Biomedical subjects

Beth Y Karlan

Publications and source records attributed to Beth Y Karlan.

At least 19 recordsLinked to original sources

PubMed2026

Exploring the Melanoma and Pancreatic Cancer Phenotype of a Potential CDKN2A Founder Variant, I49T (c.146T>C; p.Ile49Thr), in Individuals of Predominantly Mexican Ancestry.

PURPOSE: Pathogenic/likely pathogenic variants (P/LPVs) in the CDKN2A gene cause an increased risk of melanoma (MEL) and pancreatic cancer (PANC). The CDKN2A variant I49T (c.146T>C), reported to be recurrent in Hispanics, has conflicting pathogenicity classifications at laboratories, affecting clinical care. Multiple genetics clinics collaborated to explore cancers associated with I49T. METHODS: Institutional clinical databases were queried for the CDKN2A variants, I49T, known P/LPVs, and c.-2G>A (a benign variant [BV]), and history of PANC and MEL was abstracted. A combination of statistical tests was used to investigate cancer history associations. RESULTS: Data on 203 individuals, with qualifying CDKN2A variants detected on multigene testing between 2012 and 2023, were analyzed (I49T, n = 101; known CDKN2A P/LPVs, n = 57; BV, n = 45). Those with I49T were 91% less likely to have MEL than known CDKN2A P/LPVs (odd ratio [OR] = 0.089 [95% CI, 0.031 to 0.025]; P < .001) and were also less likely to have PANC (OR = 0.45 [95% CI, 0.14 to 1.41]; P = .17). However, mean age at PANC diagnosis for I49T was 56.0 years, significantly younger than known CDKN2A P/LPVs (μ = 71.0 years; P = .026). CONCLUSION: In the largest I49T study to date to our knowledge, MEL was significantly less frequent compared with known CDKN2A P/LPVs. Although a nonsignificant trend was observed for less PANC in I49T than known P/LPVs, individuals with I49T presented with PANC at a significantly younger age than those with known CDKN2A P/LPVs. The presence of I49T in Hispanics of mostly Mexican ancestry supports that it is a founder variant, relevant to understanding cancer risk in a large proportion of Hispanics in the United States.

Humans↗

PubMed2007

FOXA1: Growth inhibitor and a favorable prognostic factor in human breast cancer.

The transcription factor Forkhead-box A1 (Foxa1), a member of the FOX class of transcription factors, has been implicated in the pathogenesis of lung, esophageal and prostate cancers. We have recently identified transcriptional activation of p27 by FOXA1. In this study, we analyzed the activities and expression pattern of FOXA1 in breast cancer. Forced expression of FOXA1 inhibited clonal growth of breast cancer cell lines, and FOXA1 levels inversely correlated with growth stimuli. In the estrogen receptor (ER)-positive MCF-7 cells, FOXA1 increased p27 promoter activity and inhibited the ER pathway activity. Analysis of FOXA1 expression in breast tissue arrays revealed significantly higher expression in pure ductal carcinomas in situ compared to invasive ductal carcinomas (IDC); and in IDC, high expression of FOXA1 was associated with favorable prognostic factors. Yet, FOXA1 expression was noted in a subset of the ER-negative tumors. Taken together, our findings suggest a growth inhibitory role for FOXA1, and identify it as a novel, potential prognostic factor in breast cancer.

Breast↗

PubMed2006

Secondary cytoreductive surgery for isolated nodal recurrence in patients with epithelial ovarian cancer.

OBJECTIVES: To evaluate the feasibility and associated survival outcome of secondary cytoreductive surgery in patients with isolated lymph node recurrence of epithelial ovarian cancer. METHODS: Twenty-five patients with epithelial ovarian cancer who underwent secondary cytoreductive surgery for isolated lymph node recurrence were identified from tumor registry databases. Demographic, diagnostic, operative, pathologic, and follow-up data were abstracted retrospectively. Overall survival was calculated using the Kaplan-Meier method. RESULTS: The median age at time of primary surgery for ovarian cancer was 55 years; 72% of patients had FIGO III/IV disease, and all had high-grade tumors. All patients received platinum-based chemotherapy following primary surgery. The median time from completion of primary chemotherapy to nodal recurrence surgery was 16 months (range=6 to 40 months). The distribution of nodal involvement was pelvic=12% (n=3), para-aortic=60% (n=15), inguinal=20% (n=5), peri-cardiac=4% (n=1), and pelvic plus para-aortic=4% (n=1). The maximal nodal tumor diameter ranged from 1.5 cm to 14 cm, with a median of 3.0 cm. Optimal secondary cytoreductive surgery (residual disease </=1 cm) was achieved in 100% of patients. The median estimated intra-operative blood loss was 100 cc (range=10 cc to 600 cc). The length of hospitalization ranged from 2 days to 10 days, with a median of 4 days. There was no instance significant postoperative morbidity. At a median post-recurrence follow-up time of 19 months, 8 patients (32%) have died of the disease, 7 (28%) are alive with disease, and 10 (40%) patients are without evidence of disease. For the entire study population, the median post-recurrence OS after secondary cytoreduction of recurrent nodal disease was 37 months. CONCLUSION: Complete optimal secondary cytoreductive surgery for recurrent epithelial ovarian cancer presenting as isolated node metastases is achievable in the majority of cases and is associated with a favorable long-term survival outcome.

Adult↗

PubMed2006

Association between a functional single nucleotide polymorphism in the MDM2 gene and sporadic endometrial cancer risk.

OBJECTIVES: MDM2 is an important negative regulator of the p53 tumor suppressor protein. A naturally occurring T/G single nucleotide polymorphism (SNP) in the MDM2 gene promoter, SNP309, causes an increase in MDM2 protein levels and impairment of p53 tumor suppressor activity. SNP309 occurs at a relatively high frequency in the general population and has been associated with accelerated tumorigenesis in hereditary Li-Fraumeni associated cancers as well as in sporadic soft tissue sarcomas. The objective of this study was to examine the association between SNP309 and sporadic endometrial cancer risk. METHODS: Genomic DNA was isolated from 73 patients with endometrial cancer and 79 healthy, female controls. The MDM2 gene promoter region was amplified by PCR and the SNP309 genotype determined by restriction enzyme digestion of the amplified DNA fragment. Unconditional logistic regression analysis was used to determine the relationship between genotypes and endometrial cancer risk and histopathologic features. RESULTS: The homozygous G/G genotype was found in 25% of endometrial cancer cases and 11% of controls. In an age-adjusted analysis of cases and controls, the G/G genotype increased the risk of endometrial cancer 2.76-fold (95% CI: 1.06, 7.20; p=0.03) compared to presence of a wild-type T allele (T/G and T/T genotypes). No association was found between the SNP309 G/G genotype and either endometrial cancer histology, grade, stage, or age at diagnosis. CONCLUSIONS: The MDM2 SNP309 homozygous G/G genotype may be a genetic variant that influences sporadic endometrial cancer susceptibility.

Adult↗

PubMed2006

Tertiary cytoreductive surgery in recurrent ovarian cancer: selection criteria and survival outcome.

OBJECTIVES: Studies of tertiary cytoreductive surgery (TCS) in recurrent epithelial ovarian cancer are limited, and appropriate patient selection remains a clinical challenge. We sought to evaluate the impact of TCS on survival and to determine predictors of optimal tertiary resection. METHODS: Between January 1997 and July 2004, 47 women with recurrent epithelial ovarian cancer underwent TCS at two institutions. All patients received initial platinum and taxane-based chemotherapy following primary cytoreductive surgery. Clinico-pathologic factors and survival were retrospectively abstracted from medical records. Optimal TCS was defined as microscopic residual disease. RESULTS: Thirty of 47 (64%) patients underwent optimal TCS. Size of tumor implants<5 cm on preoperative imaging was the only significant predictor of achieving optimal TCS. Overall survival after TCS was statistically longer in patients with microscopic versus macroscopic residual disease (24 versus 16 months, p=0.03). After controlling for age, time to progression and optimal TCS, only the presence of diffuse disease at tertiary exploration remained a significant poor predictor of survival. However, in a cohort of patients with limited disease implants, multivariate analysis indicated that optimal TCS retained prognostic significance as a positive predictor of survival. Twelve patients (26%) experienced severe postoperative complications, including six with pulmonary embolism, four with fistulae and two with postoperative myocardial infarctions. CONCLUSIONS: Size of disease implants on preoperative imaging may guide the selection of candidates for TCS. In those patients with limited disease implants at laparotomy, optimal TCS is associated with improved survival.

Adult↗

PubMed2006

Effect of obesity on survival in epithelial ovarian cancer.

BACKGROUND: Epidemiologic studies suggest that obese women are more likely to die of ovarian cancer than those of ideal body weight, but it is not known whether increased incidence, comorbidities common to obese women, or altered tumor biology is responsible for this difference. The current study attempted to determine the influence of excess body weight on ovarian cancer survival, disease progression, and clinicopathologic factors. METHODS: The records of patients undergoing surgery for epithelial ovarian cancer at Cedars Sinai Medical Center between January 1, 1996 and June 30, 2003 were reviewed for height, weight, age, comorbidities, and treatment-specific details. Statistical analyses included the Fisher exact test, Kaplan-Meier survival, and Cox regression analyses. RESULTS: In all, 216 patients were identified. Eight percent were underweight (body mass index [BMI] < 18.5), 50% were ideal body weight (18.5 </= BMI < 25), 25% were overweight (25 </= BMI < 30), and 16% were obese (BMI >/= 30). Age, comorbidities including coronary artery disease and venous thromboembolism, and rates of optimal surgical cytoreduction were similar among BMI strata. Diabetes and hypertension were more common in obese women. Ten (29%) of the obese patients had International Federation of Gynecology and Obstetrics (FIGO) Stage I disease, compared with 19 (10%) of the patients with BMI < 30 (P = .01). In a subcohort of 149 patients with Stage III or IV disease, a significant trend was identified favoring increased BMI as an independent negative factor for disease-free (P = .02) and overall (P = .02) survival. CONCLUSIONS: Obese patients were more likely to have disease limited to the ovaries. For patients with advanced stage disease, obesity was independently associated with both shorter time to recurrence and shorter overall survival. These findings suggest an effect of excess body weight on tumor biology, and studies are under way to elucidate the molecular and hormonal mechanisms underlying these clinical observations.

Adolescent↗

PubMed2006

ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes.

Although the etiology of solid cancers is multifactorial, with environmental and genetic factors playing a variable role, a significant portion of the burden of cancer is accounted for by a heritable component. Increasingly, the heritable component of cancer predispositions has been linked to mutations in specific genes, and clinical interventions have been formulated for mutation carriers within affected families. The primary interventions for mutations carriers for highly penetrant syndromes such as multiple endocrine neoplasias, familial adenomatous polyposis, hereditary nonpolyposis colon cancer, and hereditary breast and ovarian cancer syndromes are primarily surgical. For that reason, the American Society of Clinical Oncology (ASCO) and the Society of Surgical Oncology (SSO) have undertaken an educational effort within the oncology community. A joint ASCO/SSO Task Force was charged with presenting an educational symposium on the surgical management of hereditary cancer syndromes at the annual ASCO and SSO meetings, resulting in an educational position article on this topic. Both the content of the symposium and the article were developed as a consensus statement by the Task Force, with the intent of summarizing the current standard of care. This article is divided into four sections addressing breast, colorectal, ovarian and endometrial cancers, and multiple endocrine neoplasia. For each, a brief introduction on the genetics and natural history of the disease is provided, followed by a detailed description of modern surgical approaches, including a description of the clinical and genetic indications and timing of prophylactic surgery, and the efficacy of prophylactic surgery when known. Although a number of recent reviews have addressed the role of genetic testing for cancer susceptibility, including the richly illustrated Cancer Genetics and Cancer Predisposition Testing curriculum by the ASCO Cancer Genetics Working Group (available through http://www.asco.org), this article focuses on the issues surrounding the why, how, and when of surgical prophylaxis for inherited forms of cancer. This is a complex process, which requires a clear understanding of the natural history of the disease and variance of penetrance, a realistic appreciation of the potential benefit and risk of a risk-reducing procedure in a potentially otherwise healthy individual, the long-term sequelae of such surgical intervention, as well as the individual patient and family's perception of surgical risk and anticipated benefit.

Female↗

PubMed2006

Characterization of CSOC 882, a novel immortalized ovarian cancer cell line expressing EGFR, HER2, and activated AKT.

OBJECTIVE: Only a small number of comprehensively characterized immortalized ovarian cancer cell lines are available for laboratory studies on ovarian cancer. We describe a new ovarian cancer cell line that arose from primary culture of a stage IC, grade III ovarian carcinoma, designated CSOC 882. METHODS: We characterized CSOC 882 by karyotyping, growth modeling, immunohistochemical staining, immunoblotting, drug sensitivity testing, and xenografting in nude mice. RESULTS: CSOC 882 possessed an abnormal tetraploid karyotype including loss of one copy of chromosomes 2, 17, 19, and 21, and deletion of 8p21. Growth of CSOC 882 was best modeled using the logistic growth equation revealing an average doubling time of 31 h. CSOC 882 cells expressed vimentin, cytokeratin, p53, BRCA1, EGF receptor, HER2, androgen receptor, estrogen receptor alpha, and progesterone receptor, while no evidence of estrogen receptor beta or factor VIII was observed. Some but not all CSOC 882 cells were positive for CA125 reflecting the primary tumor, which had patchy CA125 staining. Drug sensitivity assays demonstrated that CSOC 882 was more sensitive to cisplatin and carboplatin than SKOV3 and HCC1937 while CSOC 882 and SKOV3 were both sensitive to paclitaxel unlike HCC1937. CSOC 882 xenografts retained the original characteristics of vimentin, cytokeratin, and factor VIII labeling. CONCLUSIONS: CSOC 882 is an immortalized cell line that has survived more than 130 passages in culture and retained molecular features of the primary tumor from which it was derived. Compared to the most common ovarian carcinoma cell lines, CSOC 882 is a unique resource for genetic and cellular research on ovarian cancer.

Animals↗

PubMed2006

The prognostic significance of thrombocytosis in uterine papillary serous carcinomas.

OBJECTIVES: We have shown that preoperative thrombocytosis (platelet counts >400 x 10(9)/l) is an independent poor prognostic factor in epithelial ovarian cancers (EOC) and is associated with worse survival. In light of the similarities between uterine papillary serous carcinomas (UPSC) and EOC, we sought to determine the incidence of thrombocytosis in UPSC and examine associations with clinico-pathologic features and survival. METHODS: 68 patients with UPSC were identified between 1996 and 2004 at 3 institutions. After IRB approval, records were retrospectively reviewed and data analyzed using Chi-squared and Cox proportional hazards model; survival was analyzed by the method of Kaplan and Meier. RESULTS: 8/68 (12%) patients had thrombocytosis at primary diagnosis. Patients with thrombocytosis were found to have more advanced stage disease (p=0.002) and ascites >1 L (p<0.0001). Of the 21 patients with stage IV disease, those with normal preoperative platelet counts demonstrated a greater likelihood of optimal tumor resection to less than 1 cm residual disease (13/15 versus 1/6 in patients with thrombocytosis, p<0.002). Patients with thrombocytosis had a shorter disease-free interval (17 months versus median survival not yet reached, p=0.0067) and overall survival (24 versus 45 months, p=0.0026). On multivariate analysis, thrombocytosis retained significance as a poor prognostic indicator in patients after controlling for age and stage (p=0.04). CONCLUSIONS: Thrombocytosis may be a marker of aggressive tumor biology in UPSC. Platelet-secreted growth factors may promote aggressive cancer phenotype through contribution to metastasis, invasion, and primary tumor growth.

Cystadenocarcinoma, Papillary↗

PubMed2006

Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status.

PURPOSE: Ovarian cancers (OCs) frequently have HER2 activation in the absence of HER2 overexpression. Pertuzumab, a humanized antibody that prevents HER2 dimerization and inhibits multiple HER-mediated pathways, was studied in a phase II, multicenter trial in advanced, refractory OC. PATIENTS AND METHODS: Sixty-one patients (cohort 1) with relapsed OC received a loading dose of 840 mg pertuzumab intravenously followed by 420 mg every 3 weeks; 62 patients (cohort 2) received 1,050 mg every 3 weeks. Response rate was the primary end point. Fresh tumor biopsies were obtained in cohort 1 to assay for phosphorylated HER2 (pHER2). RESULTS: Median age was 57 years and median number of prior chemotherapy regimens was five. Fifty-five patients in cohort 1 and 62 patients in cohort 2 were assessable for efficacy. There were five partial responses (response rate [RR] = 4.3%; 95% CI, 1.7% to 9.4%), eight patients (6.8%) with stable disease (SD) lasting at least 6 months, and 10 patients with CA-125 reduction of at least 50% (includes two partial responses and four patients with SD > or = 6 months; total clinical activity, 14.5%). Median progression-free survival (PFS) was 6.6 weeks. Eight of 28 tumor biopsies (28.6%) were pHER2+ by enzyme-linked immunosorbent assay (ELISA; without gene amplification). Median PFS for pHER2+ patients was 20.9 weeks (n = 8) versus 5.8 weeks for pHER2- (n = 20; P = .14) and 9.1 weeks for unknown pHER2 status (n = 27). Pertuzumab was well tolerated with diarrhea in 69.1% (11.4% grade 3, no grade 4). Five patients had asymptomatic left ventricular ejection fraction decreases to less than 50% (one confirmed by central facility). CONCLUSION: Pertuzumab is well tolerated with a RR of 4.3% in heavily-pretreated OC patients. Further studies on pHER2 as a diagnostic are warranted.

Adult↗

PubMed2006

15-hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer.

Prostaglandin E(2) plays a growth-stimulatory role in breast cancer, and the rate-limiting enzyme in its synthesis, cyclooxygenase-2, is often overexpressed in these cancers. Little is known about the role of the key prostaglandin catabolic enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in breast cancer pathogenesis. Using a pharmacologically based screen for epigenetically silenced genes, we found low levels of 15-PGDH in MDA-MB-231 cells [estrogen receptor (ER) negative] but high levels in MCF-7 cells (ER positive) and observed its up-regulation following demethylation treatment. Further analysis revealed methylation of the 15-PGDH promoter in one breast cancer cell line and 30% of primary tumors. Analysis of 15-PGDH expression revealed low levels in 40% of primary breast tumors and identified a correlation between 15-PGDH and ER expression. Transfection assays showed that transient up-regulation of 15-PGDH levels in MDA-MB-231 cells resulted in a decreased clonal growth, and stable up-regulation significantly decreased the ability of these cells to form tumors in athymic mice. In contrast, transient silencing of 15-PGDH in MCF-7 cells resulted in their enhanced proliferation, and a stable silencing in these cells enhanced cell cycle entry in vitro and tumorigenicity in vivo. Forced expression of 15-PGDH inhibited the ER pathway and silencing of 15-PGDH up-regulated expression of aromatase. In addition, 15-PGDH levels were down-regulated by estrogen but up-regulated by the tumor suppressor gene CAAT/enhancer binding protein alpha. Our results indicate for the first time that 15-PGDH may be a novel tumor suppressor gene in breast cancer, and suggest that this enzyme can modulate the ER pathway.

Animals↗

PubMed2006

Prognostic DNA methylation biomarkers in ovarian cancer.

PURPOSE: Aberrant DNA methylation, now recognized as a contributing factor to neoplasia, often shows definitive gene/sequence preferences unique to specific cancer types. Correspondingly, distinct combinations of methylated loci can function as biomarkers for numerous clinical correlates of ovarian and other cancers. EXPERIMENTAL DESIGN: We used a microarray approach to identify methylated loci prognostic for reduced progression-free survival (PFS) in advanced ovarian cancer patients. Two data set classification algorithms, Significance Analysis of Microarray and Prediction Analysis of Microarray, successfully identified 220 candidate PFS-discriminatory methylated loci. Of those, 112 were found capable of predicting PFS with 95% accuracy, by Prediction Analysis of Microarray, using an independent set of 40 advanced ovarian tumors (from 20 short-PFS and 20 long-PFS patients, respectively). Additionally, we showed the use of these predictive loci using two bioinformatics machine-learning algorithms, Support Vector Machine and Multilayer Perceptron. CONCLUSION: In this report, we show that highly prognostic DNA methylation biomarkers can be successfully identified and characterized, using previously unused, rigorous classifying algorithms. Such ovarian cancer biomarkers represent a promising approach for the assessment and management of this devastating disease.

Adenocarcinoma↗

PubMed2006

Evolution through intelligent design.

Explore the source record for details and available documents.

Female↗

PubMed2006

ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes.

BACKGROUND: A significant portion of cancers are accounted for by a heritable component, which has increasingly been linked to mutations in specific genes. Clinical interventions have been formulated for mutation carriers within affected families. The primary interventions for mutation carriers of highly penetrant syndromes are surgical. METHODS: The American Society of Clinical Oncology and the Society of Surgical Oncology formed a task force charged with presenting an educational symposium on surgical management of hereditary cancer syndromes at annual society meetings, and this resulted in a position paper on this topic. The content of both the symposium and the position paper was developed as a consensus statement. RESULTS: This article addresses hereditary breast, colorectal, ovarian/endometrial, and multiple endocrine neoplasias. A brief introduction on the genetics and natural history of each disease is provided, followed by detailed descriptions of modern surgical approaches, clinical and genetic indications, timing of prophylactic surgery, and the efficacy of surgery (when known). Although several recent reviews have addressed the role of genetic testing for cancer susceptibility, this article focuses on the issues surrounding surgical technique, timing, and indications for surgical prophylaxis. CONCLUSIONS: Risk-reducing surgical treatment of hereditary cancer is a complex undertaking. It requires a clear understanding of the natural history of the disease, realistic appreciation of the potential benefits and risks of these procedures in potentially otherwise healthy individuals, and the long-term sequelae of such interventions, as well as the individual patient's and family's perceptions of surgical risk and anticipated benefit.

Female↗

PubMed2005

Tumor protein D52 (TPD52) is overexpressed and a gene amplification target in ovarian cancer.

Recurrent chromosome 8q gain in ovarian carcinoma is likely to reflect the existence of multiple target loci, as the separate gain of chromosome bands 8q21 and 8q24 has been reported in independent studies. Since tumor protein D52 (TPD52) has been identified as a chromosome 8q21 amplification target in breast and prostate carcinoma, we compared TPD52 expression in normal ovarian epithelium (n = 9), benign serous adenomas (n = 11), serous borderline tumors (n = 6) and invasive carcinomas of the major histologic subtypes (n = 57) using immunohistochemistry. These analyses revealed that all normal ovarian epithelium samples and benign serous tumors were predominantly TPD52-negative, whereas TPD52 was overexpressed in most (44/57; 77%) ovarian carcinomas regardless of histologic subtype. TPD52 subcellular localization was predominantly cytoplasmic, although nuclear localization was also frequently observed in mucinous and clear cell carcinomas. In an independent cohort of stage III serous carcinomas (n = 18), we also directly compared in situ TPD52 expression using immunohistochemistry and TPD52 copy number using interphase FISH analyses. This revealed that TPD52 dosage and TPD52 expression were significantly positively correlated. TPD52 therefore represents a novel molecular marker in ovarian cancer, which is broadly expressed across the different histologic subtypes and whose upregulation frequently reflects increased TPD52 copy number.

Biomarkers, Tumor↗

PubMed2005

BRCA1 promoter methylation predicts adverse ovarian cancer prognosis.

OBJECTIVE: To compare the clinical outcome of ovarian cancer patients whose tumors contain BRCA1 genes silenced by promoter hypermethylation to patients with germline BRCA1 mutations and to patients with wild-type BRCA genes. METHODS: Ovarian cancers from a hospital-based tumor bank were characterized as having a BRCA1 mutation; or a methylated BRCA1, BRCA1 pseudogene or MLH1 promotor; or a wild-type BRCA gene. Survival of patients with methylated BRCA1 promoters (N = 11) was compared to that of patients with wild-type BRCA genes (N = 30) and BRCA1 mutations (N = 22). A methylator phenotype was defined to include tumors with hypermethylation of BRCA1, hMLH1 and/or dBRCA1 pseudogene promoters (N = 23). RESULTS: All cohorts had comparable clinical factors except for age at diagnosis. Median age of methylated BRCA1 and wild-type BRCA patients was older than BRCA1 mutation carriers (60 and 63 versus 48 years; P = 0.04). The median disease-free interval was significantly shorter for patients with a methylated BRCA1 promoter (9.8 months) than for BRCA1 mutation carriers (39.5 months; P = 0.04). Median overall survival was also significantly shorter for patients with a methylated BRCA1 promoter (35.6 months) than BRCA1 mutation carriers (78.6 months; P = 0.02). The combined methylator phenotype cohort had significantly shorter survival (36.1 months) compared to wild-type BRCA patients (63.3 months; P = 0.02). CONCLUSION: These data suggest that methylation of the BRCA1 promoter is associated with poor patient outcome. BRCA1 may be part of a global panel of methylated genes associated with aggressive disease.

CpG Islands↗

PubMed2005

The fragile histidine triad gene: a molecular link between cigarette smoking and cervical cancer.

PURPOSE: Smoking is an epidemiologic risk factor for cervical cancer. The fragile histidine triad (FHIT) gene is a tumor suppressor gene that is altered in 80% of tobacco-associated lung cancers. We hypothesized that reduced FHIT protein expression, homozygous deletions (HD) or hemizygous deletions (HemiD) and microsatellite alterations (MA) at the FHIT/FRA3B locus occur more commonly in cervical cancers of smokers than nonsmokers. EXPERIMENTAL DESIGN: Archival tissues of 58 patients with stage IA1 to IB2 squamous cell carcinoma of the cervix were identified. FHIT protein expression was studied with immunohistochemistry. Laser capture microdissection was used to isolate tumor and normal DNA. HD/HemiD of FHIT exons 4 and 5 were analyzed by monoplex real-time PCR. MA at FHIT/FRA3B were studied with multiplex nested PCR with three fluorescently labeled microsatellite markers (D3S1300, D3S1312, and D3S1480). RESULTS: Eighteen of 26 tumors from smokers (69%) and 13 of 32 nonsmokers (41%; P < 0.05) showed loss of FHIT protein expression. Thirty-seven stage IB tumors yielded sufficient DNA for analyses. HD or HemiD of both exons tested occurred in 8 of 17 smokers (47%) and 2 of 20 nonsmokers (10%; P < 0.05). MA at more than two sites were found in 11 of 17 tumors of smokers (65%) and 6 of 20 nonsmokers (30%; P < 0.05). Mean composite genomic FHIT alteration scores were significantly higher for tumors of smokers versus nonsmokers (0.67 versus 0.40; P < 0.02). CONCLUSION: Loss of FHIT expression, HD, HemiD, and MA at the FHIT/FRA3B locus occur significantly more commonly in cervical cancers of smokers. These findings suggest that the tumor suppressor gene FHIT may represent a molecular target in cigarette smoking-associated cervical carcinogenesis.

Acid Anhydride Hydrolases↗

PubMed2005

Lower urinary tract reconstruction with ileum in the treatment of gynecologic malignancies.

INTRODUCTION: Advanced or recurrent gynecologic malignancies can invade or obstruct the lower urinary tract. If extirpation is necessary for cytoreduction or repair of radiation sequelae, treatment has typically involved creation of either an ileal conduit or a cutaneous continent urinary diversion. As an alternative, a more limited resection with urinary tract reconstruction using ileum for interposition or augmentation may allow for the preservation of urethral voiding. CASES: We describe the use of ileal segments for lower urinary tract reconstruction in the treatment of ten patients with advanced or recurrent gynecologic malignancies. The clinical history, surgical technique, and patient outcomes are reviewed. DISCUSSION: These cases demonstrate that limited bladder or ureteral resection with reconstruction using ileal segments may offer select patients preservation of urethral voiding.

Female↗