRCA1 mutations may develop PSCP in addition to breast and ovarian carcinomas. The purpose of this study was to utilize the androgen receptor (AR) gene locus to test the hypothesis that some cases of PSCP have a multifocal origin and to determine if patients with germline BRCA1 mutations develop multifocal PSCP., Methods: Specimens of normal and tumor tissues from 22 women with PSCP were obtained, and DNA was extracted. The AR gene locus was evaluated for patterns of loss of heterozygosity (LOH) and X-chromosome inactivation. The methylation-sensitive Hpa II restriction enzyme was used to differentiate the active and inactive X chromosomes. Germline BRCA1 mutation status of the patients was determined previously., Results: Genetic analysis of tumor specimens indicated that five (23%) of 22 case subjects had patterns of selective LOH at the AR locus, consistent with multifocal, polyclonal disease origin. Two patients with selective LOH also had alternating X-chromosome inactivation patterns. Patients with germline BRCA1 mutations were more likely to have evidence of multifocal disease (two-sided Fisher's exact test, P = .01)., Conclusions: Our results show that PSCP has a multifocal origin in at least some cases. Furthermore, patients with germline BRCA1 mutations are more likely to develop multifocal PSCP than are patients without BRCA1 mutations.

Histopathological evidence suggests that papillary serous carcinoma of the peritoneum (PSCP) may be multifocal in origin. Utilizing a PCR based method to detect tandem repeat polymorphisms in formalin fixed tissue, loss of heterozygosity at eight loci on chromosomes 1, 3, 4, and 17 was studied in six cases of PSCP. Loss of heterozygosity was assessed at between 5 and 11 tumor sites/patient. Allelic losses at 4 loci (1q32-qter, 3p14.3-21.1, 17q12, 17q21.3-23) were noted. Three cases demonstrated a different pattern of allelic loss at various anatomic sites within the same patient. In an additional case, a mutation of the p53 gene, detected by quantitative PCR followed by single-strand conformation polymorphism analysis, was detected in only 2 of 5 tumor sites. The pattern of allelic loss and the mutational pattern of the p53 gene varied at tumor sites within the same patient in 4 of 6 cases of PSCP. These findings are consistent with histopathological evidence that PSCP is multifocal in origin.