Germline Exome Sequencing for Men with Testicular Germ Cell Tumor Reveals Coding Defects in Chromosomal Segregation and Protein-targeting Genes.

BACKGROUND: Testicular germ cell tumor (TGCT) is the most common cancer among young White men. TGCT is highly heritable, although there are no known high-penetrance predisposition genes. CHEK2 is associated with moderate TGCT risk. OBJECTIVE: To identify coding genomic variants associated with predisposition to TGCT. DESIGN, SETTING, AND PARTICIPANTS: The study involved 293 men with familial or bilateral (high risk; HR)-TGCT representing 228 unique families and 3157 cancer-free controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We carried out exome sequencing and gene burden analysis to identify associations with TGCT risk. RESULTS AND LIMITATIONS: Gene burden association identified several genes, including loss-of-function variants of NIN and QRSL1. We identified no statistically significant association with the sex- and germ-cell development pathways (hypergeometric overlap test: p = 0.65 for truncating variants, p = 0.47 for all variants) or evidence of associations with the regions previously identified via genome-wide association studies (GWAS). When considering all significant coding variants together with genes associated with TGCT on GWAS, there were associations with three major pathways: mitosis/cell cycle (Gene Ontology identity GO:1903047: observed/expected variant ratio [O/E] 6.17, false discovery rate [FDR] 1.53 × 10-11), co-translational protein targeting (GO:0006613: O/E 18.62, FDR 1.35 × 10-10), and sex differentiation (GO:0007548: O/E 5.25, FDR 1.90 × 10-4). CONCLUSIONS: To the best of our knowledge, this study is the largest to date on men with HR-TGCT. As in previous studies, we identified associations with variants for several genes, suggesting multigenic heritability. We identified associations with co-translational protein targeting, and chromosomal segregation and sex determination, identified via GWAS. Our results suggest potentially druggable targets for TGCT prevention or treatment. PATIENT SUMMARY: We searched for gene variations that increase the risk of testicular cancer and found numerous new specific variants that contribute to this risk. Our results support the idea that many gene variants inherited together contribute to the risk of testicular cancer.

Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk.

BACKGROUND: Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation. METHODS: In this pathway-focused investigation, we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the international Testicular Cancer Consortium on 10,156 TGCT cases and 179,683 controls. RESULTS: In individual SNP analyses, seven SNPs, four mapping within MTHFR, were associated with TGCT risk after correction for multiple testing (q ≤ 0.05). Queries of public databases showed that three of these SNPs were associated with MTHFR changes in enzymatic activity (rs1801133) or expression level in testis tissue (rs12121543, rs1476413). Gene-based analyses revealed MTHFR (q = 8.4 × 10-4), methyl-CpG-binding protein 2 (MECP2; q = 2 × 10-3), and ZBTB4 (q = 0.03) as the top TGCT-associated genes. Stratifying by tumor histology, four MTHFR SNPs were associated with seminoma. In gene-based analysis MTHFR was associated with risk of seminoma (q = 2.8 × 10-4), but not with nonseminomatous tumors (q = 0.22). CONCLUSIONS: Genetic variants within MTHFR, potentially having an impact on the DNA methylation pattern, are associated with TGCT risk. IMPACT: This finding suggests that TGCT pathogenesis could be associated with the folate cycle status, and this relation could be partly due to hereditary factors.

Identification of 22 susceptibility loci associated with testicular germ cell tumors.

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.

Lower abdominal and pelvic radiation and testicular germ cell tumor risk.

BACKGROUND: Testicular germ cell tumor (TGCT) incidence has increased in recent decades along with the use and dose of diagnostic radiation. Here we examine the association between reported exposure to diagnostic radiation and TGCT risk. METHODS: We conducted a case-control study of men with and without TGCT recruited from hospital- and population-based settings. Participants reported on exposures to 1) x-ray or CT below the waist and 2) lower GI series or barium enema, which consists of a series of x-rays of the colon. We also derived a combined measure of exposure. We used logistic regression to determine the risk of developing TGCT according to categories of exposures (0, 1-2, or ≥3 exposures) and age at first exposure, adjusting for age, year of birth, race, county, body mass index at diagnosis, family history of TGCT, and personal history of cryptorchidism. RESULTS: There were 315 men with TGCT and 931 men without TGCT in our study. Compared to no exposures, risk of TGCT was significantly elevated among those reporting at least three exposures to x-ray or CT (OR≥3 exposures, 1.78; 95% CI, 1.15-2.76; p = 0.010), lower GI series or barium enema (OR≥3 exposures, 4.58; 95% CI, 2.39-8.76; p<0.001), and the combined exposure variable (OR≥3 exposures, 1.59; 95% CI, 1.05-2.42; p = 0.029). The risk of TGCT was elevated for those exposed to diagnostic radiation at age 0-10 years, compared to those first exposed at age 18 years or later, although this association did not reach statistical significance (OR, 2.00; 95% CI, 0.91-4.42; p = 0.086). CONCLUSIONS: Exposure to diagnostic radiation below the waist may increase TGCT risk. If these results are validated, efforts to reduce diagnostic radiation doses to the testes should be prioritized.

Mutation Rates in Cancer Susceptibility Genes in Patients With Breast Cancer With Multiple Primary Cancers.

PURPOSE: Women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. Whether mutations in genes other than BRCA1/2 are enriched in patients with breast and another primary cancer over those with a single breast cancer (S-BC) is unknown. PATIENTS AND METHODS: We identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in 2 different cohorts: cohort 1, high-risk breast cancer program (multiple primary breast cancer [MP-BC], n = 551; S-BC, n = 449) and cohort 2, familial breast cancer research study (MP-BC, n = 340; S-BC, n = 1,464). Mutation rates in these 2 cohorts were compared with a control data set (Exome Aggregation Consortium [ExAC]). RESULTS: Overall, pathogenic mutation rates for autosomal, dominantly inherited genes were higher in patients with MP-BC versus S-BC in both cohorts (8.5% v 4.9% [P = .02] and 7.1% v 4.2% [P = .03]). There were differences in individual gene mutation rates between cohorts. In both cohorts, younger age at first breast cancer was associated with higher mutation rates; the age of non-breast cancers was unrelated to mutation rate. TP53 and MSH6 mutations were significantly enriched in patients with MP-BC but not S-BC, whereas ATM and PALB2 mutations were significantly enriched in both groups compared with ExAC. CONCLUSION: Mutation rates are at least 7% in all patients with BRCA1/2 mutation-negative MP-BC, regardless of age at diagnosis of breast cancer, with mutation rates up to 25% in patients with a first breast cancer diagnosed at age < 30 years. Our results suggest that all patients with breast cancer with a second primary cancer, regardless of age of onset, should undergo multigene panel testing.

A comparative effectiveness education trial for lifestyle health behavior change in African Americans.

Obesity and excess weight are significant clinical and public health issues that disproportionately affect African Americans because of physical inactivity and unhealthy eating. We compared the effects of alternate behavioral interventions on obesity-related health behaviors. We conducted a comparative effectiveness education trial in a community-based sample of 530 adult African Americans. Outcomes variables were physical activity (PA) and fruit and vegetable intake. Outcomes were evaluated at baseline and 1-month following interventions about shared risk factors for cancer and cardiovascular disease (CVD) (integrated, INT) or CVD only (disease-specific). Significant increases were found in the proportion of participants who met PA guidelines from baseline (47.4%) to follow-up (52.4%) (P = 0.005). In the stratified analysis that were conducted to examine interaction between education and intervention group assignment, this effect was most apparent among participants who had ≤high school education and were randomized to INT (OR = 2.28, 95% CI = 1.04, 5.00, P = 0.04). Completing the intervention was associated with a 1.78 odds of meeting PA guidelines (95% CI = 1.02, 3.10, P = 0.04). Education about risk factors for chronic disease and evidence-based strategies for health behavior change may be useful for addressing obesity-related behaviors among African Americans.

Intervention completion rates among African Americans in a randomized effectiveness trial for diet and physical activity changes.

BACKGROUND: The intervention completion rate is an important metric in behavioral and intervention research; trials with limited intervention completion rates may have reduced internal validity. We examined intervention completion rates among 530 African Americans who had been randomized to an integrated (INT) or disease-specific (DSE) risk education protocol as part of a comparative effectiveness trial from September 2009 to August 2012. METHODS: The interventions were developed by an academic-community partnership using community-based participatory research. Intervention completion rates were determined based on attendance at all four intervention sessions. Intervention completers were participants who completed all four sessions and noncompleters were those who did not complete any session or only completed one to three sessions following randomization. RESULTS: Seventy-three percent of participants were intervention completers and 27% were noncompleters. There were no differences in intervention completion based on randomization to INT (72%) or DSE (75%), sociodemographic factors, or body mass index (BMI) in the total sample. Different factors were associated significantly with intervention completion within study groups. Among participants randomized to INT, the odds of intervention completion were greater with higher levels of intrinsic motivation, less exposure to information about diet and cardiovascular disease, and greater BMI. Among participants randomized to DSE, the odds of completing the intervention were associated significantly with older age and greater dietary self-efficacy. CONCLUSIONS: Many African Americans are likely to complete risk education interventions. IMPACT: Psychologic characteristics should be considered when determining intervention completion rates following randomization in behavioral and intervention trials.

Acceptance of a community-based navigator program for cancer control among urban African Americans.

Patient navigation is now a standard component of cancer care in many oncology facilities, but a fundamental question for navigator programs, especially in medically underserved populations, is whether or not individuals will use this service. In this study, we evaluated acceptance of a community-based navigator program for cancer control and identified factors having significant independent associations with navigation acceptance in an urban sample of African Americans. Participants were African American men and women ages 50-75 who were residents in an urban metropolitan city who were referred for navigation. Of 240 participants, 76% completed navigation. Age and perceived risk of developing cancer had a significant independent association with navigation acceptance. Participants who believed that they were at high risk for developing cancer had a lower likelihood of completing navigation compared with those who believed that they had a low risk for developing this disease. The likelihood of completing navigation increased with increases in age. None of the socioeconomic factors or health care variables had a significant association with navigation acceptance. There are few barriers to using community-based navigation for cancer control among urban African Americans. Continued efforts are needed to develop and implement community-based programs for cancer control that are easy to use and address the needs of medically underserved populations.

Collective efficacy and obesity-related health behaviors in a community sample of African Americans.

The social environment is important to body mass index and obesity. However, it is unknown if perceptions of the social environment are associated with obesity-related behaviors in populations at greatest risk for being overweight or obese. We evaluated the relationship between collective efficacy and diet and physical activity in a community-based sample of African American adults who were residents in an urban area. Data were collected as part of an academic-community partnership from November 2009 to 2011. We evaluated whether participants met the recommended guidelines for diet and physical activity based on collective efficacy and their sociodemographic background, health care variables, and self-efficacy in a community-based sample of African American adults (n = 338) who were residents in the Philadelphia, PA metropolitan area. Overall, many participants did not meet the recommended guidelines for fruit and vegetable intake or physical activity. The likelihood of meeting the recommended guidelines for fruit intake increased with greater levels of collective efficacy (OR 1.56, 95 % CI 1.18, 2.07, p = 0.002) and self-efficacy for diet (OR 1.56, 95 % CI 1.19, 2.04, p = 0.001). Collective efficacy was not associated with physical activity and the positive association between collective efficacy and vegetable intake was not statistically significant (OR 1.25, 95 % CI 0.94, 1.65, p = 0.12). It is important to determine the most effective methods and settings for improving diet and physical activity behaviors in urban African Americans. Enhancing collective efficacy may be important to improving adherence to recommended guidelines for obesity-related health behaviors.

Collaboration across eight research centers: unanticipated benefits and outcomes for project managers.

Managers of transdisciplinary collaborative research lack suitable didactic material to support the implementation of research methodologies and to build ongoing partnerships with community representatives and peers, both between and within multiple academic centers. This article will provide insight on the collaborative efforts of project managers involved in multidisciplinary research and their subsequent development of a tool kit for research project managers and/or directors. Project managers from the 8 Centers for Population Health and Health Disparities across the nation participated in monthly teleconferences to share experiences and offer advice on how to achieve high participation rates and maintain community involvement in collaboration with researchers and community leaders to achieve the common goal of decreasing health inequities. In the process, managers recognized and seized the opportunity to produce a tool kit that was designed for future project managers and directors. Project managers in geographically distinct locations maintained a commitment to work together over 4 years and subsequently built upon an existing communications network to design a tool kit that could be disseminated easily to a diverse audience.

Understanding participation by African Americans in cancer genetics research.

PURPOSE: Understanding genetic factors that contribute to racial differences in cancer outcomes may reduce racial disparities in cancer morbidity and mortality. Achieving this goal will be limited by low rates of African American participation in cancer genetics research. METHOD: We conducted a qualitative study with African American adults (n = 91) to understand attitudes about participating in cancer genetics research and to identify factors that are considered when making a decision about participating in this type of research. RESULTS: Participants would consider the potential benefits to themselves, family members, and their community when making a decision to participate in cancer genetics research. However, concerns about exploitation, distrust of researchers, and investigators' motives were also important to participation decisions. Individuals would also consider who has access to their personal information and what would happen to these data. Side effects, logistical issues, and the potential to gain knowledge about health issues were also described as important factors in decision making. CONCLUSION: African Americans may consider a number of ethical, legal, and social issues when making a decision to participate in cancer genetics research. These issues should be addressed as part of recruitment efforts.

Low rates of African American participation in genetic counseling and testing for BRCA1/2 mutations: racial disparities or just a difference?

Low rates of genetic counseling among African American women have generated concerns about disparities; however, to the extent that women's decisions to accept or decline counseling are consistent with their values, then lower participation may reflect preferences and not disparities. We evaluated the extent to which women were satisfied with their decision about participating in genetic counseling for BRCA1/2 mutations and identified variables that were associated significantly with satisfaction. Prospective study of decision satisfaction with 135 African American women who had a minimum 5% prior probability of having a BRCA1/2 mutation. Decision satisfaction was evaluated one month after women were offered participation in genetic counseling using a structured questionnaire. Women were satisfied with their participation decision; more than 80% reported that their decision was consistent with their family values. However, women who declined pre-test counseling had significantly lower satisfaction scores. Our findings highlight the importance ensuring that racial differences that are due to preferences and values are not misclassified as disparities in order to identify and address the root causes of disparate treatment.

Donation intentions for cancer genetics research among African Americans.

AIMS: Scientific agencies rely on individuals to donate their DNA to support research on chronic conditions that disproportionately affect African Americans; however, donation is variable in this population. The purpose of this study was to identify sociodemographic characteristics, health care variables, and cultural values having significant independent associations with intentions to donate blood or saliva samples for cancer genetics research among African American adults. METHOD: Cross-sectional survey of donation intentions. RESULTS: The majority of respondents (73%) were willing to donate a biological sample for cancer genetics research. The results of the multivariate regression model found that respondents who received care at a facility other than a doctor's office (e.g., community center) were about five times more likely to be willing to donate a sample for cancer genetics research (odds ratio [OR]=5.28, 95% confidence interval [CI]=1.16-24.12, p=0.03); whereas, greater levels of religiosity (OR=0.09, 95% CI=0.01-0.75, p=0.02) and present temporal orientation (OR=0.23, 95% CI=0.06-0.79, p=0.02) were associated with a lower likelihood of donating a sample. CONCLUSION: Efforts to enhance donation of biological samples for cancer genetics research may need to target diverse clinical sites for recruitment. Additionally, recruitment materials may need to address cultural values related to religiosity and present temporal orientation.

Long-term reactions to genetic testing for BRCA1 and BRCA2 mutations: does time heal women's concerns?

PURPOSE: Short-term reactions to BRCA1 and BRCA2 (BRCA1/2) genetic test results have been described in several reports, but the long-terms effects of testing have not been examined extensively. METHODS: We conducted an observational study to characterize the long-term impact of genetic testing for BRCA1/2 mutations in 167 women who had received genetic test results at least 4 years ago. We also evaluated the relationship between genetic testing-specific reactions and breast and ovarian cancer screening to determine the behavioral significance of adverse reactions. RESULTS: Seventy-four percent of women were not experiencing any distress regarding their test result, 41% were not experiencing any uncertainty, and 51% had a score for positive experiences that was suggestive of low levels of adverse reactions in terms of family support and communication. Mutation carriers (odds ratio, 3.96; 95% CI, 1.44 to 10.89; P = .01) were most likely to experience distress. Only less time since disclosure was related significantly to experiencing uncertainty (odds ratio, 0.62; 95% CI, 0.44 to 0.88; P = .008). In terms of cancer screening, 81% of women had a mammogram during the year before study enrollment, 25% had magnetic resonance imaging (MRI), 20% had a transvaginal ultrasound, and 20% had a CA-125. Experiencing distress was associated significantly with having a CA-125 (χ(2) = 3.89, P = .05), and uncertainty was associated with having an MRI (χ(2) = 8.90, P = .003). CONCLUSION: Our findings show that women are not likely to experience genetic testing concerns several years after receiving BRCA1/2 test results; distress and uncertainty are not likely to have adverse effects on screening among women at risk for hereditary disease.

Cultural, economic, and psychological predictors of colonoscopy in a national sample.

BACKGROUND: Although colorectal cancer (CRC) is the second leading cause of cancer death among adults in the US and colonoscopy is efficacious in reducing morbidity and mortality from CRC, screening rates are sub-optimal. Understanding the socioeconomic, cultural, and health care context within which decisions about colonoscopy are made allows physicians to address patients' most salient beliefs and values and other constraints when making screening recommendations. OBJECTIVE: To evaluate the direct and interactive effects of socioeconomics, health care variables, psychological characteristics, and cultural values on colonoscopy use. DESIGN, SETTING, PARTICIPANTS: National survey completed between January-August 2009 in a random sample of African American, white, and Hispanic adults ages 50-75 without cancer (n = 582). MAIN MEASURE: Self-reported colonoscopy use. KEY RESULTS: Only 59% of respondents reported having a colonoscopy. The likelihood of colonoscopy increased with having health insurance (OR = 2.82, 95% CI = 1.24, 6.43, p = 0.004), and increasing age (OR = 1.40, 95% CI = 1.11, 1.77, p = 0.001). In addition, respondents with greater self-efficacy were more likely to have a colonoscopy (OR = 2.41, 95% CI = 1.35, 4.29, p = 0.003). CONCLUSIONS: Programs that help patients to overcome access and psychological barriers to screening are needed.

Using a mixed-methods approach to identify health concerns in an African American community.

OBJECTIVES: We used qualitative and quantitative data collection methods to identify the health concerns of African American residents in an urban community and analyzed the extent to which there were consistencies across methods in the concerns identified. METHODS: We completed 9 focus groups with 51 residents, 27 key informant interviews, and 201 community health surveys with a random sample of community residents to identify the health issues participants considered of greatest importance. We then compared the issues identified through these methods. RESULTS: Focus group participants and key informants gave priority to cancer and cardiovascular diseases, but most respondents in the community health survey indicated that sexually transmitted diseases, substance abuse, and obesity were conditions in need of intervention. How respondents ranked their concerns varied in the qualitative versus the quantitative methods. CONCLUSIONS: Using qualitative and quantitative approaches simultaneously is useful in determining community health concerns. Although quantitative approaches yield concrete evidence of community needs, qualitative approaches provide a context for how these issues can be addressed. Researchers should develop creative ways to address multiple issues that arise when using a mixed-methods approach.

Effects of integrated risk counseling for cancer and cardiovascular disease in African Americans.

OBJECTIVE: We evaluated a risk counseling intervention designed to enhance understanding about risk factors for cancer and cardiovascular disease, to improve self-efficacy for diet and physical activity, and to increase intentions to eat healthier and be physically active. METHODS: We conducted a quasi-experimental study developed by academic investigators and community stakeholders to evaluate the effects of integrated risk counseling in a community-based sample of African American adults (n = 101). The intervention provided education about the overlap in risk factors for cancer and cardiovascular disease and included components from motivational interviewing. RESULTS: Changes in behavioral intentions were not statistically significant (p > .05). Participants reported significantly greater levels of self-efficacy for diet (t = 2.25, p = .03) and physical activity (t = 2.55, p = .01), and significantly increased perceived risks of developing colon cancer (chi2 = 3.86, p = .05) and having a heart attack (chi2 = 4.50, p = .03). CONCLUSIONS: Integrated risk counseling may have some benefits among African Americans.

Racial differences in quality of life following prostate cancer diagnosis.

OBJECTIVES: To evaluate the effects of race on QOL while adjusting for subjective stress and religiosity among African American and white prostate cancer patients. Although racial differences in quality of life (QOL) have been examined between African American and white prostate cancer patients, it is not known whether differences exist while adjusting for psychological and cultural factors. We predicted that African American men would report poorer emotional and physical functioning after adjusting for these factors and that greater subjective stress and lower levels of religiosity would be associated with poorer well-being. METHODS: We conducted an observational study of QOL among 194 African American and white men who were recruited from February 2003 through March 2008. RESULTS: Race had a significant effect on emotional functioning after adjusting for perceptions of stress and religiosity. Compared with white men, African American men (P = .03) reported significantly greater emotional well-being. Greater subjective stress was associated significantly with poorer emotional functioning (P = .0001) and physical well-being (P = .0001). There were no racial differences in physical functioning (P = .76). CONCLUSIONS: The results of this study highlight the importance of developing a better understanding of the context within which racial differences in QOL occur and translating this information into support programs for prostate cancer survivors.

Participation rates and representativeness of African Americans recruited to a health promotion program.

When using community-based participatory methods to develop health promotion programs for specific communities, it is important to determine if participation differs based on sociodemographics and the extent to which program participants are demographically representative of the target community, especially when non-random recruitment methods are used. We evaluated rates of participating in a health promotion program among African American residents in an urban community and determined if program participants were representative of community residents in terms of sociodemographic factors. While participation in the program was modest, participation did not differ based on psychological factors or body mass index. However, individuals who were unemployed were significantly more likely to participate in the program compared with those who were employed. Our sample included a greater proportion of individuals who only had a high school education compared with community residents but was similar to community residents in terms of gender, marital status and employment.

Sociocultural determinants of men's reactions to prostate cancer diagnosis.

OBJECTIVE: To develop a better understanding of how men react to being diagnosed with prostate cancer and identify factors that influence these responses, we conducted an observational study to identify sociocultural predictors of men's psychological reactions. METHODS: Participants were 70 African American and 124 white prostate cancer patients who completed a structured telephone interview that evaluated psychological reactions in terms of intrusive thoughts about cancer and attempts to avoid cancer-related thoughts and feelings. Perceptions of disease-specific stress, cultural beliefs and values, and social constraints were also assessed during the interview. RESULTS: There were no racial differences in men's reactions to being diagnosed with prostate cancer; however, greater perceptions of disease-specific stress, increasing levels of present temporal orientation, and more social constraints had significant positive effects on avoidant reactions. Greater perceptions of stress also had a significant positive effect on intrusive thoughts. CONCLUSIONS: The results of this study highlight the need for individualized approaches to help men address their thoughts and feelings about being diagnosed with prostate cancer. These efforts should include strategies that help men to communicate more effectively with social support resources and address cultural beliefs and values related to temporal orientation.