Search

This study assessed the effects of multiplex genetic testing on disease risk perceptions among 216 healthy adults. Participants, aged 25-40, were recruited through the Multiplex Initiative, which offered a genetic susceptibility test for eight common diseases. Participants completed baseline telephone and web-based surveys prior to making the testing decision. Three months after the receipt of mailed test results, participants completed a follow-up telephone survey. Risk perceptions for the eight diseases were measured at baseline and follow-up, along with beliefs about genetic causation of those diseases. The main results were: (i) mean risk perceptions were considerably stable from baseline to follow-up; (ii) the best predictors of follow-up risk perceptions were the corresponding baseline perceptions and family history; and (iii) within-individuals, most participants increased or decreased their risk perceptions for specific diseases in concordance with the number of risk markers they carry, their family history and their beliefs about genetic causality of diseases. In conclusion, participants presented a vigilant approach to the interpretation of genetic test results, which provides reassurance with regard to a potential inflation of risk perceptions in the population because of multiplex genetic testing. [ABSTRACT FROM AUTHOR]

Purpose: Drug repurposing is an effective means of increasing treatment options for diseases, however identifying candidate molecules for the indication of interest from the thousands of approved drugs is challenging. We have performed a computational analysis of published literature to rank existing drugs according to predicted ability to reduce alpha synuclein (aSyn) oligomerization and analyzed real-world data to investigate the association between exposure to highly ranked drugs and PD., Methods: Using IBM Watson for Drug Discoveryâ (WDD) we identified several antihypertensive drugs that may reduce aSyn oligomerization. Using IBM MarketScanâ Research Databases we constructed a cohort of individuals with incident hypertension. We conducted univariate and multivariate Cox proportional hazard analyses (HR) with exposure as a time-dependent covariate. Diuretics were used as the referent group. Age at hypertension diagnosis, sex, and several comorbidities were included in multivariate analyses., Results: Multivariate results revealed inverse associations for time to PD diagnosis with exposure to the combination of the combination of angiotensin receptor II blockers (ARBs) and dihydropyridine calcium channel blockers (DHP-CCB) (HR = 0.55, p < 0.01) and angiotensin converting enzyme inhibitors (ACEi) and diuretics (HR = 0.60, p-value <0.01). Increased risk was observed with exposure to alpha-blockers alone (HR = 1.81, p < 0.001) and the combination of alpha-blockers and CCB (HR = 3.17, p < 0.05)., Conclusions: We present evidence that a computational approach can efficiently identify leads for disease-modifying drugs. We have identified the combination of ARBs and DHP-CCBs as of particular interest in PD., (© 2020 John Wiley & Sons Ltd.)

Objectives: Adipocyte derived free fatty acids (FFA) promote epithelial ovarian cancer (EOC) by acting as a fuel source to support the energy requirement of the cancer cells. FFA may also exert biological effects through signaling pathways. Recently, a family of FFA activated G-protein coupled receptors (FFAR/GPCRs) was identified. Our objective was to investigate the role of FFAR/GPCRs in EOC and assess their potential as therapeutic targets., Methods: The mRNA (RT-PCR) expression of FFAR/GPCR family members (FFAR1/GPR40; FFAR2/GPR43, FFAR3/GPR41, FFAR4/GPR120 and GPR84) was examined in: (1) a syngeneic mouse model of EOC fed high energy diet (60% fat) or regular diet (30% fat), (2) EOC cell lines exposed to free fatty acids and (3) specimens from 13 histologically normal ovaries and 28 high grade ovarian serous carcinomas. The GPR 40 antagonist, GW1100, was used to inhibit FFAR1/GPR40 and cell survival was assayed by MTT in various cell lines., Results: High Grade Serous carcinoma specimens expressed significantly increased GPR40 compared to normal ovaries (p=0.0020). Higher expression was noted in advanced stage disease. ID8 ovarian tumors from mice fed with high fat diet also showed higher GPR40 expression. Exposing EOC cells to FFAs, increased GPR40 expression. Treatment of EOC cell lines with GW100 resulted in growth inhibition and was associated with an alteration in their energy metabolism., Conclusion: FFA-induced cancer cell growth may be partly mediated through FFAR1/GPR40. Targeting of FFAR1/GPR40 may be an attractive treatment strategy in EOC, and possibly offers a targeted treatment for a subset of EOC patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy.

Background: Acquisition of metabolic alterations has been shown to be essential for the unremitting growth of cancer, yet the relation of such alterations to chemosensitivity has not been investigated. In the present study our aim was to identify the metabolic alterations that are specifically associated with platinum resistance in ovarian cancer. A global metabolic analysis of the A2780 platinum-sensitive and its platinum-resistant derivative C200 ovarian cancer cell line was performed utilizing ultra-high performance liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy. Per-metabolite comparisons were made between cell lines and an interpretive analysis was carried out using the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic library and the Ingenuity exogenous molecule library., Results: We observed 288 identified metabolites, of which 179 were found to be significantly different (t-test p < 0.05) between A2780 and C200 cells. Of these, 70 had increased and 109 had decreased levels in platinum resistant C200 cells. The top altered KEGG pathways based on number or impact of alterations involved the cysteine and methionine metabolism. An Ingenuity Pathway Analysis also revealed that the methionine degradation super-pathway and cysteine biosynthesis are the top two canonical pathways affected. The highest scoring network of altered metabolites was related to carbohydrate metabolism, energy production, and small molecule biochemistry. Compilation of KEGG analysis and the common network molecules revealed methionine and associated pathways of glutathione synthesis and polyamine biosynthesis to be most significantly altered., Conclusion: Our findings disclose that the chemoresistant C200 ovarian cancer cells have distinct metabolic alterations that may contribute to its platinum resistance. This distinct metabolic profile of platinum resistance is a first step towards biomarker development for the detection of chemoresistant disease and metabolism-based drug targets specific for chemoresistant tumors.

Background: Evidence shows underutilization of cancer genetics services. To explore the reasons behind this underutilization, this study evaluated characteristics of women who were referred for genetic counseling and/or had undergone BRCA1/2 testing., Methods: An ovarian cancer risk perception study stratified 16,720 eligible women from the Henry Ford Health System into average-, elevated-, and high-risk groups based on family history. We randomly selected 3,307 subjects and interviewed 2,524 of them (76.3% response rate)., Results: Among the average-, elevated-, and high-risk groups, 2.3, 10.1, and 20.2%, respectively, reported genetic counseling referrals, and 0.8, 3.3, and 9.5%, respectively, reported having undergone BRCA testing. Personal breast cancer history, high risk, and perceived ovarian cancer risk were associated with both referral and testing. Discussion of family history with a doctor predicted counseling referral, whereas belief that family history influenced risk was the strongest BRCA testing predictor. Women perceiving their cancer risk as much higher than other women their age were twice as likely (95% confidence interval: 2.0-9.6) to report genetic counseling referral., Conclusion: In a health system with ready access to cancer genetic counseling and BRCA testing, women who were at high risk underutilized these services. There were strong associations between perceived ovarian cancer risk and genetic counseling referral, and between a belief that family history influenced risk and BRCA testing.

Aims: Personal genomic testing (PGT) for common disease risk is becoming increasingly frequent, but little is known about people's array of emotional reactions to learning their genomic risk profiles and the psychological harms/benefits of PGT. We conducted a study of post-PGT affect, including positive, neutral, and negative states that may arise after testing., Methods: A total of 228 healthy adults received PGT for common disease variants and completed a semistructured research interview within 2 weeks of disclosure. The study participants reported how the PGT results made them feel in their own words. Using an iterative coding process, the responses were organized into three broad affective categories: negative, neutral, and positive affect., Results: Neutral affect was the most prevalent response (53.9%), followed by positive affect (26.9%) and negative affect (19.2%). We found no differences by gender, race, or education., Conclusions: While <20% of participants reported negative affect in response to learning their genomic risk profile for common diseases, a majority experienced either neutral or positive emotions. These findings contribute to the growing evidence that PGT does not impose significant psychological harms. Moreover, they point to a need to better link theories and assessments in both emotional and cognitive processing to capitalize on PGT information for healthy behavior change., (© 2015 S. Karger AG, Basel.)

Objective: There are known disparities in endometrial cancer survival with black women who experience a greater risk of death compared with white women. The purpose of this investigation was to evaluate the role of comorbid conditions as modifiers of endometrial cancer survival by race., Study Design: Two hundred seventy-one black women and 356 white women who had been diagnosed with endometrial cancer from 1990-2005 were identified from a large urban integrated health center. A retrospective chart review was conducted to gather information on comorbid conditions and other known demographic and clinical predictors of survival., Results: Black women experienced a higher hazard of death from any cause (hazard ratio [HR] 1.51; 95% confidence interval [CI], 1.22-1.87) and from endometrial cancer (HR, 2.42; 95% CI, 1.63-3.60). After adjustment for known clinical prognostic factors and comorbid conditions, the hazard of death for black women was elevated but no longer statistically significant for overall survival (HR, 1.22; 95% CI, 0.94-1.57), and the hazard of death from endometrial cancer remained significantly increased (HR, 2.27; 95% CI, 1.39-3.68). Both black and white women with a history of hypertension experienced a lower hazard of death from endometrial cancer (HR, 0.47; 95% CI, 0.23-0.98; and HR, 0.35; 95% CI, 0.19-0.67, respectively)., Conclusion: The higher prevalence of comorbid conditions among black women does not explain fully the racial disparities that are seen in endometrial cancer survival. The association between hypertension and a lower hazard of death from endometrial cancer is intriguing, and further investigation into the underlying mechanism is needed., (Copyright © 2014. Published by Elsevier Inc.)

Risk perceptions and disease worry of 1,959 healthy adults were measured in a telephone-based survey. In the model for each of eight health conditions, people's perceived risk was related to their worry for that condition (p < .0001) and their worry for the other seven conditions (p < .001). There was also an interaction indicating that the less people were worried about a certain condition, the more their worry about the other seven conditions increased their risk perception for that condition (p < .0001). The results are important for preventing biased risk perceptions in multiple-disease contexts.

Background: The aim of the current study was to learn how people integrate attitudes about multiple health conditions to make a decision about genetic testing uptake., Methods: This study recruited 294 healthy young adults from a parent research project, the Multiplex Initiative, conducted in a large health care system in Detroit, Michigan. All participants were offered a multiplex genetic test that assessed risk for 8 common health conditions (e.g., type 2 diabetes). Data were collected from a baseline survey, a web-based survey, and at the time of testing., Results: Averaging attitudes across diseases predicted test uptake but did not contribute beyond peak attitudes, the highest attitude toward testing for a single disease in the set. Peak attitudes were found sufficient to predict test uptake., Limitations: The effects of set size and mode of presentation could not be examined because these factors were constant in the multiplex test offered., Conclusions: These findings support theories suggesting that people use representative evaluations in attitude formation. The implication of these findings for further developments in genetic testing is that the communication and impact of multiplex testing may need to be considered in the light of a bias toward peak attitudes.

Objective: To describe parents' attitudes toward pediatric genetic testing for common, adult-onset health conditions and to identify factors underlying these attitudes., Participants and Methods: Parents (n = 219) enrolled in a large, group-practice health plan were offered a "multiplex" genetic test for susceptibility to 8 common, adult-onset health conditions and completed an online survey assessing attitudes and beliefs about the risks and benefits of the test for their child, their willingness to consider having their child tested, and other psychosocial variables., Results: Parents viewed the benefits of pediatric testing to outweigh its risks (positive decisional balance) and were moderately interested in pediatric testing. Variables associated with positive decisional balance included greater interest in knowing about gene-health associations in their child, anticipation of less difficulty understanding their child's genetic health risks, and more positive emotional reactions to learning about their child's decreased health risks (adjusted R(2) = 0.33, P < .0001). Similarly, variables associated with greater parental willingness to test were being a mother (versus being a father), greater perceived risk of diseases in their child, greater interest in knowing about gene-health relationships in their child, anticipating less difficulty learning about their child's genetic health risks, anticipating more positive emotional reactions to learning about their child's decreased health risks, and positive decisional balance (adjusted R(2) = 0.57, P < .0001)., Conclusions: As genetic susceptibility testing for common, adult-onset health conditions proliferates, pediatricians should anticipate parents' interest in testing children and be prepared to facilitate informed decision making about such testing.

Background: Advances in technology have made individual access to personal genetic information foreseeable in the near future. Policy makers and the media forecast that the ready availability of personal genetic profiles would benefit both the individual and the health care system by improving outcomes and decreasing cost. However, there is a significant gap between having access to genetic data and either wanting or understanding the information it provides., Objective: Our primary aim was to evaluate, using a population-based sample of healthy adults, whether gender, race and education status influences interest and participation in a multiplex genetic susceptibility test., Methods: Healthy, insured individuals, 25-40 years of age, were approached via a large, integrated health system in which primary and specialty care is available. Study participants were offered personalized genetic risk information on 8 common chronic health conditions. Social groups historically known not to participate in genetic research (men, African Americans and those from lower education neighborhoods) were oversampled. We describe the recruitment outcomes and testing decisions of these social groups., Results: We found that even among those with access to health care, African Americans were less likely to participate in the multiplex genetic susceptibility test, while those from higher education neighborhoods were more likely to participate., Conclusions: Our results suggest that large social groups will likely be underrepresented in research in personalized genomics even when robust population-based recruitment strategies are employed., (Copyright © 2010 S. Karger AG, Basel.)

BACKGROUND.: Lymphatic invasion is necessary for regional lymph node (RLN) metastasis in breast cancer (BC), while systemic metastasis requires blood vessel (BV) invasion. The site of BV invasion could be at the primary BC site or through lymphovascular anastomoses. The vague pathologic term "lymphovascular invasion" (LVI) encourages the belief that peri/intratumoral BV invasion may be common. We investigated the relative contribution of RLN metastasis to systemic metastasis by studying the relationship among LVI and RLN and/or systemic metastasis in a population-based cohort of breast cancer patients. METHODS.: Fisher's exact test was done to assess global associations among LVI and RLN and/or systemic metastasis in a prospective database of breast cancer patients undergoing RLN biopsy. Logistic regression was used to determine multivariable contributions of LVI to metastasis when controlling for available demographic, radiologic, and pathologic variables. RESULTS.: Of 1668 patients evaluated 25.4% were RLN positive and 10.4% had LVI. RLN metastasis was predicted by tumor size (P < .0001), HER-2/neu overexpression (P = .0022) and the interaction between LVI positive and HER-2/neu positive tumors (< .0001). Patients with LVI/HER-2-neu positive were 3 times as likely to have positive RLNs compared with patients LVI/HER-2-neu negative. Systemic metastasis was significantly (P = .0013) associated with LVI/ RLN positive, but not with LVI positive/RLN negative patients (P = .137). CONCLUSIONS.: LVI predicted RLN metastasis. LVI also significantly predicted systemic metastasis, but only when the RLN was also positive. Since RLN requires lymphatic invasion, these data support the hypothesis that primary breast cancers often invade lymphatics to gain access to the systemic circulation.

Tamoxifen reduces primary breast cancer incidence, yet causes serious side effects. To date, few women with increased breast cancer risk have elected to use tamoxifen for chemoprevention. The objective of the study was to determine women's knowledge of and attitudes toward tamoxifen following exposure to a tailored decision aid (DA). A total of 632 women with a 5-year risk of breast cancer > or = 1.66% (Mean = 2.56, range = 1.7-17.3) were recruited from two healthcare organizations. Participants viewed an online DA that informed them about their 5-year risk of breast cancer and presented individually tailored content depicting the risks/benefits of tamoxifen prophylaxis. Outcome measures included behavioral intentions (to seek additional information about tamoxifen, to talk to a physician about tamoxifen, and to take tamoxifen); knowledge; and perceived risks and benefits of tamoxifen. After viewing the DA, 29% of participants said they intended to seek more information or talk to their doctor about tamoxifen, and only 6% believed they would take tamoxifen. Knowledge was considerable, with 63% of women answering at least 5 of 6 knowledge questions correctly. Participants were concerned about the risks of tamoxifen, and many believed that the benefits of tamoxifen did not outweigh the risks. This study is the largest to date to test women's preferences for taking tamoxifen and one of the largest to have tested the impact of a tailored DA. After viewing the DA, women demonstrated good understanding of tamoxifen's risks and benefits, but most were not interested in taking tamoxifen for breast cancer chemoprevention.

Background: Data from Arab world studies suggest that Arab women may experience a more aggressive breast cancer phenotype. To investigate this finding, we focused on one of the largest settlements of Arabs and Iraqi Christians (Chaldeans) in the US, metropolitan Detroit- a SEER reporting site since 1973., Materials and Methods: We identified a cohort of primary breast cancer cases diagnosed 1973-2003. Using a validated name algorithm, women were identified as being of Arab/Chaldean descent if they had an Arab last or maiden name. We compared characteristics at diagnosis (age, grade, histology, SEER stage, and marker status) and overall survival between Arab-, European-, and African-Americans., Results: The cohort included 1,652 (2%) women of Arab descent, 13,855 (18%) African-American women, and 63,615 (80%) European-American women. There were statistically significant differences between the racial groups for all characteristics at diagnosis. Survival analyses overall and for each SEER stage showed that Arab-American women had the best survival, followed by European-American women. African-American women had the poorest overall survival and were 1.37 (95% confidence interval: 1.23-1.52) times more likely to be diagnosed with an aggressive tumor (adjusting for age, grade, marker status, and year of diagnosis)., Conclusion: Overall, Arab-American women have a distribution of breast cancer histology similar to European-American women. In contrast, the stage, age, and hormone receptor status at diagnosis among Arab-Americans was more similar to African-American women. However, Arab-American women have a better overall survival than even European-American women.

Objective: To describe the impact on patients and physicians at a managed care organization (MCO) of a direct-to-consumer advertising (DTC-ad) campaign concerning testing for the BRCA1 and BRCA2 genes., Study Design: Observational study., Methods: In 2003, we mailed a 30-item questionnaire to 750 randomly chosen female members of Kaiser Permanente Colorado (KPCO) aged 25 to 54 years, and 100 female KPCO members with a history of breast cancer genetic referral. We mailed a 7-item questionnaire to 180 randomly chosen KPCO primary care providers., Results: Of 394 patient respondents, 245 (62%) reported exposure to the DTC-ad of whom 63% reported that the DTC-ad caused no anxiety at all. A high level of perceived breast cancer risk and being of Hispanic ethnicity each were independently associated with reported anxiety due to the DTC-ad (adjusted odds ratio [OR] = 3.23, 95% confidence interval [CI] = 1.35, 7.73, and adjusted OR = 4.19, 95% CI = 1.48, 11.83, respectively). Greater knowledge was seen among respondents exposed to the DTC-ad than among those reporting no exposure (P = .015). Of the physician respondents, 84% reported that the DTC-ad caused no strain on the doctor-patient relationship, and nearly 80% reported no effect on daily clinical practice. Genetic referrals soared more than 200% compared with the prior year, when there was no advertising., Conclusion: The DTC-ad had a marked impact on genetic services, but little apparent negative impact on patients or primary care providers at an MCO.

Purpose: To describe the impact of Myriad Genetics, Inc.'s direct-to-consumer advertising (DTC-ad) campaign on cancer genetic services within two Managed Care Organizations, Kaiser Permanente Colorado (KPCO), Denver, Colorado, where the ad campaign occurred, and Henry Ford Health System (HFHS), Detroit, Michigan, where there were no advertisements., Methods: The main outcome measures were the changes in number and pretest mutation probability of referrals approved for cancer genetic services at KPCO and HFHS during the campaign versus the year prior, and mutation probability of those undergoing testing., Results: At KPCO, referrals increased 244% during the DTC-ad compared to the same time period a year earlier (P value<0.001). The proportion of referrals at high pretest probability of a mutation (10% or greater) dropped from 69% the previous year to 48% during the campaign (P value<0.001). There was no significant change in pretest mutation probability among women who underwent testing between the two time periods. HFHS reported no significant change between the two time periods for numbers or mutation probability of referrals, or for mutation probability of women tested., Conclusion: The DTC-ad caused significant increase in demand for cancer genetic services. In the face of potential future DTC-ad for inherited cancer risk, providers and payers need to consider the delivery of genetic services and genetic education for persons of all risk levels.

Purpose: The purpose of this analysis is to describe factors associated with colorectal surveillance following diagnosis and treatment of nonmetastatic colorectal cancer., Methods: Subjects were identified as part of the HMO Cancer Research Network's study of colorectal cancer survivors. To be eligible for the main study, patients had to be part of the staff model components of health maintenance organizations in southeastern Michigan and Minnesota. Using computerized databases, individuals were identified who were 40 years or older with incident nonmetastatic colorectal cancer diagnosed between January 1, 1990, and December 31, 2000. Using data current through 2002, we analyzed the cohort using chi-square test statistics, life tables, and Cox proportional hazards models to understand variations in posttreatment surveillance practices. Subjects were followed up from date of diagnosis to date of recurrence, death, disenrollment from the health plan, or loss to follow-up, which ever came first. We assessed factors associated with colorectal surveillance at 1, 3, and 5 years after treatment. We also included an analysis comparing those who received an exam and those who didn't regardless of exam timing., Results: A total of 908 patients were eligible for the main study. Of these, we excluded subjects who were not white or African American (n = 27), resulting in an analytic sample of 881 (97% of the eligible cohort). Twenty-five percent of subjects were African American, 43% were female, and 48% were aged 70 years or older. The proportion who received an exam at 1 year was 18%, at 3 years was 60%, and at 5 years was 67%. Chi-square tests showed that African Americans were statistically significantly less likely than whites to receive an exam at all three time points. The Cox proportional hazards model for examinations regardless of timing and adjusted for confounders showed that African Americans were still less likely than whites to receive an exam (hazard ratio = 0.62; 95% confidence interval [CI] = 0.51 to 0.75). The same trend in undersurveillance was also observed for those 80 years of age or older at diagnosis, with an adjusted hazard ratio of 0.39 (95% CI = 0.26 to 0.57)., Conclusion: Our data indicate that colorectal cancer survivors who are African American or aged 80 years or more at diagnosis are less likely to receive posttreatment colorectal surveillance. Whether these differences are due to system or patient level barriers needs further study.

Purpose: To describe referral guidelines for hereditary breast and ovarian cancer (HBOC) counseling among a group of Health Maintenance Organizations (HMOs) and awareness of such among primary care clinicians., Methods: An organizational assessment of plan policies and a primary care clinician survey., Results: Five of the 7 HMOs reported having HBOC referral guidelines. Differences between plan's criteria included age of breast cancer onset, inclusion of male breast cancer, and second-degree relatives. Of the 91% clinicians responding, only half were aware of the HBOC guidelines. Awareness was higher in the plan with the most intense implementation effort (OR=3.0, 1.5-5.9) and among gynecologists (OR=2.8, 1.5-5.4)., Conclusions: Although HBOC counseling guidelines within participating HMOs identify persons for referral that can be easily incorporated into routine practice, continued work is needed to better understand how to help primary care providers identify high-risk persons, and new models of providing genetic services may need to be considered.