National Cancer Institute®
Last Modified: January 1, 2002
UI - 11248061
AU - Levy-Lahad E; Lahad A; Eisenberg S; Dagan E; Paperna T; Kasinetz L;
TI - Catane R; Kaufman B; Beller U; Renbaum P; Gershoni-Baruch R A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers.
SO - Proc Natl Acad Sci U S A 2001 Mar 13;98(6):3232-6
AD - Medical Genetics Unit, Shaare Zedek Medical Center and Hebrew University/Hadassah Medical School, P.O. Box 3235, Jerusalem 91031, Israel. firstname.lastname@example.org
BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages.
UI - 11434389
AU - Campos B; Diez O; Cortes J; Domenech M; Pericay C; Alonso C; Baiget M
TI - Conditions for single-strand conformation polymorphism (SSCP) analysis of BRCA1 gene using an automated electrophoresis unit.
SO - Clin Chem Lab Med 2001 May;39(5):401-4
AD - Servei de Genetica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
The single-strand conformation polymorphism procedure has been applied in routine testing for hereditary diseases and cancer. However, temperature, running time, gel composition, fragment length, etc. can influence its sensitivity. Mutation detection in the clinical setting depends on the development of automated technology, especially for large genes such as the breast cancer gene BRCA1. We analysed DNA samples with BRCA1 mutations in an automated system (GenePhor System; Amersham-Pharmacia Biotech, Uppsala, Sweden). The concentrations of DNA template and PCR primers, the effect of chilling after denaturation, and the temperature and time of the electrophoresis were investigated. All band-shifts were detected by electrophoresis at 5 degrees C for 2 h 15 min. Concentrations of DNA and samples used in the PCR did not affect the SSCP pattern, but chilling the PCR product in ice after denaturation was required. The type and position of mutation in the fragments did not influence the probability of a mobility shift, although SSCP analysis was more sensitive for fragments shorter than 350 bp. This automated SSCP method meets the requirements of fast turnaround and sensitivity and can be readily adapted to the screening of large genes such as BRCA1.
UI - 11474658
AU - Mahavni V; Kim SC; Benda TA; Sanders L; Buller RE
TI - The androgen receptor and DXS15-134 markers show a high rate of discordance for germline X chromosome inactivation.
SO - J Med Genet 2001 Jul;38(7):474-8
UI - 11444200
AU - Garrett AP; Lee KR; Colitti CR; Muto MG; Berkowitz RS; Mok SC
TI - k-ras mutation may be an early event in mucinous ovarian tumorigenesis.
SO - Int J Gynecol Pathol 2001 Jul;20(3):244-51
AD - Laboratory of Gynecologic Oncology, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, Massachusetts, USA.
We explored the possible pathogenetic pathway for mucinous ovarian tumorigenesis by examining the k-ras mutational patterns in ovarian mucinous tumors (OMTs) with benign, borderline, and invasive epithelium in which the different types of mucinous epithelium are in close proximity. Sixteen patients with ovarian mucinous borderline tumors (OMBTs) and 4 patients with grade 1 ovarian mucinous adenocarcinomas (OMCs) were selected for the presence of a single histologic section which contained a clear "transition" zone from benign mucinous epithelium to borderline mucinous epithelium, and in four cases, to invasive epithelium. A PixCell II Laser Capture Microscope was used to microdissect and retrieve benign, borderline, and invasive epithelium separately from the 20 OMTs. Normal ovarian stroma from the same histologic section in each case was also microdissected and retrieved for use as a control. k-ras mutations were detected in these samples by PCR-SSCP analysis followed by direct PCR cycle sequencing. k-ras mutations were found in 8/16 (50%) of the OMBTs and 2/4 (50%) of the grade 1 OMCs. In 6 of these 10 cases (4 in OMBTs, 2 in grade 1 OMCs), the same k-ras mutation was found in both the benign and borderline (and invasive) regions. In 3 cases in which k-ras mutations were identified, the mutation was found in either the benign or borderline tissue samples alone, and in one case, two distinct mutations were found. No k-ras mutations were identified in the normal ovarian stroma. The presence of a k-ras mutation in adjacent benign and borderline regions of a single OMT may suggest a progression in the development of OMTs from benign to borderline and grade 1 OMCs. k-ras mutations, when they occur, are likely early genetic changes but may not alone be sufficient for malignant transformation of ovarian epithelium.
UI - 11462239
AU - Jakubowska A; Gorski B; Byrski T; Huzarski T; Gronwald J; Menkiszak J;
TI - Cybulski C; Debniak T; Hadaczek P; Scott RJ; Lubinski J Detection of germline mutations in the BRCA1 gene by RNA-based sequencing.
SO - Hum Mutat 2001 Aug;18(2):149-56
AD - Department of Genetics and Pathology, Pomeranian Academy of Medicine, Polabska, Poland. email@example.com
BRCA1 mutation detection is expensive and has sensitivity limitations, which might at least partially be overcome by RNA-based sequencing. There are claims that RNA tests are unreliable due to differential splicing, exon skipping, or nonsense-mediated mRNA decay that results in either the absence or low expression of mRNA harboring mutations. The major aim of this study was to determine if the application of specific high temperature annealing primers can assure high sensitivity of detection of BRCA1 sequence alterations by cDNA sequencing. The study group comprised 21 Polish cancer families with aggregations of breast and/or ovarian cancer. We detected mutations in 10 out of 21 unrelated patients. These were: nucleotide substitutions (c.309T>C; c.300T>G); nucleotide insertions (c.5382insC) three cases; nucleotide deletions (c.4154delA) one case, (c. 185delAG) one case, (c.3819delGTAAA) two cases; and the deletion of the entire sequence of exon 22, one case. In addition, we identified three transcript variants resulting from alternative splice sites affecting the last six nucleotides of exon 1a (GTAAAG), and the first three nucleotides (CAG) of exon 8 and exon 14. In all cases these were cDNA heterozygous changes. Two of these splice site changes have not been previously described. Sequencing of genomic DNA "exon by exon" did not result in the detection of any additional abnormalities. The sensitivity of our analyses was sufficient to reliably detect mutations without the necessity of tissue culturing to obtain enough template cDNA for analysis. Copyright 2001 Wiley-Liss, Inc.
UI - 11462242
AU - Baudi F; Quaresima B; Grandinetti C; Cuda G; Faniello C; Tassone P;
TI - Barbieri V; Bisegna R; Ricevuto E; Conforti S; Viel A; Marchetti P; Ficorella C; Radice P; Costanzo F; Venuta S Evidence of a founder mutation of BRCA1 in a highly homogeneous population from southern Italy with breast/ovarian cancer.
SO - Hum Mutat 2001 Aug;18(2):163-4
AD - Dipartimento di Medicina Sperimentale e Clinica "G. Salvatore", Universita degli Studi di Catanzaro "Magna Graecia", Italy.
Several genes have been involved in the pathogenesis of hereditary breast/ovarian cancer (BOC), but mutations in the BRCA1 gene are by far the most recurrent. In this study, we report the identification of a founder mutation in a geographically and historically homogeneous population from Calabria, a south Italian region. A screening performed on 24 patients from unrelated families highlighted the high prevalence of a 5083del19 alteration in the BRCA1 gene, which accounts for 33% of the overall gene mutations. The same mutation was also detected in 4 patients, all of Calabrian origin, referred to us by research centres from the north of Italy. Allelotype analysis, performed on probands and unaffected family members revealed the presence a common allele, therefore suggesting a founder effect due to a common ancestor. Our findings underscore the importance of ethnic background homogeneity in patients' selection and highlight the usefulness of founder mutations as a potential tool for optimisation of preclinical diagnosis in gene carriers and therapeutic approaches in affected individuals. Copyright 2001 Wiley-Liss, Inc.
UI - 11499690
AU - Srivastava A; McKinnon W; Wood ME
TI - Risk of breast and ovarian cancer in women with strong family histories.
SO - Oncology (Huntingt) 2001 Jul;15(7):889-902; discussion 902, 905-7, 911-13
AD - Division of Hematology and Oncology, University of Vermont College of Medicine, Burlington 05401, USA.
Assessing the risk of breast and ovarian cancer starts with obtaining a complete and accurate family history. This can reveal evidence of inherited cancer risk. The highest risk of cancer is associated with germ-line abnormalities in several genes, including BRCA1, BRCA2, and TP53. Moderate-risk genes associated with syndromes that are inherited in an autosomal dominant pattern (such as Cowden's disease, hereditary non-polyposis colorectal cancer, Muir-Torre syndrome, and Peutz-Jeghers syndrome) exhibit lower penetrance and thus less risk of breast and/or ovarian cancer. Low-risk genes likely require significant environmental exposure, and although they are associated with the lowest risk of cancer, they account for more cancer than high- and moderate-risk genes. Lifetime risks for breast or ovarian cancer can be estimated. The Gail and Claus models, the more widely utilized models for calculation of lifetime breast cancer risk, are discussed. Models are also available for determining the likelihood of finding a BRCA1/2 mutation (the BRCAPRO and Myriad models). Appropriate candidates for testing include affected individuals who are most likely to have a hereditary form of cancer. Testing should proceed only after a thorough discussion of the risks, benefits, and limitations of testing. Risk-reducing options are available to women with a strong family history of breast and ovarian cancer. These options include high-risk screening, chemoprevention, and prophylactic surgery.
UI - 11501783
AU - Kaya H; Evans MF; Ekicioglu G; Tuzlali S; Kullu S; Foster C
TI - Antimetastasis gene expression and numerical chromosomal abnormalities of chromosomes 1 & 17 in serous tumours of the ovary.
SO - Eur J Gynaecol Oncol 2001;22(3):240-2
AD - Marmara University, School of Medicine, Department of Pathology, Istanbul, Turkey.
OBJECTIVE(S): The aim of this study was to examine the expression of the antimetastasis gene nm23 and numerical changes on chromosome 1 and 17 in ovarian tumours. METHODS: In this study 20 serous cystadenocarcinomas, ten borderline and five benign tumours were analysed for expression of the nm23 antimetastasis gene by immunohistochemistry and for numerical chromosomal abnormalities of chromosomes 1 and 17 by interphase cytogenetics. RESULTS: Strong intracytoplasmic immunoreactivity with the antimetastasis gene was observed in late stage carcinomas but not in benign or borderline tumours or in lymph node metastases. Numerical abnormalities were only observed in carcinomas. CONCLUSION(S): These sets of data are consistent with the majority of benign and borderline tumours lacking invasive potential. Odds Ratio (OR) assessment indicates that the presence of numerical aberrations correlates with immunopositivity.
UI - 11499181
AU - Memarzadeh S; Berek JS
TI - Advances in the management of epithelial ovarian cancer.
SO - J Reprod Med 2001 Jul;46(7):621-9; discussion 629-30
AD - Division of Gynecologic Oncology, University of California-Los Angeles School of Medicine, 27-136 CNS, 10833 Le Conte Avenue, Los Angeles, CA 90095-1740, USA.
More than 23,400 new cases of ovarian cancer and 13,900 deaths are expected in the United States this year. Epithelial ovarian cancer is the most common histologic type of ovarian malignancy. Although there have been advances in the chemotherapeutic treatment of ovarian cancer, the five year survival of women with advanced-stage disease is 25-30%. Because the disease is typically asymptomatic until the disease has metastasized and because effective screening strategies are not unavailable, 70-75% of women present with advanced-stage disease. Of ovarian cancer cases, 90-95% are sporadic and 5-10% associated with germ-line mutations, including BRCA1 and BRCA2. Known risk factors for ovarian cancer include nulliparity and a strong family history of ovarian cancer. The use of oral contraceptives is known to decrease the risk of ovarian cancer: five years of use will decrease the risk by 50%. The staging of ovarian cancer (according to the International Federation of Obstetrics and Gynecology) requires surgical exploration. Determining the extent of disease is essential to appropriate management. Survival in patients with metastatic disease is improved in those who undergo optimal primary cytoreductive surgery. Adjuvant chemotherapy is recommended in patients with high-risk, early-stage disease and all patients with advanced-stage disease. Standard chemotherapy is a combination of paclitaxel and carboplatin. Selected patients with recurrent disease can undergo secondary cytoreductive surgery. Second-line chemotherapy for patients who initially respond to paclitaxel and carboplatin and who have a prolonged disease progression-free intervals (longer than 12 months) can be re-treated with either drug or both. Those whose responses to initial therapy were less successful can be treated with other chemotherapeutic agents--e.g., liposomal doxorubicin, topotecan, etoposide, gemcitabine or taxotere.
UI - 11529589
AU - Phillips KA
TI - Current perspectives on BRCA1- and BRCA2-associated breast cancers.
SO - Intern Med J 2001 Aug;31(6):349-56
AD - Department of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia. PhillipsKelly@petermac.unimelb.edu.au
The identification of two breast cancer predisposition genes, BRCA1 and BRCA2, in the mid-1990s has led to a better understanding of the molecular pathogenesis of hereditary breast cancer and to a new era in breast cancer research. The present article reviews the current state of knowledge regarding the biology of BRCA1 and BRCA2, the cancer risks associated with carrying a pathogenic mutation in either of these genes and the possible genetic and environmental risk modifiers. The phenotypes of BRCA1- and BRCA2-associated hereditary breast cancers are reviewed. Research into BRCA1- and BRCA2-associated breast cancer is in its infancy and much remains to be learned, particularly about modifiers of genetic risk and the clinical implications of carrying a mutation in one of these two genes. Australia has an excellent research infrastructure in place, through the Australian Breast Cancer Family Study and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, to contribute substantially to future research in this area.
UI - 11572989
AU - Paige AJ; Taylor KJ; Taylor C; Hillier SG; Farrington S; Scott D;
TI - Porteous DJ; Smyth JF; Gabra H; Watson JE WWOX: a candidate tumor suppressor gene involved in multiple tumor types.
SO - Proc Natl Acad Sci U S A 2001 Sep 25;98(20):11417-22
AD - Imperial Cancer Research Fund (ICRF) Medical Oncology Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom. firstname.lastname@example.org
We previously reported the construction of a P1-derived artificial chromosome (PAC) contig encompassing a set of homozygous deletions of chromosome 16q23-24.1 found in primary ovarian tumor material and several tumor cell lines. Using these PAC clones in a cDNA selection experiment, we have isolated a Sau3A fragment homologous to the WWOX transcript (GenBank accession no. ) from normal human ovarian surface epithelial (HOSE) cells. We demonstrate the homozygous deletion of WWOX exons from ovarian cancer cells and three different tumor cell lines. We also identify an internally deleted WWOX transcript from a further primary ovarian tumor. In three of these samples the deletions result in frameshifts, and in each case the resulting WWOX transcripts lack part, or all, of the short chain dehydrogenase domain and the putative mitochondrial localization signal. Sequencing revealed several missense polymorphisms in tumor cell lines and identified a high level of single nucleotide polymorphism (SNP) within the WWOX gene. This evidence strengthens the case for WWOX as a tumor suppressor gene in ovarian cancer and other tumor types.
UI - 11578810
AU - Lin H; Morin PJ
TI - A novel homozygous deletion at chromosomal band 6q27 in an ovarian cancer cell line delineates the position of a putative tumor suppressor gene.
SO - Cancer Lett 2001 Nov 8;173(1):63-70
AD - Laboratory of Cellular and Molecular Biology, Gerontology Research Center, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Chromosomal band 6q27 is believed to contain a tumor suppressor gene important in the development of several cancer types, including ovarian cancer. However, repeated efforts to identify a tumor suppressor gene in this region have been unsuccessful. Because homozygous deletions have been useful in the positional cloning of a number of tumor suppressor genes, we initiated a systematic search for such deletions in ovarian cancer cell lines using 6q microsatellite markers. One of the cell lines, OV167, was found to contain an 80 kb homozygous deletion encompassing marker D6S193 at 6q27 but excluding nearby marker D6S297. No known genes were present in the deleted region. Because the homozygous deletion might affect the expression of nearby genes, we analyzed the expression of the two closest known genes flanking the deletion, RNASE6PL and RSK-3. The expression of these genes were unaffected by the homozygous deletion, suggesting that the functional target of the deletion is located between these two genes. A search of the region against expressed sequence tag (EST) databases revealed that it contained four sets of expressed sequences. The first expressed sequences were derived from a LINE repetitive element and were considered unlikely to represent a tumor suppressor gene. The other expressed sequence tags identified did not show homology to known genes and are currently being investigated. This data may significantly reduce the magnitude of the search for the 6q tumor suppressor gene as it suggests a small area as a prime target for investigation.
UI - 11583950
AU - Giordano TJ; Shedden KA; Schwartz DR; Kuick R; Taylor JM; Lee N; Misek
TI - DE; Greenson JK; Kardia SL; Beer DG; Rennert G; Cho KR; Gruber SB; Fearon ER; Hanash S Organ-specific molecular classification of primary lung, colon, and ovarian adenocarcinomas using gene expression profiles.
SO - Am J Pathol 2001 Oct;159(4):1231-8
AD - Department of Pathology, The University of Michigan, Ann Arbor, Michigan 48109-0054, USA. email@example.com
Molecular classification of tumors based on their gene expression profiles promises to significantly refine diagnosis and management of cancer patients. The establishment of organ-specific gene expression patterns represents a crucial first step in the clinical application of the molecular approach. Here, we report on the gene expression profiles of 154 primary adenocarcinomas of the lung, colon, and ovary. Using high-density oligonucleotide arrays with 7129 gene probe sets, comprehensive gene expression profiles of 57 lung, 51 colon, and 46 ovary adenocarcinomas were generated and subjected to principle component analysis and to a cross-validated prediction analysis using nearest neighbor classification. These statistical analyses resulted in the classification of 152 of 154 of the adenocarcinomas in an organ-specific manner and identified genes expressed in a putative tissue-specific manner for each tumor type. Furthermore, two tumors were identified, one in the colon group and another in the ovarian group, that did not conform to their respective organ-specific cohorts. Investigation of these outlier tumors by immunohistochemical profiling revealed the ovarian tumor was consistent with a metastatic adenocarcinoma of colonic origin and the colonic tumor was a pleomorphic mesenchymal tumor, probably a leiomyosarcoma, rather than an epithelial tumor. Our results demonstrate the ability of gene expression profiles to classify tumors and suggest that determination of organ-specific gene expression profiles will play a significant role in a wide variety of clinical settings, including molecular diagnosis and classification.
UI - 11584052
AU - Mills GB; Bast RC Jr; Srivastava S
TI - Future for ovarian cancer screening: novel markers from emerging technologies of transcriptional profiling and proteomics.
SO - J Natl Cancer Inst 2001 Oct 3;93(19):1437-9
UI - 11584061
AU - Mok SC; Chao J; Skates S; Wong K; Yiu GK; Muto MG; Berkowitz RS; Cramer
TI - DW Prostasin, a potential serum marker for ovarian cancer: identification through microarray technology.
SO - J Natl Cancer Inst 2001 Oct 3;93(19):1458-64
AD - Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. firstname.lastname@example.org
BACKGROUND: Screening biomarkers for ovarian cancer are needed because of its late stage at diagnosis and poor survival. We used microarray technology to identify overexpressed genes for secretory proteins as potential serum biomarkers and selected prostasin, a serine protease normally secreted by the prostate gland, for further study. METHODS: RNA was isolated and pooled from three ovarian cancer cell lines and from three normal human ovarian surface epithelial (HOSE) cell lines. Complementary DNA generated from these pools was hybridized to a microarray slide, and genes overexpressed in the cancer cells were identified. Real-time quantitative polymerase chain reaction was used to examine prostasin gene expression in ovarian cancer and HOSE cell lines. Anti-prostasin antibodies were used to examine prostasin expression and to measure serum prostasin by an enzyme-linked immunosorbent assay in 64 case patients with ovarian cancer and in 137 control subjects. Previously determined levels of CA 125, an ovarian cancer marker, were available from about 70% of all subjects. All statistical tests were two-sided. RESULTS: Prostasin was detected by immunostaining more strongly in cancerous ovarian epithelial cells and stroma than in normal ovarian tissue. The mean level of serum prostasin was 13.7 microg/mL (95% confidence interval [CI] = 10.5 to 16.9 microg/mL) in 64 case patients with ovarian cancer and 7.5 microg/mL (95% CI = 6.6 to 8.3 microg/mL) in 137 control subjects (P<.001, after adjustment for the subject's age, year of collection, and specimen quality). In 14 of 16 case patients with both preoperative and postoperative serum samples, postoperative prostasin levels were statistically significantly lower than preoperative levels (P =.004). In 37 case patients with nonmucinous ovarian cancer and in 100 control subjects for whom levels of CA 125 and prostasin were available, the combination of markers gave a sensitivity of 92% (95% CI = 78.1% to 98.3%) and a specificity of 94% (95% CI = 87.4% to 97.7%) for detecting ovarian cancer. CONCLUSIONS: Prostasin is overexpressed in epithelial ovarian cancer and should be investigated further as a screening or tumor marker, alone and in combination with CA 125.
UI - 11586035
AU - Ozalp S; Yalcin OT; Gulbas Z; Tanir HM; Minsin T
TI - Effect of cellular DNA content on the prognosis of epithelial ovarian cancers.
SO - Gynecol Obstet Invest 2001;52(2):93-7
AD - Department of Gynecology and Obstetrics, Gynecologic Oncology Unit, Osmangazi University School of Medicine, Eskisehir, Turkey.
OBJECTIVE: To assess the cellular DNA status of epithelial ovarian cancers with regard to clinicopathological findings and its effect on prognosis. MATERIALS AND METHODS: Twenty-six consecutive patients with a diagnosis of epithelial ovarian cancer who had been treated by primary surgery and six courses of platinum-based chemotherapy were enrolled in this study. Second-look laparotomy (SLL) was performed in all cases following confirmation of the clinical remission state. Surgical stage, tumor grade, initial tumor volume, residual tumor volume, histopathologic differentiation, and SLL findings were analyzed in correlation with DNA ploidy and DNA index. DNA analysis was performed via DNA flow cytometry through paraffin-embedded tissue specimens. RESULTS: Of 26 patients, flow cytometric studies revealed 16 aneuploidy cases (61.5%). DNA index values ranged from 1.1 to 1.82 (average 1.29 +/- 0.28). The flow cytometry coefficient of variation mean value was set to 6.7. Taking the cutoff value of 1.2 for DNA indices, a fairly good correlation was detected between DNA ploidy and DNA indices (p < 0.001). The aneuploidy incidence was found to be high in advanced and poorly differentiated tumors (p < 0.05). There was statistically more residual tumor volume in aneuploid tumors during primary cytoreductive surgery and also higher recurrence rates following six courses of chemotherapy compared with diploid tumors (p < 0.05). No significant correlation was detected between the histopathologic subtypes and tumor volume (p > 0.05). Residual tumor volumes were larger in cases with DNA indices of 1.2 yielding higher residual tumor volume following surgery and being in good correlation with SLL results (p < 0.05). The mean survival rates of cases with aneuploid tumor and a DNA index of >1.2 were low compared to those with diploid tumors and DNA indices of <1.2 tumors (p < 0.05). CONCLUSION: DNA ploidy and DNA indices are important prognosticators for malignant epithelial ovarian tumors. They should be evaluated together with the patient's clinical status and other prognostic factors. Copyright 2001 S. Karger AG, Basel
UI - 11590094
AU - Yeung KY; Ruzzo WL
TI - Principal component analysis for clustering gene expression data.
SO - Bioinformatics 2001 Sep;17(9):763-74
AD - Computer Science and Engineering, Box 352350, University of Washington, Seattle, WA 98195, USA. email@example.com
MOTIVATION: There is a great need to develop analytical methodology to analyze and to exploit the information contained in gene expression data. Because of the large number of genes and the complexity of biological networks, clustering is a useful exploratory technique for analysis of gene expression data. Other classical techniques, such as principal component analysis (PCA), have also been applied to analyze gene expression data. Using different data analysis techniques and different clustering algorithms to analyze the same data set can lead to very different conclusions. Our goal is to study the effectiveness of principal components (PCs) in capturing cluster structure. Specifically, using both real and synthetic gene expression data sets, we compared the quality of clusters obtained from the original data to the quality of clusters obtained after projecting onto subsets of the principal component axes. RESULTS: Our empirical study showed that clustering with the PCs instead of the original variables does not necessarily improve, and often degrades, cluster quality. In particular, the first few PCs (which contain most of the variation in the data) do not necessarily capture most of the cluster structure. We also showed that clustering with PCs has different impact on different algorithms and different similarity metrics. Overall, we would not recommend PCA before clustering except in special circumstances.
UI - 11592838
AU - Rudginsky S; Siders W; Ingram L; Marshall J; Scheule R; Kaplan J
TI - Antitumor activity of cationic lipid complexed with immunostimulatory DNA.
SO - Mol Ther 2001 Oct;4(4):347-55
AD - Genzyme Corporation, Framingham, Massachusetts 01701, USA.
We previously reported that treatment of intraperitoneal tumors with complexes of cationic lipid and noncoding plasmid DNA leads to the development of a specific, cytotoxic T-cell response correlating with the rejection of established tumor cells as well as subsequent tumor re-challenge. Here, focusing on an intraperitoneal AB12 mesothelioma model, we show that the anticancer effects of the lipid:DNA complex are associated with DNA containing immunostimulatory CpG motifs. Complexes prepared with cationic lipid and bacterial plasmid DNA, Escherichia coli genomic DNA fragments, or synthetic immunostimulatory CpG oligodeoxynucleotides provided a substantial survival benefit, whereas eukaryotic DNA and methylated bacterial DNA had little or no therapeutic activity. Alternative inflammatory stimuli such as thioglycolate, poly(I:C), and incomplete or complete Freund's adjuvant failed to reproduce the antitumor activity obtained with the lipid:DNA complex. The innate immune response triggered by lipid:DNA complexes led to the development of a systemic immune response against tumor cells that allowed animals to reject tumors not only at the intraperitoneal treatment site, but also at a distal subcutaneous site. These data demonstrate that immunostimulatory DNA complexed with cationic lipid is a potent inducer of innate and adaptive immune responses against tumor cells and represents a potentially useful tool in the immunotherapy of cancers for which tumor-associated antigens have not been identified.
UI - 11595686
AU - Reles A; Wen WH; Schmider A; Gee C; Runnebaum IB; Kilian U; Jones LA;
TI - El-Naggar A; Minguillon C; Schonborn I; Reich O; Kreienberg R; Lichtenegger W; Press MF Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer.
SO - Clin Cancer Res 2001 Oct;7(10):2984-97
AD - Department of Pathology, University of Southern California School of Medicine, Los Angeles, CA 90033, USA.
PURPOSE: The p53 tumor suppressor gene plays a central role in cell cycle regulation and induction of apoptosis. We analyzed p53 alterations and their impact on response to chemotherapy and clinical outcome in ovarian cancer patients. EXPERIMENTAL DESIGN: One hundred seventy-eight ovarian carcinomas, snap frozen and stored at -80 degrees C, were analyzed for mutations of the p53 gene (exons 2-11) by single-strand conformation polymorphism and DNA sequencing and for p53 overexpression by immunohistochemistry (monoclonal antibody DO7). RESULTS: p53 mutations were found in 56% (99 of 178) of the tumors, and 62% of these were located in evolutionary highly conserved domains of the gene. Time to progression and overall survival were significantly shortened in patients with p53 mutations compared with wild-type p53 (P = 0.029 and P = 0.014) and patients with mutations in highly conserved domains as opposed to nonconserved domains or wild-type p53 (P = 0.010 and P = 0.007). p53 protein overexpression (>10% positively stained nuclei) was found in 62% (110 of 178). Time to progression and overall survival were shorter in cases with p53 overexpression (cutpoint, 10%: P = 0.071 and P = 0.056) but only marginally significant. Resistance to adjuvant cisplatin or carboplatin chemotherapy was significantly more frequent in patients with p53 overexpression (P = 0.001) or p53 missense mutations (P = 0.008) than patients with normal p53. CONCLUSIONS: p53 alterations correlate significantly with resistance to platinum-based chemotherapy, early relapse, and shortened overall survival in ovarian cancer patients in univariate analysis. In multivariable analysis though, p53 was not an independent prognostic factor.
UI - 11595708
AU - Sekine M; Nagata H; Tsuji S; Hirai Y; Fujimoto S; Hatae M; Kobayashi I;
TI - Fujii T; Nagata I; Ushijima K; Obata K; Suzuki M; Yoshinaga M; Umesaki N; Satoh S; Enomoto T; Motoyama S; Tanaka K; Japanese Familial Ovarian Cancer Study Group Mutational analysis of BRCA1 and BRCA2 and clinicopathologic analysis of ovarian cancer in 82 ovarian cancer families: two common founder mutations of BRCA1 in Japanese population.
SO - Clin Cancer Res 2001 Oct;7(10):3144-50
AD - Department of Obstetrics and Gynecology, Niigata University School of Medicine, 1-757, Asahimachi-dori, Niigata City 951-8510, Japan.
We analyzed genetic alterations in BRCA1 and BRCA2 genes among 82 ovarian cancer families in Japan. The clinical characteristics of BRCA-associated ovarian cancer patients were compared with cases carrying no mutations as well as with population controls. Using a direct sequencing method, 45 of the 82 ovarian cancer families were found to carry BRCA1 or BRCA2 germ-line mutations (40 with BRCA1 and 5 with BRCA2). In 24 independent mutations of BRCA1, 5 recurrent mutations were found and 2 of them, the L63X and Q934X mutations, were detected in seven and eight independent families, respectively. In addition, 16 mutations of BRCA1 and 3 mutations of BRCA2 have never been described previously. In consideration of clinicopathological features, there was a significantly higher proportion of tumors with serous adenocarcinoma and of cases of advanced stages in the BRCA1 or BRCA2 cases than in those of the controls. On the other hand, there were no differences of mean age at diagnosis between patients with BRCA1 or BRCA2 mutation and those of the controls. Our results indicate that the features of BRCA-associated ovarian cancer in Japan appear to be similar to those in Western countries, and the L63X and Q934X mutations of BRCA1 appear to be common founder mutations unique to the Japanese population.
UI - 11597388
AU - Verhoog LC; van den Ouweland AM; Berns E; van Veghel-Plandsoen MM; van
TI - Staveren IL; Wagner A; Bartels CC; Tilanus-Linthorst MM; Devilee P; Seynaeve C; Halley DJ; Niermeijer MF; Klijn JG; Meijers-Heijboer H Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families.
SO - Eur J Cancer 2001 Nov;37(16):2082-90
AD - Division of Tumour Endocrinology, Department of Medical Oncology,