Ana M. Rodriguez

Structure-Function of the Tumor Suppressor BRCA1

BRCA1, a multi-domain protein, is mutated in a large percentage of hereditary breast and ovarian cancers. BRCA1 is most often mutated in three domains or regions: the N-terminal RING domain, exons 11-13, and the BRCT domain. The BRCA1 RING domain is responsible for the E3 ubiquitin ligase activity of BRCA1 and mediates interactions between BRCA1 and other proteins. BRCA1 ubiquitinates several proteins with various functions. The BRCA1 BRCT domain binds to phosphoproteins with specific sequences recognized by both BRCA1 and ATM/ATR kinases. Structural studies of the RING and BRCT domains have revealed the molecular basis by which cancer causing mutations impact the functions of BRCA1. While no structural data is available for the amino acids encoded by exons 11-13, multiple binding sites and functional domains exist in this region. Many mutations in exons 11-13 have deleterious effects on the function of these domains. In this mini-review, we examine the structure-function relationships of the BRCA1 protein and the relevance to cancer progression.

Trends in the National Distribution of Laparoscopic Hysterectomies From 2003 to 2010

STUDY OBJECTIVE The purpose of this analysis was to compare the trends in undergoing laparoscopic hysterectomy (versus abdominal or vaginal hysterectomy) based on patient age, race, median income and insurance type, from 2003 to 2010. DESIGN Retrospective study (Canadian Task Force classification II-3). SETTING National sample of hospital admissions after hysterectomy. PATIENTS Health Cost and Utilization Project-Nationwide Inpatient Sample database was used to review records of women who underwent hysterectomy for either menorrhagia or leiomyoma from 2003-2010. INTERVENTION The predicted probability of undergoing laparoscopic hysterectomy was determined for each year according to patient age, race, median income, and insurance type. The slopes of these values (i.e. the trend) was compared for each subgroup (i.e. black, white, Asian, etc.) in these categories. MAIN RESULTS A total of 530, 154 cases were included in this study. Total number of hysterectomies decreased by 39% from 60,364 to 36,835 from 2003 to 2010. The percent of hysterectomies that were laparoscopic increased from 11% in 2003 to 29% in 2010. All groups analyzed experienced an increase in predicted probability of undergoing a laparoscopic hysterectomy. Of all women undergoing hysterectomy, the probability of undergoing a laparoscopic hysterectomy remained highest for women who were less than 35 years old, white, with the highest median income, and with private insurance from 2003-2010. The slope was significantly greater for (1) white females versus all other races analyzed (p<0.01), (2) females in the highest income quartile versus females in the lowest income quartile (p<0.01) and (3) females with private insurance versus females with Medicaid (p<0.01) or Medicare (p<0.01). CONCLUSIONS There remains a gap in distribution of laparoscopic hysterectomies with regards to age, race, median income and insurance type that does not seem to be closing, despite the increased availability of laparoscopic hysterectomies.

The BRCA1 tumor suppressor binds to inositol 1,4,5-trisphosphate receptors to stimulate apoptotic calcium release

Background: The non-nuclear BRCA1 tumor suppressor can stimulate cell death, but the mechanisms are unknown. Results: BRCA1 binds to the inositol 1,4,5-trisphophate receptor (IP3R) calcium channel at the endoplasmic reticulum to stimulate apoptotic calcium release. Conclusion: BRCA1 tumor suppressor activity includes direct stimulation of apoptotic cell death via increased IP3R activity. Significance: We identify a novel role for the tumor suppressor BRCA1. The inositol 1,4,5-trisphosphate receptor (IP3R) is a ubiquitously expressed endoplasmic reticulum (ER)-resident calcium channel. Calcium release mediated by IP3Rs influences many signaling pathways, including those regulating apoptosis. IP3R activity is regulated by protein-protein interactions, including binding to proto-oncogenes and tumor suppressors to regulate cell death. Here we show that the IP3R binds to the tumor suppressor BRCA1. BRCA1 binding directly sensitizes the IP3R to its ligand, IP3. BRCA1 is recruited to the ER during apoptosis in an IP3R-dependent manner, and, in addition, a pool of BRCA1 protein is constitutively associated with the ER under non-apoptotic conditions. This is likely mediated by a novel lipid binding activity of the first BRCA1 C terminus domain of BRCA1. These findings provide a mechanistic explanation by which BRCA1 can act as a proapoptotic protein.

Incidence of occult leiomyosarcoma in presumed morcellation cases: a database study.

OBJECTIVE Our objective was to estimate the incidence of uterine leiomyosarcoma in patients with leiomyomas following laparoscopic supracervical hysterectomy and myomectomy procedures. STUDY DESIGN For this study, we analyzed records of 13,964 women aged 25-64 years who underwent laparoscopic supracervical hysterectomies or myomectomies for leiomyomas from 2002 to 2011 using Clinformatics DataMart. Patient records were divided into two groups: history of laparoscopic supracervical hysterectomy and history of myomectomy. Subjects were tracked to identify diagnosis of leiomyosarcoma within 1 year of the procedure. We analyzed data from the 25-39, 40-49, and 50-64 age brackets. Evidence was obtained from a cohort study from national private insurance claims in the US. RESULTS Our results showed the incidence of occult leiomyosarcoma developing within 1 year following supracervical hysterectomy using a laparoscopic-assisted approach are 9.8, 10.7, and 33.4 per 10,000 for the 25-39, 40-49, and 50-64 age brackets, respectively; the overall incidence rate is 13.1 per 10,000. The incidence rate of occult leiomyosarcoma developing within 1 year following myomectomy using a laparoscopic-assisted approach are 0.0, 33.8, and 90.1 per 10,000 for the 25-39, 40-49, and 50-64 age brackets, respectively; the overall incidence rate is 17.3 per 10,000. CONCLUSION Our analysis shows the overall risk of being diagnosed with occult leiomyosarcoma is 12.9 per 10,000 in laparoscopic-assisted supracervical hysterectomy and myomectomy for patients younger than 49. There is no evidence of occult leiomyosarcoma 1 year after operation for patients younger than 40 who underwent laparoscopic myomectomy.

Cigarette smoking, comorbidity, and general health among survivors of adolescent and young adult cancer

We examined the associations between cigarette smoking, comorbidity, and general health among survivors of adolescent and young adult (AYA) cancer and a comparison group.

Disparities in endometrial cancer outcomes between non-Hispanic White and Hispanic women

OBJECTIVE To compare demographics, tumor characteristics, the first course of treatment, and cancer-specific survival of non-Hispanic White and Hispanic women with endometrial cancer. METHODS We used public-use data from the Surveillance, Epidemiology, and End Results (SEER) Program. The study included 69,764 non-Hispanic White and Hispanic women diagnosed with endometrial cancer between 2000 and 2010. Using Cox proportional hazards models, demographics, tumor characteristics, and treatment were assessed as potential explanatory variables for the survival disparity between non-Hispanic Whites and Hispanics. RESULTS Kaplan-Meier estimation with Bonferroni correction showed statistically different cancer-specific survival for U.S.-born and foreign-born Hispanics compared to non-Hispanic Whites, but no difference between birthplace-unknown Hispanics and non-Hispanic Whites. In 2000-2005, U.S.-born and foreign-born Hispanics had a higher risk of endometrial cancer death compared to non-Hispanic Whites after full adjustment (hazard rate (HR)=1.61, 95% Confidence Interval (CI):1.44-1.79 and 1.27, 95% CI:1.13-1.43). In 2006-2010, the risk of endometrial death was not statistically significant for U.S.-born Hispanics (HR=1.16, 95% CI:0.99-1.36), but increased for foreign-born Hispanics (HR=1.31, 95% CI:1.12-1.52). Most of the survival disparity between Hispanic and non-Hispanic White women was mediated by cancer characteristics, specifically, stage and node involvement. CONCLUSIONS Hispanic women have higher cancer-specific mortality compared to non-Hispanic Whites. Compared to 2000-2005, more Hispanics were diagnosed at later stages and fewer received combination therapy in 2006-2010. Early detection is vital to improving endometrial cancer survival as most of the disparity was mediated by stage. Increased efforts are needed to improve education and access to care for Hispanic women.

Cost‐related medication nonadherence among adolescent and young adult cancer survivors

This study investigated cost‐related medication nonadherence among survivors of adolescent and young adult cancer and a comparison group in the United States.

Project ECHO: A Telementoring Program for Cervical Cancer Prevention and Treatment in Low-Resource Settings

Cervical cancer incidence and mortality rates are significantly higher in low- and middle-income countries compared with the United States and other developed countries. This disparity is caused by decreased access to screening, often coupled with low numbers of trained providers offering cancer prevention and treatment services. However, similar disparities are also found in underserved areas of the United States, such as the Texas-Mexico border, where cervical cancer mortality rates are 30% higher than in the rest of Texas. To address these issues, we have adopted the Project ECHO (Extension for Community Healthcare Outcomes) program, a low-cost telementoring model previously proven to be successful in increasing local capacity, improving patient management skills, and ultimately improving patient outcomes in rural and underserved areas. We use the Project ECHO model to educate local providers in the management of cervical dysplasia in a low-resource region of Texas and have adapted it to inform strategies for the management of advanced cervical and breast cancer in Latin America and sub-Saharan Africa. This innovative approach, using ECHO, is part of a larger strategy to enhance clinical skills and develop collaborative projects between academic centers and partners in low-resource regions.

Initial Experience with Robotic Retropubic Urethropexy Compared to Open Retropubic Urethropexy

Study Objective. To compare the clinical outcomes of robotic retropubic urethropexy versus open retropubic urethropexy. Design. Retrospective case-control study (II-2). Setting. University Hospital. Patients. All patients who underwent robotic retropubic urethropexy from 1/1/12 to 6/1/12 by a single gynecologic surgeon were included in the case series. The control cases consisted of the last five consecutive open retropubic urethropexies performed by the same surgeon. Main Results. A total of 10 patients (5 robotic cases and 5 open cases) were included in this study. Both groups were similar with respect to age, BMI, and obstetrical history. Mean hospital stay length and mean EBL were overall less for robotic cases than for open cases (1.2 days versus 2.6 days; 169 mL versus 300 mL). One of the 5 patients who underwent the open approach and 2 of the 5 patients who underwent the robotic approach sustained a minor intraoperative complication. All but one patient from each group experienced resolution of incontinence after the procedure. Two of the patients who underwent the open approach had postoperative complications. Conclusions. Robotic retropubic urethropexy may be a feasible alternative to open retropubic urethropexy. A larger study is necessary to support our observations.

Abstract A95: Overall endometrial cancer survival among non-Hispanic white and Hispanic women: A trend analysis of SEER reported cases 1992-2010

Objective: To compare demographic and tumor characteristics, treatment, and overall and cancer-specific survival of non-Hispanic White and Hispanic women with endometrial cancer. Background: Hispanics are one of the fastest growing minority groups in the U.S. Limited research has looked at age distribution, disease presentation, and outcome of endometrial cancer among ethnic minority women. Methods: We used public use data from the SEER registry between 1992 and 2010. Inclusion criteria included non-Hispanic and Hispanic women who were diagnosed with endometrial cancer after 1992; not missing age, the first course of treatment, lymphadenectomy or lymph node status; and not diagnosed by autopsy or death certificate Results: A total of 83,904 non-Hispanic and Hispanic patients were analyzed. Factors predictive of overall survival included being U.S.-born Hispanic, year of diagnosis, age at diagnosis, being single or other marital status, stage, histology-based risk, grade, extent of lymphadenectomy, and the first course of treatment. Factors predictive of cancer-specific survival included year of diagnosis, age at diagnosis, marital status, stage, other histology-based risk, grade, extent of lymphadenectomy, and the first course of treatment. Conclusions: U.S.-born Hispanic women with endometrial cancer exhibited significantly poorer overall survival compared to non-Hispanic white women even after controlling for confounding variables. There was no difference in overall survival or cancer-specific survival between U.S.-born and foreign-born Hispanics compared to non-Hispanic Whites. Citation Format: Ana M. Rodriguez, ThuyQuynh Ngoc Do. Overall endometrial cancer survival among non-Hispanic white and Hispanic women: A trend analysis of SEER reported cases 1992-2010. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr A95.