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A Berchuck

Publications and source records attributed to A Berchuck.

At least 73 records · Page 4Linked to original sources
PubMed1996

BRCA2 mutations in primary breast and ovarian cancers.

The second hereditary breast cancer gene, BRCA2, was recently isolated. Germline mutations of this gene predispose carriers to breast cancer, and, to a lesser extent, ovarian cancer. Loss of heterozygosity (LOH) at the BRCA2 locus has been observed in 30-40% of sporadic breast and ovarian tumours, implying that BRCA2 may act as a tumour suppressor gene in a proportion of sporadic cases. To define the role of BRCA2 in sporadic breast and ovarian cancer, we screened the entire gene for mutations using a combination of techniques in 70 primary breast carcinomas and in 55 primary epithelial ovarian carcinomas. Our analysis revealed alterations in 2/70 breast tumours and none of the ovarian carcinomas. One alteration found in the breast cancers was a 2-basepair (bp) deletion (4710delAG) which was subsequently shown to be a germline mutation, the other was a somatic missense mutation (Asp3095Glu) of unknown significance. Our results suggest that BRCA2 is a very infrequent target for somatic inactivation in breast and ovarian carcinomas, similar to the results obtained for BRCA1.

Aged↗
PubMed1996

Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair.

Many human tumours have length alterations in repetitive sequence elements. Although this microsatellite instability has been attributed to mutations in four DNA mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) kindreds, many sporadic tumours exhibit instability but no detectable mutations in these genes. It is therefore of interest to identify other genes that contribute to this instability. In yeast, mutations in several genes, including RTH and MSH3, cause microsatellite instability. Thus, we screened 16 endometrial carcinomas with microsatellite instability for alterations in FEN1 (the human homolog of RTH) and in MSH3 (refs 12-14). Although we found no FEN1 mutations, a frameshift mutation in MSH3 was observed in an endometrial carcinoma and in an endometrial carcinoma cell line. Extracts of the cell line were deficient in repair of DNA substrates containing mismatches or extra nucleotides. Introducing chromosome 5, encoding the MSH3 gene, into the mutant cell line increased the stability of some but not all microsatellites. Extracts of these cells repaired certain substrates containing extra nucleotides, but were deficient in repair of those containing mismatches or other extra nucleotides. A subsequent search revealed a second gene mutation in HHUA cells, a missense mutation in the MSH6 gene. Together the data suggest that the MSH3 gene encodes a product that functions in repair of some but not all pre-mutational intermediates, its mutation in tumours can result in genomic instability and, as in yeast, MSH3 and MSH6 are partially redundant for mismatch repair.

Base Sequence↗
PubMed1996

Role of BRCA1 mutation screening in the management of familial ovarian cancer.

Families with multiple cases of ovarian cancer have long been observed, and in the past prophylactic oophorectomy has been advocated for women with a history of ovarian cancer in two first-degree relatives. It is now thought that > 90% of familial ovarian cancer is due to inherited mutations in the BRCA1 breast-ovarian cancer susceptibility gene on chromosome 17q. BRCA1 testing is being performed in several academic medical centers on a research basis and is also now commercially available. With the ability to identify inherited mutations in BRCA1, prophylactic oophorectomy and other interventions intended to decrease cancer mortality can be offered specifically to women who carry a mutation, but the optimal strategy for decreasing cancer mortality in BRCA1 families has not yet been determined. To facilitate further clinical and basic research in this field, our group and others have established multidisciplinary hereditary breast-ovarian cancer clinics that offer a wide range of services including BRCA1 testing, genetic counseling, and cancer prevention and treatment.

Chromosomes, Human, Pair 17↗
PubMed1996

BRCA1 expression is induced before DNA synthesis in both normal and tumor-derived breast cells.

Insight into the function of the BRCA1 tumor suppressor gene may be gained by studying its regulation. In this study, the expression of BRCA1 was examined as a function of the cell cycle in normal and tumor-derived breast epithelial cells. Cells arrested in G(zero) or early in G1 contained low levels of BRCA1 mRNA. After release, populations of cells reached maximal levels of BRCA1 in late G1 and S phase. Induction of BRCA1 was shown to occur before the onset of DNA synthesis by synchronizing cells at the G1-S boundary. Levels of the BRCA1 protein were regulated in a similar manner. No difference was observed between primary cultures of normal mammary epithelial cells and immortalized tumor-derived cell lines. These results suggest that BRCA1 may function at the G1-S checkpoint.

Adult↗
PubMed1996

Relationship between p21 expression and mutation of the p53 tumor suppressor gene in normal and malignant ovarian epithelial cells.

In many cell types, p53-mediated growth inhibition is dependent on induction of p21, which is an inhibitor of cyclin-dependent kinases that are required for cell cycle progression. Failure of mutant p53 proteins to transactivate p21 may lead to uncontrolled proliferation. Because many ovarian cancers have mutations in the p53 gene, we examined p21 levels in normal and malignant ovarian epithelial cells to determine whether p21 expression is dependent on wild-type p53. Normal ovarian epithelial cells and two ovarian cancer cell lines with wild-type p53 expressed readily detectable levels of p21, whereas in p53 null and mutant cell lines, expression of p21 was diminished strikingly. A correlation between the status of the p53 gene and p21 expression also was noted in 23 primary epithelial ovarian cancers. Normal levels of p21 RNA were seen in 4/7 (57%) cancers with wild-type p53, whereas 14/16 (88%) cancers with mutant p53 had reduced p21 expression (P < 0.05). In addition, we found that lambda-irradiation of normal and malignant ovarian epithelial cells with wild-type, but not mutant, p53 resulted in induction of p21. These data are suggestive that induction of p21 is a feature of p53-mediated growth inhibition in normal ovarian epithelial cells. Conversely, mutation of the p53 gene in ovarian cancers usually is associated with decreased p21 expression. The lack of an absolute correlation between p21 expression and the status of the p53 gene in ovarian cancers is consistent with other studies that have suggested that p21 may also be regulated by p53-independent pathways.

Blotting, Northern↗
PubMed1995

Microsatellite instability in gynecological sarcomas and in hMSH2 mutant uterine sarcoma cell lines defective in mismatch repair activity.

We have examined a panel of gynecological sarcomas for microsatellite instability. The genomic DNA from 11 of 44 sarcomas contained somatic alterations in the lengths of one or more di-, tri-, tetra-, or pentanucleotide microsatellite sequence markers, and 6 of these cases had alterations in two or more markers. In addition, di-, tri-, and tetranucleotide microsatellites were found to be highly unstable in single cell clones of two cell lines derived from a uterine mixed mesodermal tumor. Since such instability is characteristic of cells defective in postreplication mismatch repair, we examined mismatch repair activity in extracts made from these lines. Both extracts were repair deficient, while an extract of another gynecological sarcoma cell line not exhibiting microsatellite instability was repair proficient. The repair deficiency was complemented by a colon tumor cell extract that was defective in the hMLH1 protein but not by an extract defective in hMSH2 protein. This suggested that the defect in the uterine sarcoma line could be in hMSH2. Subsequent analysis of the gene revealed a 2-bp deletion in exon 14, leading to premature truncation of the hMSH2 protein at codon 796 and no detectable wild-type gene present. These data suggest that the microsatellite instability observed in these cell lines, and possibly in a significant number of gynecological sarcomas, is due to defective postreplication mismatch repair. There was no apparent correlation with microsatellite instability and clinical outcome.

DNA Repair↗
PubMed1995

Molecular basis of endometrial cancer.

BACKGROUND: Most human cancers are thought to arise from alterations in oncogenes and tumor suppressor genes. METHODS: Molecular techniques have been used to identify specific genetic alterations in endometrial cancers. RESULTS: Overexpression of the HER-2/neu oncogene occurs in 10% of endometrial cancers and correlates with poor survival. Alterations in other receptor tyrosine kinases (c-fms and epidermal growth factor receptor) also occur in some cases. The c-myc oncogene, which encodes a nuclear transcription factor, also may be overexpressed in some invasive cancers. Mutations in the K-ras oncogene occur in 10% and in 20-30% of American and Japanese endometrial cancers, respectively. K-ras mutations also have been observed in endometrial hyperplasias, and this may represent an early event in the development of some cancers. Mutation of the p53 tumor suppressor gene, with resultant overexpression of mutant p53 protein, occurs in 20% of endometrial adenocarcinomas. Overexpression of p53 is associated with advanced stage and poor survival. Because p53 mutations do not occur frequently in endometrial hyperplasias, this may be a relatively late event in endometrial carcinogenesis. Recent studies have shown that mutations occur in microsatellite sequences in some endometrial cancers. Because microsatellite instability in hereditary nonpolyposis colon cancer has been found to be caused by mutations in DNA repair genes, similar mutations are being sought in endometrial cancers. CONCLUSIONS: Although several molecular alterations have been identified, the molecular pathogenesis of endometrial cancer remains poorly understood.

Amidohydrolases↗
PubMed1995

Soluble interleukin-2 receptor alpha is elevated in sera of patients with benign ovarian neoplasms and epithelial ovarian cancer.

BACKGROUND: Previous studies have established that soluble interleukin-2 receptor alpha (sIL-2R alpha) levels are elevated in ascites and sera from individuals with advanced ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] Stage III/IV). This study was undertaken to evaluate sIL-2R alpha levels in individuals with benign ovarian neoplasms and early stage ovarian cancer (FIGO Stage I/II). Comparison with CA 125 levels was performed to assess screening potential. METHODS: Sera from 92 healthy individuals, 61 with benign adnexal masses, 12 patients with FIGO Stage I/II ovarian cancers, and 27 patients with FIGO Stage III/IV ovarian cancers were assayed for sIL-2R alpha by enzyme-linked immunosorbent assay and CA 125 by radioimmunoassay. RESULTS: The mean serum sIL-2R alpha levels for benign pelvic masses, and Stage I/II and Stage III/IV epithelial ovarian cancer were 1507 +/- 82, 1631 +/- 274, and 2596 +/- 384 U/ml, respectively. The difference between mean serum sIL-2R alpha levels in individuals with benign adnexal masses and Stage III/IV epithelial ovarian cancer was statistically significant (P < 0.05). In addition, of the four individuals with FIGO Stage I/II ovarian cancer who had CA125 levels below 35 U/ml, the accepted upper limit of normal, three patients had elevated serum sIL-2R alpha levels. Eleven of 12 patients (92%) with potentially curable Stage I/II disease had elevated serum levels of either sIL-2R alpha or CA125 and 8 of 12 (67%) had elevations of both sIL-2R alpha and CA125. Sensitivity and specificity of a combination of CA 125 and soluble IL-2R alpha were 88.5% and 27.1%, respectively. CONCLUSION: Soluble interleukin-2 receptor alpha levels do not appear to differentiate between benign adnexal lesions and early malignancy; however, measurement of sIL-2R alpha levels in combination with CA125 warrants further evaluation to determine if together they will identify individuals with Stages I and II ovarian cancer.

Biomarkers, Tumor↗
PubMed1995

Regulation of apoptosis in normal and malignant ovarian epithelial cells by transforming growth factor beta.

Previously, we found that transforming growth factor beta (TGF-beta) inhibits proliferation of normal human ovarian epithelial cells. In addition, although only 1 of 5 immortalized ovarian cancer cell lines was inhibited, TGF-beta inhibited proliferation of 19 of 20 primary epithelial ovarian cancers. In this study, we examined whether TGF-beta induces apoptosis in normal and malignant ovarian epithelial cells. Among 5 immortalized cell lines, only OVCA 420 is markedly growth inhibited by TGF-beta, and this was the only cell line in which TGF-beta elicited DNA fragmentation characteristic of apoptosis. Induction of apoptosis in OVCA 420 was time and concentration dependent and could be partially inhibited by concurrent treatment with an anti-TGF-beta mAb. Although apoptosis was not seen in normal ovarian epithelial cells (n = 7), [3H]thymidine incorporation was inhibited in all cases [mean = 61.2 +/- 7.2% (SD) of untreated control; P < 0.01]. Similarly, TGF-beta inhibited [3H]thymidine incorporation in all 10 primary ovarian cancers (mean = 40.4 +/- 7.1% of control; P < 0.01), but only 3 of 10 (30%) were found to undergo apoptosis when treated with TGF-beta. There was no relationship between p53 status of the ovarian cancers and the ability of TGF-beta to elicit apoptosis. In conclusion, TGF-beta inhibits proliferation but does not induce apoptosis in normal human ovarian epithelial cells. In contrast, some ovarian cancers that are growth inhibited by TGF-beta also undergo apoptosis. These data are consistent with the hypothesis that malignant cells are more susceptible to apoptosis than their normal nontransformed counterparts.

Antibodies↗
PubMed1995

Biomarkers in the endometrium.

A number of oncogenes and tumor suppressor genes that may serves as surrogate biomarkers of transformation are altered during the process of endometrial carcinogenesis. Overexpression of HER-2/neu occurs in 10% of endometrial adenocarcinomas and correlates with intraperitoneal spread of disease and poor survival. The c-myc oncogene is amplified in 10% of cases. Point mutations in codon 12 of the K-ras oncogene have been reported to occur in 10-20% of endometrial cancers. K-ras mutations also have been noted in some endometrial hyperplasias, which may represent an early event in the development of some endometrial cancers. Mutation of the p53 tumor suppressor gene, with resultant overexpression of mutant p53 protein, occurs in 20% of endometrial adenocarcinomas. Overexpression of p53 is associated with advanced stage and poor survival. Because p53 mutations have not been observed in endometrial hyperplasias, this is thought to be a relatively late event in endometrial carcinogenesis. Microsatellite instability has also been noted in approximately 15% of sporadic endometrial cancers, but mutations in DNA repair genes have not yet been reported. Chemoprevention trials in endometrial cancer may be feasible due to the existence of a premalignant lesion and surrogate biomarkers.

Biomarkers, Tumor↗
PubMed1995

Molecular approaches to prevention and detection of epithelial ovarian cancer.

More than 90% of epithelial ovarian cancers arise from single cells. Malignant transformation can be associated with a number of molecular alterations including upregulation of tyrosine kinases and phosphatases, physiologic activation o ras, mutation of p53, amplification of myc, and increased activity of matrix metalloproteinases 2 and 9. Proliferation of transformed epithelial cells can be enhanced through the persistence of autocrine growth stimulation by TGF-alpha, loss of autocrine growth inhibition by TGF-beta, as well as paracrine growth stimulation by macrophage derived cytokines and OCAF, a novel lyso-phospholipid. Ascites tumor cells retain responsiveness to growth inhibition by TGF-beta which induces apoptosis in malignant ovarian epithelial cells, but not in normal ovarian surface epithelium. Proliferation of surface epithelial cells following ovulation may contribute to the pathogenesis of ovarian cancer. Use of oral contraceptives that suppress ovulation has been associated with reduced risk of ovarian cancer in later life. Retinoids also deserve further evaluation for chemoprevention. Treatment with fenretinide was associated with decreased incidence of ovarian cancer. Additive or synergistic inhibition of ovarian tumor cell proliferation has been observed with TGF-beta in combination with all-trans-retinoic acid. Early detection of ovarian cancer could improve survival. Transvaginal sonography (TVS) and serum markers such as CA-125 have been evaluated in multiple clinical trials. The former lacks adequate specificity, whereas the latter is not sufficiently sensitive. Use of multiple serum markers can improve sensitivity. A combination of CA-125, M-CSF and OVX-1 has detected > 95% of Stage I ovarian cancers. If similar results are obtained with different data sets, multiple serum markers could be used to trigger the performance of TVS, providing a potentially cost effective screening strategy. Prospective trials will be required to demonstrate that screening for early stage ovarian actually impacts on survival.

Diagnosis, Differential↗
PubMed1995

Gestational trophoblastic disease metastatic to the central nervous system.

OBJECTIVE: To evaluate characteristics of patients with central nervous system (CNS) lesions of gestational trophoblastic disease (GTD) and determine prognostic and therapeutic implications applicable to management. METHODS: We retrospectively reviewed the records of 454 patients treated at the Southeastern Regional Trophoblastic Disease Center between 1966 and 1992 with at least 2 years of follow-up, and identified 42 (9.3%) with CNS metastases. Sixteen patients presented for primary therapy and 27 patients had received significant therapy prior to presentation. Three heavily treated moribund patients died before their first cycle of chemotherapy and were excluded from analysis. Brain metastases were documented by physical exam and radionuclide imaging (before 1976), computed tomography scan (after 1976), or magnetic resonance imaging (after 1986). Patients received multiagent chemotherapy with methotrexate, actinomycin D, and chlorambucil (MAC)- or etoposide-based regimens. All patients received radiation therapy. No intrathecal chemotherapy was given. Craniotomy was employed in seven cases. Remission was defined as three weekly hCG levels below assay sensitivity (< 5 mIU/ml). RESULTS: Overall survival was 44%. Twelve of 16 patients (75%) who presented with CNS metastases with no prior therapy (Group A), 5 of 13 (38%) patients who had prior treatment (Group B), and none of 10 patients who developed CNS metastases during therapy (Group C) survived (P < 0.05). Two of four patients who failed in the CNS after treatment for CNS lesions were salvaged. Demographic characteristics of Groups A and B were similar. No significant differences with respect to WHO score, interval from pregnancy to onset of disease, or age among these groups were found. Group B patients had a four-fold higher incidence of liver metastases. Survival of Group A patients was not related to conventional clinical prognostic factors. Inverse (nonsignificant) correlations were found for Group B patients between survival and WHO score, hCG level, size and number of metastatic lesions, but not type of prior therapy. Survival was higher in those with prior molar pregnancies (56%) as contrasted with aborted (50%) or term (27%) gestations. Selective use of craniotomy helped alleviate intracranial pressure and resect refractory foci. CONCLUSIONS: Chemotherapy combined with radiation therapy in GTD patients with CNS metastases yields survival rates comparable to those reported for intrathecal methotrexate regimens. Tumor burden as indicated by hCG level and size/number of metastases in previously treated patients may correlate with survival. Patients who develop CNS metastases during active therapy have a very poor outcome.

Adolescent↗
PubMed1995

Long and short gracilis myocutaneous flaps for vulvovaginal reconstruction after radical pelvic surgery: comparison of flap-specific complications.

The purpose of this study was to determine the factors associated with flap-specific complications in patients receiving gracilis myocutaneous flaps for pelvic reconstruction, specifically to determine whether the short gracilis flap increases the risk of major flap loss. Records of consecutive women undergoing gracilis flap pelvic reconstruction procedures were analyzed retrospectively. Twenty-two received classical "long" flaps, while 24 received short flaps. In the short gracilis flap modification, the dominant vascular pedicle is deliberately sacrificed. Clinical factors for association with flap-specific complications were analyzed. Eighty-three flaps were used in 46 women for reconstruction after radical pelvic surgery. Those receiving short flaps were more likely to have a preoperative diagnosis of cervical cancer and to have undergone exenteration with rectosigmoid anastomosis, and all short flaps were performed by gynecologic oncologists (all P < 0.05). Distribution of other patient characteristics were similar. Loss of more than one or both flaps occurred in seven (15%) patients, three (14%) with long and four (17%) with short flaps, a nonsignificant difference. Age, weight, tobacco use, associated medical conditions, diagnosis, prior therapy, type of procedure, previous lymphadenectomy, use of bilateral flaps, postoperative abscess/fistula, and type of surgeon were not significantly associated with major flap loss. Four (50%) of eight patients undergoing exenteration with rectosigmoid anastomosis had major flap loss, compared to 2 of 29 with exenteration only, and 1 of 9 with other pelvic reconstructions (P < 0.05). In conclusion, sacrifice of the dominant vascular pedicle in the short gracilis flap does not increase the risk of major flap loss. Vaginal reconstruction after exenteration with rectosigmoid anastomosis significantly increases the risk of this complication.

Adult↗
PubMed1995

Etoposide-platin combination therapy for chemorefractory gestational trophoblastic disease.

The purpose of this study was to determine activity of etoposide-platin combination chemotherapy for chemorefractory gestational trophoblastic disease. A retrospective review of patients treated with etoposide-platin chemotherapy for chemorefractory trophoblastic disease was conducted. Patients received etoposide 100 mg/m2 and cisplatin 20 mg/m2 on Days 1 through 5 of 14- to 21-day cycles. Patient characteristics, responses, and toxicity were recorded. Seven women received etoposide-platin for chemorefractory disease. The median WHO prognostic index score upon initiation of therapy was 16 (range, 10-20) and patients had received a median 6 cycles of prior combination chemotherapy. Five patients developed grade IV neutropenia, four developed neutropenic sepsis, and two required platelet transfusions. Two patients developed significant deterioration of renal function. Six (86%) patients had complete responses, with normalization of hCG values, but only three (43%) patients with low pretherapy hCG levels have had sustained remissions. Etoposide-platin chemotherapy is an active regimen for the treatment of women with chemorefractory gestational trophoblastic disease but has significant hematologic and renal toxicity when used as salvage therapy. Future studies should investigate the incorporation of etoposide-platin into initial therapy of women with high-risk disease.

Adult↗
PubMed1995

Postsurgical surveillance of patients with FIGO stage I/II endometrial adenocarcinoma.

OBJECTIVE: To examine the effect of postsurgical surveillance on survival of patients with FIGO stage I/II endometrial adenocarcinoma. METHODS: We examined the records of 354 patients who underwent primary surgical therapy for FIGO stage I/II endometrial adenocarcinoma. In patients who developed recurrent disease, we determined whether symptoms or signs of disease were present at recurrence and whether there was evidence of disease on Pap smear or chest radiograph. RESULTS: Among the 354 patients in this study, 44 (12%) developed recurrent disease. Sites of recurrence included 12 (27%) isolated vaginal, 12 (27%) pelvic with vagina or abdomen, 4 (10%) isolated lung, 13 (29%) pelvic/abdominal with other distant sites, and 3 (7%) other distant sites. At diagnosis of recurrence 61% of patients had symptoms related to their cancer, 68% had physical exam findings suggestive of recurrence, and 84% had symptoms and/or signs. Findings consistent with recurrent cancer were detected by Pap smear in 25% and on chest radiograph in 20%. Among the 44 patients who developed recurrent disease, 8 (18%) remain alive without evidence of disease, including 6/12 (50%) with isolated vaginal disease and 2/34 (6%) with other patterns of recurrent disease (P = 0.01). Among the 12 patients with isolated vaginal recurrence, 1/3 (33%) in whom recurrent disease was diagnosed by Pap smear alone was salvaged compared to 5/9 (56%) who had symptoms or signs of vaginal recurrence. None of the three patients in whom an abnormal chest radiograph was the only evidence of recurrence survived. CONCLUSIONS: Because of the low recurrence rate of FIGO stage I/II endometrial cancer and the paucity of effective second-line treatment, surveillance Pap smears and chest radiographs appear to have little impact on survival. Although few asymptomatic potentially curable recurrences were detected due to surveillance examinations, the value of psychological reassurance associated with a normal examination is difficult to quantitate.

Adenocarcinoma↗
PubMed1995

Combinations of multiple serum markers are superior to individual assays for discriminating malignant from benign pelvic masses.

To determine whether measurement of the levels of multiple tumor markers in the preoperative serum of women presenting with a pelvic mass distinguished benign from malignant disease better than the assay of CA 125 alone, sera from 429 patients, 192 of whom had malignant histology, were assayed for 8 different markers: CA 125, macrophage colony-stimulating factor, OVX1, lipid-associated sialic acid (LASA), CA15-3, CA72-4, CA19-9, and CA54/61. The sensitivity and specificity of CA 125 alone (> 35 U/ml) was 78.1 and 76.8%, respectively. A panel consisting of CA 125, OVX1, LASA, CA15-3, and CA72-4 had a sensitivity of 83.3% and specificity of 84.0% when two or more markers were elevated. Using the concentrations of these five markers, logistic regression analysis had a sensitivity of 85.4% and a specificity of 83.1%. Considering the values of markers in different sequences, classification and regression tree analysis substantially improved the sensitivity to 90.6% and the specificity to 93.2%. When applied in clinical practice this approach could improve the management of women presenting with a pelvic mass and may also have application in screening for ovarian cancer.

Biomarkers, Tumor↗