Faculty Bibliography
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227
Expression of Ezrin and Estrogen Receptors During Cervical Carcinogenesis
RATIONALE: Development of cervical squamous carcinoma (CXCA) is accompanied by changes in estrogen receptors (ERs, ERalpha and ERbeta) and ezrin expression; however, reports have been conflicting. Using histologically documented staging of cervical biopsies, we determined ezrin and ER relationships during CXCA development. METHODS: Immunoreactive (ir) ezrin, ir-ERalpha, and ir-ERbeta were studied in normal epithelium, carcinoma in situ/cervical intraepithelial neoplasia (CIN) 1 to 3, and local invasion or metastatic CXCA. Results were compared using H scoring. Cultures of Caski metastatic CXCA cells were treated with estradiol and/or tamoxifen and studied for ER-driven ir-ezrin and the morphologic response. RESULTS: Koilocytosis was present and indicated viral presence. The ezrin H score increased from CIN1 to CIN3, reaching significant differences from normal by CIN3 (P = .004) and 2x normal in metastatic CXCA. Estrogen receptor alpha and ERbeta H scores fell, reaching significance by CIN3 (ERalpha, P = .0001; ERbeta, P = .024). During estradiol treatment, ezrin in Caski cells increased and localized to the periphery, in ruffles and processes. The selective ER modulator tamoxifen blocked the estradiol-induced changes. CONCLUSIONS: During cervical carcinogenesis, the usual relationship between estrogen and ezrin induction is abridged. This is consistent with the effects of human papilloma virus viral proteins such as E6 and E7 that upregulate SIX1, a protein that induces ezrin. Cervical carcinogenesis is progressive but arrests at the preinvasive stage for varying lengths of time. These studies suggest that changes in ezrin may be associated with the development of the invasive phenotype and penetration of the basement membrane. They also raise the possibility that inhibiting ezrin expression could be a target for the prevention of invasive CXCA.
PMID: 27688241
ISSN: 1933-7205
CID: 2262782
Demographic, lifestyle, and other factors in relation to antimullerian hormone levels in mostly late premenopausal women
OBJECTIVE: To identify reproductive, lifestyle, hormonal, and other correlates of circulating antimullerian hormone (AMH) concentrations in mostly late premenopausal women. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): A total of 671 premenopausal women not known to have cancer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Concentrations of AMH were measured in a single laboratory using the picoAMH ELISA. Multivariable-adjusted median (and interquartile range) AMH concentrations were calculated using quantile regression for several potential correlates. RESULT(S): Older women had significantly lower AMH concentrations (>/=40 [n = 444] vs. <35 years [n = 64], multivariable-adjusted median 0.73 ng/mL vs. 2.52 ng/mL). Concentrations of AMH were also significantly lower among women with earlier age at menarche (<12 [n = 96] vs. >/=14 years [n = 200]: 0.90 ng/mL vs. 1.12 ng/mL) and among current users of oral contraceptives (n = 27) compared with never or former users (n = 468) (0.36 ng/mL vs. 1.15 ng/mL). Race, body mass index, education, height, smoking status, parity, and menstrual cycle phase were not significantly associated with AMH concentrations. There were no significant associations between AMH concentrations and androgen or sex hormone-binding globulin concentrations or with factors related to blood collection (e.g., sample type, time, season, and year of blood collection). CONCLUSION(S): Among premenopausal women, lower AMH concentrations are associated with older age, a younger age at menarche, and currently using oral contraceptives, suggesting these factors are related to a lower number or decreased secretory activity of ovarian follicles.
PMCID:5426228
PMID: 28366409
ISSN: 1556-5653
CID: 2519352
Australian & New Zealand journal of obstetrics & gynaecology. 2017:57(1):99-104.DOI: 10.1111/ajo.12580
Placenta praevia and the risk of adverse outcomes during second trimester abortion: A retrospective cohort study
BACKGROUND: There are few reports in the literature of the risks associated with second trimester abortion in women with placenta praevia (PP). We hypothesise that PP increases the risk of complications. AIMS: We sought to determine if PP is associated with a higher risk of blood loss and blood transfusion at the time of dilation and evacuation (D&E). MATERIALS AND METHODS: The records of 612 consecutive women undergoing abortion at 15-24 weeks of gestation were reviewed. Participant characteristics, need for blood transfusion, estimated blood loss (EBL) during the abortion and other complications were compared between women with and without ultrasound-documented PP. RESULTS: Eighty-seven of 612 (14.2%, 95% CI 11.5-17.2%) women had ultrasound-documented PP. The rate of blood transfusion was 3.4 and 1.3% in the group with PP and without PP, respectively (adjusted relative risk (RR = 2.8, 95% CI 0.7-11.3). An estimated blood loss of 500 cc or greater during the D&E procedure was observed in 12.6% of women in the PP group compared with 4.2% of women in the group without PP (adjusted RR 3.1, 95% CI 1.4-6.8, P = 0.004). CONCLUSIONS: Second-trimester abortion in women with PP is associated with a higher risk of blood loss of 500 cc or greater. Our study represents a larger sample size of patients with PP undergoing second-trimester abortion than previously reported in the literature. Women with PP may have a higher estimated blood loss and may require access to blood transfusion.
PMID: 28251636
ISSN: 1479-828x
CID: 2471192
Factors associated with cesarean delivery rates: a single-institution experience
BACKGROUND: The aim of this study was to identify factors associated with variability in Cesarean delivery (CD) rates amongst providers at a single institution. METHODS: A retrospective cohort analysis was carried out on all births at NYU Langone Medical Center from 2005-2013. Data was collected for subjects and linked to diagnosis codes for singleton and twin deliveries. Descriptive characteristics were generated for all deliveries, and inferential analysis was performed including multiple covariates for singleton deliveries in the 2010-2013 cohort, including both univariate and multivariate regression analyses to identify factors associated with higher CD rates. RESULTS: 37,692 deliveries were identified at our institution during the study period, performed by 88 unique providers. The mean CD rate was 29.6%, with a range for individual physicians from 9.9% to 75.6%. In multivariate regression analysis, CD rate was directly correlated with average patient age, physician male gender, proportion of high-risk deliveries, and Maternal-Fetal Medicine specialty, and it was inversely correlated with total number of deliveries by physician and forceps delivery rate. There was no significant difference in CD rates between group and solo practices. Within the same group practice, each member's CD rate was strongly correlated with the average CD rate of the group. CONCLUSION: Our study demonstrates the wide range of CD rates for providers practicing within the same institution and reiterates the association of CD rates with patient age, high-risk pregnancy, and provider volume. Among operative vaginal deliveries, forceps delivery rate was associated with lower CD rates whereas vacuum delivery rate was not. Despite these findings, practice patterns within individual practices appear to contribute significantly to the wide range of CD rates.
PMCID:5401466
PMID: 28439421
ISSN: 2054-958x
CID: 2542452
Serum biomarkers of polyomavirus infection and risk of lung cancer in never smokers
BACKGROUND: Lung cancer in never smokers is a significant contributor of cancer mortality worldwide. In this analysis, we explored the role of nine human polyomaviruses, including JC virus (JCV), BK virus (BKV) and Merkel cell virus (MCV), in lung cancer development in never smokers as there are data to support that polyomaviruses are potentially carcinogenic in the human lung. METHODS: We used multiplex serology to detect serum antibodies to polyomaviruses in a nested case-control design combining lung cancer cases and controls from four cohort studies - NYU Women's Health Study (NYU-WHS), Janus Serum Bank, Shanghai Women's Health Study and Singapore Chinese Health Study (SCHS). RESULTS: The final analyses included 511 cases and 508 controls. Seroprevalence for each polyomavirus showed significant heterogeneity by study, but overall there were no statistically significant differences between cases and controls. In total, 69.1% of the cases and 68.7% of the controls were seropositive for JCV VP1 antibody. Seropositivity for BKV was higher at 89.0% in cases and 89.8% in controls and lower for MCV at 59.3% in cases and 61.6% in controls. Similar results were obtained after adding an additional retrospective case-control study (Xuanwei study) to the analysis. CONCLUSIONS: Our results do not support the hypothesis that seropositivity for polyomaviruses is associated with increased lung cancer risk in never smokers. Future research to evaluate relationship between polyomavirus infection and lung carcinogenesis should focus more on evaluating the presence of virus or viral nucleic acids (DNA or RNA) in lung tumour samples.British Journal of Cancer advance online publication, 15 September 2016; doi:10.1038/bjc.2016.285 www.bjcancer.com.
PMCID:5117783
PMID: 27632373
ISSN: 1532-1827
CID: 2247082
Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21
Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10-15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10-9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10-8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10-8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10-4-2.0x10-3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
PMCID:5340084
PMID: 27579533
ISSN: 1949-2553
CID: 2232522
Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium
PURPOSE: An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3). PATIENTS AND METHODS: Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. RESULTS: Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het
PMCID:5012665
PMID: 27325851
ISSN: 1527-7755
CID: 2159102
Easy sonographic differential diagnosis between intrauterine pregnancy and cesarean section scar pregnancy in the early first trimester
BACKGROUND: Cesarean scar pregnancy is a serious complication of pregnancy, which consists of implantation of the gestational sac in the hysterotomy scar. This condition is increasing in frequency and often poses a diagnostic challenge. Its diagnosis is dependent on visual assessment of the uterus on the longitudinal sagittal ultrasound plane. Misdiagnosing a low intrauterine chorionic sac as a cesarean scar pregnancy, or a true scar pregnancy as an intrauterine pregnancy may lead to adverse outcomes including hysterectomy. OBJECTIVE: The objective of the study is to describe a sonographic method for the differential diagnosis of cesarean scar pregnancy versus intrauterine pregnancy in early gestation. The current study addressed to test the hypothesis that on a first-trimester ultrasound performed between 5 and 10 weeks of gestation, the relative location of the center of gestational sac to the midpoint of the uterus along a longitudinal line between the external cervical os and the fundus, can be used for early detection of cesarean scar pregnancies. STUDY DESIGN: This is a retrospective review of electronically archived ultrasound images of intrauterine and cesarean scar pregnancies between 5 and 10 weeks of gestation. A total of 242 ultrasound images were analyzed: 185 cases of normal intrauterine pregnancies (including 128 in anteverted uteri, 31 in retroverted uteri and 26 intrauterine pregnancies with history of previous cesarean delivery) and 57 cases of cesarean scar pregnancies diagnosed throughout 2004-2015 in a single institution. The following measurements were made for each case: distance from the external cervical os to the uterine fundus, the midpoint axis of the uterus, the distance from the external cervical os to the center of gestational sacs and the distance from the external cervical os to the most distant edge of the gestational sacs from the cervix. RESULTS: The location of the center of the gestational sac relative to the midpoint axis of the uterus between 5 and 10 weeks of gestation differentiated between intrauterine and cesarean scar pregnancies (mean, 17.8 vs -10.6 mm, respectively, p = 0.0001), indicating that most of the cesarean scar pregnancies are located proximally to the midpoint axis of the uterus whereas most of the normal intrauterine pregnancies are located distally from the midpoint of the uterus. Using location of the center of the gestational sac as a marker of cesarean scar pregnancies between 5 and 10 weeks of gestation yielded the following characteristics of diagnostic accuracy: sensitivity 93.0% and specificity 98.9%. The likelihood ratio of the positive test was 84.5. The likelihood ratio of the negative test was 0.07. CONCLUSIONS: The location of the center of the gestational sac relative to the midpoint axis of the uterus can be used as an easy, method for sonographic differentiation of intrauterine and cesarean scar pregnancies between 5 and 10 weeks of gestation.
PMID: 26899908
ISSN: 1097-6868
CID: 1965342
Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
PMCID:4909985
PMID: 27291797
ISSN: 2041-1723
CID: 2143242
Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types
BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. RESULTS: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE =0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. CONCLUSION: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
PMCID:4806328
PMID: 26464424
ISSN: 1460-2105
CID: 1909402
