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A Berchuck

Publications and source records attributed to A Berchuck.

At least 37 records · Page 2Linked to original sources
PubMed1999

Managing hereditary ovarian cancer risk.

Ovarian cancer is the fourth leading cause of cancer deaths in American women. About 10% of cases are thought to have a hereditary basis, and family history is the strongest known risk factor. In the past, prophylactic oophorectomy has been advocated for women with two or more affected first-degree relatives. More recently, with the identification of the genes responsible for most hereditary ovarian cancers (BRCA1, BRCA2), oophorectomy can now be offered specifically to women who are mutation carriers. Conversely, noncarriers in these families can be reassured that their risk of ovarian cancer is not increased. The value of oophorectomy in mutation carriers has not yet been proven, however, and concern exists that the benefit may be less than intuitively expected. First, although the lifetime risk of ovarian cancer initially was reported to be as high as 60%, more recent studies have suggested risks in the range of 15 to 30%. A better understanding of the factors that underlie variable penetrance in mutation carriers is needed to augment our ability to counsel individual women. In addition, peritoneal papillary serous carcinoma indistinguishable from ovarian cancer occurs in some women after oophorectomy. Studies that better define the frequency with which this occurs are needed to establish the magnitude of the protective effect conferred by prophylactic oophorectomy. In view of the uncertainty regarding the efficacy of prophylactic oophorectomy, chemopreventive and early detection approaches also deserve consideration as strategies for decreasing ovarian cancer mortality in women who carry mutations in ovarian cancer susceptibility genes.

BRCA1 Protein↗
PubMed1999

Combination of multiple serum markers using an artificial neural network to improve specificity in discriminating malignant from benign pelvic masses.

A panel of four selected tumor markers, CA 125 II, CA 72-4, CA 15-3, and lipid-associated sialic acid, was analyzed collectively using an artificial neural network (ANN) approach to differentiate malignant from benign pelvic masses. A dataset of 429 patients, 192 of whom had malignant histology, was retrospectively used in the study. A prototype ANN classifier was developed using a subset of the data which included 73 patients with malignant conditions and 101 patients with benign conditions. The ANN classifier demonstrated a much improved specificity over that of the assay CA 125 II alone (87.5% vs 68.4%) while maintaining a statistically comparable sensitivity (79.0% vs 82.4%) in discriminating malignant from benign pelvic masses in an independent validation test using data from the remaining 255 patients which had been set aside and kept blind to the developers of the ANN system. A similar improvement in specificity was observed among patients under 50 years of age (82.3% vs 62.0%). The ANN system was further tested using additional serum specimens collected from 196 apparently healthy women. The ANN system had a specificity of 100.0% compared to that of 94.8% with the assay CA 125 II alone.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1999

Cost-effectiveness of treatment of early stage endometrial cancer.

OBJECTIVE: The purpose of this study was to determine the average life-years gained and cost per life-year gained in treatment of early endometrial cancer. METHODS: We performed a decision analysis using statistical models for survival after treatment for Stage I endometrial cancer. Estimates for survival probabilities without treatment, with surgery alone, and with surgery and radiation were derived from the literature. Charges and costs of treatment were estimated based on data from our institution. We calculated the average number of life-years gained and the cost per life-year gained of various treatment options based on these estimates. Sensitivity analyses were performed to determine the effect of uncertainty about parameter estimates on the results derived from our model. RESULTS: Based on the assumptions of our model, most of the life-years gained in treatment of early endometrial cancer are attributable to hysterectomy, with a very low associated cost. For the "average" woman with endometrial cancer, about 10 life-years are gained from hysterectomy at a cost of $1000 per life-year gained, whereas adjuvant radiation yields on average 1 year of life gained at $4000 per life-year gained. Both life-years gained and cost are dramatically affected by age at diagnosis and to a lesser extent by histologic grade and comorbid medical conditions. CONCLUSIONS: This analysis suggests that the use of hysterectomy and adjuvant radiation in treatment of early endometrial cancer is a worthwhile use of health care resources. More sophisticated models may help determine the cost-effectiveness of various treatment strategies in specific subgroups of patients.

Adult↗
PubMed1999

Allelic loss on chromosome arm 8p: analysis of sporadic epithelial ovarian tumors.

OBJECTIVE: Our objective was to determine the frequency of allelic loss at 8p21 in sporadic epithelial ovarian cancer. We recently described allelic loss at this locus in 7/9 ovarian cancers from patients with BRCA1 gene mutations. METHODS: We anonymously obtained and examined 40 unselected invasive epithelial ovarian cancers and 5 low-malignant-potential (LMP) ovarian tumors for loss of heterozygosity (LOH) at 8p12-22. Pure epithelial and stromal cell populations were procured selectively by laser capture microdissection and extracted DNA was amplified with polymorphic microsatellite markers spanning the region of interest. RESULTS: LOH was highest (50%) at marker D8S136 located at 8p21 with 15 of 30 informative cases exhibiting an allelic deletion. None of the LMP tumors evaluated showed LOH at 8p12-22. A trend toward more frequent LOH at 8p12-22 was identified with increasing disease aggressiveness from LMP to early stage invasive ovarian cancer to advanced stage invasive ovarian cancer (Lehman's test, P2 < 0.024). CONCLUSIONS: Fifty percent allelic loss at the distal portion of 8p21 has not been reported to date for sporadic epithelial ovarian carcinomas. The higher rate of loss in our cohort, in contrast to previous allelotyping studies, is due likely to analysis from homogenous cell populations. These results, in concert with our previous study of BRCA1 mutation-positive patients, suggest a tumor suppressor gene locus at 8p21 for epithelial ovarian cancer.

Adult↗
PubMed1999

Genetic susceptibility testing and prophylactic oophorectomy.

About 10% of ovarian cancer cases are thought to have a hereditary basis and family history is the strongest risk factor for the development of this disease. In the past, prophylactic oophorectomy has been advocated for women with two or more affected first-degree relatives. More recently, with the identification of the genes responsible for most hereditary ovarian cancers (BRCA1, BRCA2), oophorectomy can now be offered specifically to women who are mutation carriers. Conversely, non-carriers in these families can be reassured that their risk of ovarian cancer is not increased. The value of oophorectomy in mutation carriers has not yet been proven, however, and there are concerns that the benefit may be less than intuitively expected. First, although the lifetime risk of ovarian cancer initially was reported to be as high as 60%, more recent studies have reported risks in the range of 15-30%. A better understanding of the genetic and/or environmental basis of variable penetrance is needed to augment our ability to counsel women regarding their risk. In addition, peritoneal papillary serous carcinoma indistinguishable from ovarian cancer occurs in some women following oophorectomy. Studies that better define how often this occurs also are needed to establish more firmly the value of prophylactic oophorectomy. In view of the uncertainty regarding the efficacy of prophylactic oophorectomy, chemopreventive and early detection approaches also deserve consideration as strategies for decreasing ovarian cancer mortality in women who carry mutations in ovarian cancer susceptibility genes.

BRCA2 Protein↗
PubMed1999

Bcl10 is not a target for frequent mutation in human carcinomas.

The recently described Bcl10 gene has been suggested to be a major target gene for inactivation in a variety of human cancers. In order to further evaluate the role of this gene in human adult malignancies, we have analysed a series of carcinomas for mutations in the Bcl10 gene. We have screened a panel of 174 carcinoma samples in total, comprised of 47 breast, 36 epithelial ovarian, 36 endometrial, 12 cervical, 23 colorectal and 20 head/neck carcinomas, all unselected for grade or stage. This panel reflects, in part, tumours reported to have involvement of the 1p22 region of chromosome 1, the region harbouring the Bcl10 gene. No deleterious mutations were detected in any of the samples analysed, strongly suggesting that Bcl10 is not a common target for inactivation in adult malignancies and that BCL10 is not the gene targeted for frequent inactivation at 1p22.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Accumulation of p53 protein is frequent in ovarian cancers associated with BRCA1 and BRCA2 germline mutations.

BACKGROUND: Mutations in the BRCA1 or BRCA2 genes are responsible for up to 95% of hereditary ovarian cancer cases. Both genes function as tumour suppressor genes, and development of a cancer is thought to require an accumulation of somatic genetic events in addition to the inherited germline predisposition. It is unknown whether these somatic events in BRCA associated ovarian cancer are similar to or distinct from those in sporadic cases. The most frequent somatic genetic event in ovarian cancer is a mutation of the p53 gene. AIM: To study the role of p53 in hereditary ovarian cancer, by analysing accumulation of the p53 protein in ovarian cancers which occurred in BRCA1 or BRCA2 germline mutation carriers and comparing the results with a panel of ovarian cancers from patients who tested negative for both BRCA1 and BRCA2. METHODS: The study group consisted of 39 ovarian cancer patients in whom a BRCA mutation had been confirmed previously. p53 Immunohistochemistry was performed on archival tissue using a standard microwave antigen retrieval technique. The rate of p53 accumulation was compared with 40 ovarian cancer cases who tested negative for BRCA1 and BRCA2 germline mutations. RESULTS: P53 Accumulation was similar in BRCA related ovarian cancers and BRCA negative controls. Overall 27 of 39 BRCA1 or BRCA2 positive cases (69%) had evidence of p53 accumulation, compared with 24 of 40 invasive ovarian cancer cases (60%) which tested negative for BRCA1 and BRCA2 germline mutations. BRCA1 related ovarian cancers showed p53 accumulation in 22 of 30 cases (73%); p53 accumulation was present in five of nine BRCA2 related ovarian cancers. CONCLUSIONS: In addition to germline BRCA1 and BRCA2 mutations, somatic p53 alterations leading to p53 accumulation are an important event in hereditary ovarian cancer and are as frequent as in non-BRCA-related ovarian cancer.

BRCA2 Protein↗
PubMed1998

Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias.

Mutation and deletion of the PTEN tumor suppressor gene occurs in about 40% of endometrial carcinomas. The purpose of this study was to determine whether PTEN mutations also are present in endometrial hyperplasias, which are premalignant precursors of invasive endometrial adenocarcinomas. Genomic DNA from 51 endometrial hyperplasias was extracted from paraffin blocks, and PCR was used to amplify the nine exons of the PTEN gene. These products were screened using single-strand conformation analysis, and variant bands were sequenced. Somatic mutations in the PTEN gene were seen in 10 of 51 cases (20%), and two mutations were found in one case. An identical 4-bp deletion in exon 8 was seen in three cases, and 8 of 11 PTEN mutations predicted truncated protein products. There was no higher frequency of PTEN mutations in endometrial hyperplasias with atypia (6 of 32; 19%) relative to those without atypia (4 of 19; 21%). These data suggest that inactivation of the PTEN tumor suppressor gene is an early event in the development of some endometrial cancers.

Endometrial Hyperplasia↗
PubMed1998

Allelotype analysis of uterine leiomyoma: localization of a potential tumor suppressor gene to a 4-cM region of chromosome 7q.

Uterine leiomyoma is a benign smooth muscle tumor of the myometrium and is the most commonly encountered neoplasm in women of reproductive age. As for most benign tumors, the pathogenesis of leiomyoma remains obscure, especially at the molecular genetic level. The purpose of this study was to perform a genome-wide allelotype analysis to identify potential sites of tumor suppressor gene inactivation. Fifty-two cases of uterine leiomyoma were subjected to allelotype analysis by using matched pairs of tumor and blood DNA. Loss of heterozygosity (LOH) was assessed at 61 microsatellite markers distributed throughout the genome and representing all 41 chromosome arms. In general, LOH was very rare except on chromosome 7q, where LOH was observed in 34% of all informative tumors. Fine-deletion mapping with 25 microsatellite markers from the 7q22 region revealed a minimal deletion unit of approximately 4 cM, bounded by the markers D7S2453 proximally and D7S496 distally, that probably harbors a novel tumor suppressor gene involved in the etiology of this tumor.

Alleles↗
PubMed1998

Mutation of the PTEN tumor suppressor gene is not a feature of ovarian cancers.

OBJECTIVE: The PTEN tumor suppressor gene on chromosome 10q23 undergoes inactivating mutations in several types of malignancies including glioblastomas and prostate and endometrial carcinomas. The aim of this study was to determine if mutation of the PTEN tumor suppressor gene is a feature of sporadic or BRCA1-associated ovarian carcinomas. METHODS: Genomic deoxyribonucleic acid was extracted from 11 ovarian cancer cell lines and 50 frozen ovarian cancers, including 4 cases that developed in women with germline mutations in the BRCA1 breast/ovarian cancer susceptibility gene. The polymerase chain reaction was used to amplify each of the nine exons and intronic splice sites of the PTEN gene. These products were then screened for mutations using single strand conformation polymorphism analysis. Variant bands were further evaluated using automated DNA sequencing. RESULTS: A previously unreported silent polymorphism at codon 240 (TAT to TAC) in exon 7 was noted in one of the primary ovarian carcinomas. Mutations in the PTEN gene were not found in any of the 50 primary ovarian cancers or 11 immortalized ovarian cancer cell lines. CONCLUSION: Alteration of the PTEN tumor suppressor gene does not appear to be a feature of sporadic or BRCA1-associated ovarian cancers.

Exons↗
PubMed1998

Suppression of diacylglycerol levels by antibodies reactive with the c-erbB-2 (HER-2/neu) gene product p185c-erbB-2 in breast and ovarian cancer cell lines.

Seven of 10 murine monoclonal antibodies reactive with the extracellular domain of p185c-erbB-2 inhibited the anchorage independent growth of the SKBr3 breast cancer cell line that overexpressed p185c-erbB-2. Significant inhibition (56-72%) of diacylglycerol (DAG) levels (P < 0.0001) was observed with the 10 antibodies that inhibited SKBr3 growth (RC1, NB3, RC6, PB3, 741F8, DB5, ID5), whereas the 3 antibodies (TA1, 520C9, 454C11) that failed to inhibit SKBr3 growth also failed to affect DAG levels. Thus, DAG levels correlated with antibody-mediated growth regulation for each of the 10 monoclonal reagents. Antibody-induced inhibition of anchorage-independent growth of SKBr3 could be reversed by incubation with phorbol myristate acetate. The ID5 antibody inhibited growth of the SKBr3, SKOv3, and OVCA 432 tumor cell lines, but not of OVCA 420, OVCA 429, and OVCA 433. DAG levels were significantly decreased after ID5 treatment of the SKBr3 and SKOv3 cell lines, but not the OVCA 420, OVCA 429, and OVCA 433 lines. In the 432 line, there was a decrease which did not reach significance. Consequently, changes in DAG levels correlated with growth regulation in 5 of 6 breast and ovarian carcinoma cell lines tested with a trend toward correlation in the sixth. Decreases in DAG may be one mediator of the growth regulatory signals produced by anti-p185c-erbB-2 antibodies.

Antibodies, Monoclonal↗
PubMed1998

Coexpression of the HER-2 gene product, p185HER-2, and epidermal growth factor receptor, p170EGF-R, on epithelial ovarian cancers and normal tissues.

Monoclonal antibodies (MAbs) and immunoconjugates reactive with different antigens expressed by neoplastic cells can inhibit tumor growth. Use of these agents in combination with one another or with chemotherapy can exert additive or synergistic cytotoxicity against tumor cells. An augmented therapeutic activity with favorable therapeutic index might be attained when coexpression is observed on tumor cells, but not in normal tissues. In this study frozen sections of 19 ovarian cancers (2 stage I, 10 stage III, 2 stage IV, and 5 recurrent), as well as 29 normal tissues, were evaluated by immunohistochemistry using 11 distinct MAbs against HER-2/p185 and 2 antibodies against EGF-R/p170 to assess coexpression of these receptors. HER-2/p185 expression was detected in 5 to 100% of ovarian cancers and 0 to 50% of normal ovarian epithelia, depending on the antibody used. EGF-R/p170 expression was detected in approximately 70% of cancers and 40% of normal ovaries by both antibodies. Coexpression of p185 and p170 was observed in 47-68% of ovarian cancers and 9-18% of normal ovarian epithelial specimens depending upon the combination of antibodies used. Staining of 273 specimens from 29 normal tissues indicated that coexpression of HER-2 and EGF-R is rare. Normal tissues that coexpressed both receptors in > or =50% of the cases included cervix, endometrium, esophagus, skin, and prostate. These data confirm that HER-2 and EGF-R are more frequently expressed in advanced ovarian cancers than in normal ovarian epithelium and a significant fraction of these tumors coexpress both HER-2 and EGF-R.

Antibodies, Monoclonal↗
PubMed1998

Frequency of germline and somatic BRCA1 mutations in ovarian cancer.

Germline mutations in the BRCA1 tumor suppressor gene are thought to be the most common cause of hereditary ovarian cancer. The aim of this study was to explore further the role of BRCA1 alterations in the development of ovarian cancers. We sought to determine whether somatic BRCA1 mutations are ever present in ovarian cancers and whether mutation is always accompanied by loss of the wild-type allele. The entire coding region and intronic splice sites of BRCA1 were sequenced using genomic DNA samples from 103 unselected ovarian cancers. Thirteen clearly deleterious BRCA1 mutations and two variants of uncertain significance were found. Blood DNA was available in all but two cases and demonstrated that 4 of 13 mutations and both variants of uncertain significance were germline alterations, whereas in seven cases the mutation was a somatic change present only in the cancer. Using four microsatellite markers, loss of heterozygosity at the BRCA1 locus was found in all 15 ovarian cancers with BRCA1 sequence alterations, compared with only 58% of ovarian cancers that did not have BRCA1 mutations. BRCA1-associated ovarian cancers were characterized by serous histology and moderate histological grade. These data confirm prior reports suggesting that germline mutations in BRCA1 are present in about 5% of women with ovarian cancer. In addition, somatic mutations in BRCA1 occur in the development of some sporadic cases. The finding that both germline and somatic BRCA1 mutations are accompanied by loss of heterozygosity, suggests that loss of this tumor suppressor gene is a critical event in the development of these cancers.

Adult↗
PubMed1998

PTEN mutation in endometrial cancers is associated with favorable clinical and pathologic characteristics.

Mutation of the PTEN tumor suppressor gene is a frequent event in endometrial cancers. In other types of cancers, PTEN mutation has been associated with metastatic behavior and advanced stage. To examine the relationship between PTEN mutation and clinical features of endometrial cancers, we screened 136 cases for mutations in the nine exons and intronic splice sites of the PTEN gene, using single-strand conformation analysis, and aberrant bands were sequenced. Mutations were noted in 44 of 136 (32%) endometrial cancers, and two mutations were present in 8 cases. There were 36 cases with mutations resulting in truncated protein products, 6 cases with missense mutations in the phosphatase domain, 1 case with an in-frame deletion, and 1 case with a large insertion. Mutation of the PTEN gene correlated most closely with endometrioid histology; mutations were seen in only 5% (1 of 21) of serous/clear cell cancers compared with 37% (43 of 115) of endometrioid cancers (P = 0.004). PTEN mutation was associated with early stage, nonmetastatic disease and more favorable survival in both the entire group of 136 cases and in the 115 endometrioid cases. In addition, PTEN mutation correlated with other molecular features associated with favorable clinical behavior, including microsatellite instability and absence of p53 overexpression. Microsatellite instability was found in 60% of cases with PTEN mutations compared with only 25% of cases without mutations (P = 0.004). Overexpression of p53 was seen in only 14% of cases with PTEN mutations compared to 39% of cases without mutations (P = 0.006). In conclusion, PTEN mutation is associated with endometrioid histology and other favorable pathological, clinical, and molecular features rather than with increased metastatic potential as has been noted in some other types of cancers.

Adult↗
PubMed1997

PTEN/MMAC1 mutations in endometrial cancers.

Endometrial carcinomas represent the most common gynecological cancer in the United States, yet the molecular genetic events that underlie the development of these tumors remain obscure. Chromosome 10 is implicated in the pathogenesis of endometrial carcinoma based on loss of heterozygosity (LOH), comparative genomic hybridization, and cytogenetics. Recently, a potential tumor suppressor gene, PTEN/MMAC1, with homology to dual-specificity phosphatases and to the cytoskeletal proteins tensin and auxillin was identified on chromosome 10. This gene is mutated in several types of advanced tumors that display frequent LOH on chromosome 10, most notably glioblastomas. Additionally, germ-line mutations of PTEN/MMAC1 are responsible for several familial neoplastic disorders, including Cowden disease and Bannayan-Zonana syndrome. Because this locus is included in the region of LOH in many endometrial carcinomas, we examined 70 endometrial carcinomas for alterations in PTEN/MMAC1. Somatic mutations were detected in 24 cases (34%) including 21 cases that resulted in premature truncation of the protein, 2 tumors with missense alterations in the conserved phosphatase domain, and 1 tumor with a large insertion. These data indicate that PTEN/MMAC1 is more commonly mutated than any other known gene in endometrial cancers.

Adenocarcinoma↗
PubMed1997

Human ovarian cancer of the surface epithelium.

Epidemiologic studies have shown that the risk of cancer in the ovarian surface epithelium is decreased by factors that suppress ovulation, whereas uninterrupted ovulation has been associated with increased risk. This suggests that ovulation may play a critical role in ovarian carcinogenesis. More recently, molecular studies have demonstrated alterations in specific oncogenes and tumor suppressor genes in ovarian cancers. Overexpression of the HER-2/neu oncogene occurs in approximately 30% of ovarian cancers and correlates with poor survival. Although mutation of the K-ras oncogene has been found in some mucinous ovarian cancers, mutations in this gene appear to be more common in borderline ovarian tumors. Amplification of c-myc occurs in approximately 30% of ovarian cancers and is more frequently seen in serous cancers. Mutation of the p53 tumor suppressor gene, with resultant overexpression of mutant p53 protein, occurs in 50% of stage III/IV and 15% of stage I/II ovarian cancers. Most p53 mutations in ovarian cancers are transitions, which suggests that they arise spontaneously rather than due to exogenous carcinogens. In contrast to the acquired genetic alterations described above that are a feature of sporadic ovarian cancers, 5-10% of ovarian cancers probably arise due to inherited genetic defects. Recently, the BRCA1 tumor suppressor gene has heen identified and shown to be responsible for most cases of hereditary ovarian cancer. Further studies are needed to augment our understanding of the molecular pathogenesis of ovarian cancer.

BRCA1 Protein↗