A panel-based mutational signature of homologous recombination deficiency associates with response to PARP inhibition in metastatic castration-resistant prostate cancer.

BACKGROUND: The PARP inhibitor (PARPi) olaparib is approved for homologous recombination repair (HRR) gene-altered metastatic castration-resistant prostate cancer (mCRPC). However, there is significant heterogeneity in response to PARPi in patients with mCRPC. Better clinical biomarkers are needed to identify patients likely to benefit from PARPi. METHODS: Patients with prostate adenocarcinoma and panel sequencing at Dana-Farber Cancer Institute were identified. Mutational signature analysis was performed using SigMA to characterize tumors as HRR deficient (HRD). The validity of SigMA to identify patients likely to benefit from olaparib was compared to the current FDA label (presence of a deleterious alteration in one of 14 HRR genes). RESULTS: 546 patients were identified, of which 34% were HRD. Among patients with HRR gene alterations, only patients with BRCA2 two-copy loss (2CL) were more likely to be HRD compared to patients without HRR gene alterations (74% vs 31%; P = 9.1 × 10-7). 28 patients with mCRPC received olaparib, of which 13 were HRD and 9 had BRCA2 2CL. SigMA improved upon the current FDA label for predicting PSA50 (sensitivity: 100% vs 90%; specificity: 83% vs 44%; PPV: 77% vs 47%; NPV: 100% vs 89%) and rPFS > 6 months (sensitivity: both 92%; specificity: 93% vs 53%; PPV: 92% vs 63%; NPV: 93% vs 89%). On multivariate analysis, incorporating prognostic clinical factors and HR gene alterations, SigMA-predicted HRD independently associated with improved PSA-PFS (HR = 0.086, p = 0.00082) and rPFS (HR = 0.078, p = 0.0070). CONCLUSIONS: SigMA-predicted HRD may better identify patients likely to benefit from olaparib as compared to the current FDA label. Larger studies are needed for further validation.

Differential responses to taxanes and PARP inhibitors in ATM- versus BRCA2-mutated metastatic castrate-resistant prostate cancer.

BACKGROUND: PARP (poly(ADP-ribose) polymerase) inhibitors (PARPi) are now standard of care in metastatic castrate-resistant prostate cancer (mCRPC) patients with select mutations in DNA damage repair (DDR) pathways, but patients with ATM- and BRCA2 mutations may respond differently to PARPi. We hypothesized that differences may also exist in response to taxanes, which may inform treatment sequencing decisions. METHODS: mCRPC patients (N = 158) with deleterious ATM or BRCA2 mutations who received taxanes, PARPi, or both were retrospectively identified from 11 US academic centers. Demographic, treatment, and survival data were collected. Kaplan-Meier analyses were performed and Cox hazard ratios (HR) were calculated for progression-free survival (PFS) as well as overall survival (OS), from time of first taxane or PARPi therapy. RESULTS: Fifty-eight patients with ATM mutations and 100 with BRCA2 mutations were identified. Fourty-four (76%) patients with ATM mutations received taxane only or taxane before PARPi, while 14 (24%) received PARPi only or PARPi before taxane. Patients with ATM mutations had longer PFS when taxane was given first versus PARPi given first (HR: 0.74 [95% confidence interval [CI]: 0.37-1.50]; p = 0.40). Similarly, OS was longer in patients with ATM mutations who received taxane first (HR: 0.56 [CI: 0.20-1.54]; p = 0.26). Among patients with BRCA2 mutations, 51 (51%) received taxane first and 49 (49%) received PARPi first. In contrast, patients with BRCA2 mutations had longer PFS when PARPi was given first versus taxane given first (HR: 0.85 [CI: 0.54-1.35]; p = 0.49). Similarly, OS was longer in patients with BRCA2 mutations who received PARPi first (HR: 0.75 [CI: 0.41-1.37]; p = 0.35). CONCLUSIONS: Our retrospective data suggest differential response between ATM and BRCA2 mutated prostate cancers in terms of response to PARPi and to taxane chemotherapy. When considering the sequence of PARPi versus taxane chemotherapy for mCRPC with DDR mutations, ATM, and BRCA2 mutation status may be helpful in guiding choice of initial therapy.

Suppression of Kv3.3 channels by antisense oligonucleotides reverses biochemical effects and motor impairment in spinocerebellar ataxia type 13 mice.

Mutations in KCNC3, the gene that encodes the Kv3.3 voltage dependent potassium channel, cause Spinocerebellar Ataxia type 13 (SCA13), a disease associated with disrupted motor behaviors, progressive cerebellar degeneration, and abnormal auditory processing. The Kv3.3 channel directly binds Hax-1, a cell survival protein. A disease-causing mutation, Kv3.3-G592R, causes overstimulation of Tank Binding Kinase 1 (Tbk1) in the cerebellum, resulting in the degradation of Hax-1 by promoting its trafficking into multivesicular bodies and then to lysosomes. We have now tested the effects of antisense oligonucleotides (ASOs) directed against the Kv3.3 channel on both wild type mice and those bearing the Kv3.3-G592R-encoding mutation. Intracerebroventricular infusion of the Kcnc3-specific ASO suppressed both mRNA and protein levels of the Kv3.3 channel. In wild-type animals, this produced no change in levels of activated Tbk1, Hax-1 or Cd63, a tetraspanin marker for late endosomes/multivesicular bodies. In contrast, in mice homozygous for the Kv3.3-G592R-encoding mutation, the same ASO reduced Tbk1 activation and levels of Cd63, while restoring the expression of Hax-1 in the cerebellum. The motor behavior of the mice was tested using a rotarod assay. Surprisingly, the active ASO had no effects on the motor behavior of wild type mice but restored the behavior of the mutant mice to those of age-matched wild type animals. Our findings indicate that, in mature intact animals, suppression of Kv3.3 expression can reverse the deleterious effects of a SCA13 mutation while having little effect on wild type animals. Thus, targeting Kv3.3 expression may prove a viable therapeutic approach for SCA13.

Promoting Strong Latino Families Within an Emerging Immigration Context: Results of a Replication and Extension Trial of a Culturally Adapted Preventive Intervention.

We conducted a randomized controlled trial (RCT) of Nuestras Familias: Andando Entre Culturas, a culturally adapted evidence-based parent management training (PMT) preventive intervention, with a sample of 241 Spanish-speaking Latino parents and their middle-school-aged children residing in an emerging immigration context. Scientifically rigorous studies of programs designed for this setting are rare. The intervention was designed to promote prosocial parenting practices and to prevent youth substance use and related problem behaviors. The RCT was designed as an extension and replication of a prior trial (Martinez & Eddy in Journal of Consulting and Clinical Psychology, 73, 841-851, 2005) which was also conducted in an emerging immigration context. Two key issues were of primary interest: intervention feasibility and intervention efficacy. Intervention feasibility was assessed through weekly session attendance, participation, and parent-reported session satisfaction as well as overall program satisfaction. Intervention efficacy was assessed by comparing changes within the intervention and control groups on parenting practices and youth adjustment from pre-intervention baseline to post-intervention termination 6 months later. Results provided support for the feasibility of delivering the intervention on a large scale within communities. Consistent with the prior trial, positive effects of the intervention were detected on parenting practices and on youth outcomes. Differential effects of the intervention were detected based on youth gender and nativity status, such that girls benefited the most with respect to tobacco use likelihood, and foreign-born youth benefited the most with respect to decreased depressive symptoms.Findings provide additional evidence for Nuestras Familias as an efficacious family-based intervention for Latino families within communities that are sites of emerging immigration in terms of both improving parenting practices and decreasing risk for youth substance use and related problem behaviors.

Alcohol use severity, depressive symptoms, and optimism among Hispanics: Examining the immigrant paradox in a serial mediation model.

OBJECTIVE: Hispanic immigrants exhibit more positive outcomes than U.S.-born Hispanics across educational, psychological, and physical health indices, a phenomenon called the immigrant paradox. We examined the immigrant paradox in relation to alcohol use severity among Hispanic young adults while considering both positive (optimism) and negative (depressive symptoms) processes. METHOD: Among 200 immigrant and U.S.-born Hispanic young adults (Mage = 21.30; 49% male) in Arizona and Florida, we tested whether optimism and depressive symptoms statistically mediated the relationship between nativity and alcohol use severity. Specifically, we examined whether Hispanic immigrants reported greater optimism than their U.S.-born counterparts, and whether such optimism was, in turn, associated with less depressive symptoms and thus lower alcohol use severity. RESULTS: Indirect effects were significant in hypothesized directions (nativity → optimism → depressive symptoms → alcohol use severity). CONCLUSIONS: Both positive and negative psychological processes are important to consider when accounting for the immigrant paradox vis-à-vis alcohol use severity among Hispanic young adults.

Latinx Immigrant Farmworker Community Health Promotion: A Needs Assessment.

The present study examined the health promotion intervention needs of Latinx immigrant farmworker families residing in Oregon. Grounded theory qualitative procedures were used to analyze the needs assessment data from 31 Latinx immigrant farmworker residents and key informant interviews as well as four focus groups with resident youth and parents. A theoretical model of how key family-based health behaviors can both confer risk for and protection against negative physical, mental, and social health outcomes among Latinx farmworking communities emerged. Six primary areas of concern emerged from these data, leading to the identification of primary health promotion intervention needs with three foci: (a) the provision of sustainable supports and resources, (b) skill development so that individuals could successfully negotiate identified challenges, and (c) greater community efficacy. Findings underscore the importance of social support and resource accessibility for Latinx immigrant populations.

The Effects of Cooperative Learning on Peer Relations, Academic Support, and Engagement in Learning Among Students of Color.

Despite Brown vs. Board of Education, prejudice still exists in the American school system. These attitudes can give rise to negative social experiences for students of color (i.e., discrimination), negatively impacting their mental and physical health and creating disparities in educational outcomes. Rather than seeking to ameliorate these negative experiences, our approach attempts to address the underlying prejudices and, in so doing, reduce these disparities. Using 4 waves of data from a cluster randomized trial (N = 15 middle schools, 1,890 students, 47.1% female, 75.2% White), we hypothesized that cooperative learning, which has been shown to reduce prejudice in previous research, would create positive gains in peer relatedness, perceptions of academic support, and engagement in learning, and that gains would be larger for students of color; our results confirmed these hypotheses. Our findings highlight the potential role of cooperative learning in reducing disparities and creating greater equity in education.

Climbing the ladder of decline: Income and acculturation associated with chronic inflammation among Mexican immigrants.

OBJECTIVES: Financial hardship and immigrant status are often associated with poorer health as immigrant groups acculturate to life in the US. Known as the Latino health paradox, studies have shown that Latino/a immigrants in particular often experience declines in health the more they embrace ways of life considered "dominant" by US society. At present, critical biological pathways linking socioeconomic and acculturative processes remain to be better explained. The present study investigates associations among financial strain, acculturation, and chronic inflammation. METHODS: In our study of 129 Mexican-born immigrants living in the US, we used Pearson's correlations and multiple regression analyses to investigate links among income-to-poverty ratio (an indicator of financial strain), English language engagement (acculturation), and C-reactive protein (CRP), a measure of systemic inflammation. RESULTS: Results showed that for men, but not women, acculturation as defined by English language engagement moderated the association between an income-to-poverty ratio and CRP levels. CONCLUSIONS: Consistent with the Latino health paradox, more acculturated men with relatively higher income levels (compared with the study sample) had significantly higher levels of CRP.

Mind the Gap: Bridging the Divide Between Current Binge Drinking Prevention and the Needs of Hispanic Underage Emerging Adults.

In this article, we highlight the urgent public health need for prevention of heavy episodic drinking among underage Hispanic emerging adults in the USA. We outline the current state of binge drinking prevention programming and contrast it with the unique cultural, social, and developmental realities of this population using an ecodevelopmental framework (Szapocznik and Coatsworth 1999). Finally, we advance specific recommendations for the development and delivery of culturally tailored, multisystemic binge drinking prevention programs for underage Hispanic emerging adults.

Longitudinal effects of acculturation and enculturation on mental health: Does the measure matter?

A great deal of research has focused on acculturation and enculturation, which represent the processes of adapting to a new culture. Despite this growing literature, results have produced inconsistent findings that may be attributable to differences in terms of the instruments used to assess acculturation and enculturation. Utilizing a 3-year longitudinal data set (with 1-year lags between assessments), the present study explored the psychometric properties of the Bicultural Involvement Questionnaire-Short Version (BIQ-S) and the Acculturation Rating Scale for Mexican Americans II (ARSMA-II) and examined the overlap between changes in these measures as they relate to internalizing and externalizing problem behavior. The present sample consisted of 216 immigrant Latino youth (43% boys; mean age 13.6 years at baseline; SD = 1.44 years, range 10 to 17). Exploratory structural equation modeling identified factor structures for the BIQ-S and ARSMA-II that diverged from their hypothesized structure. Growth curve models also indicate divergence between the BIQ-S and ARSMA-II in terms of change in acculturation and enculturation processes. Finally, the present findings emphasized that measures of acculturation and enculturation are not equivalent in terms of their effects on internalizing and externalizing problems.

Food insecurity partially mediates associations between social disadvantage and body composition among older adults in india: Results from the study on global AGEing and adult health (SAGE).

OBJECTIVE: Our objective was to test whether food insecurity mediates cross-sectional associations between social disadvantage and body composition among older adults (aged 50+) in India (n = 6556). METHODS: Adjusting for key sociodemographic and dietary variables, we examined whether markers of social disadvantage (lower educational attainment, lower household wealth, belonging to a disadvantaged caste/tribe, and belonging to a minority religion) were associated with food insecurity. We then examined whether food insecurity, in turn, was associated with anthropometric measures of body composition, body mass index (BMI), and waist circumference (WC). We also tested whether food insecurity mediated the relationship between social disadvantage and body composition. RESULTS: In adjusted models, lower household wealth [lowest quintile (Q5) vs highest quintile (Q1): odds ratio (OR) = 13.57, P < .001], having less than a high-school education (OR = 2.12. P < .005), being Muslim (OR = 1.82, P < .001), and being in a scheduled caste (historically marginalized) (OR = 1.49, P < .005) were associated with greater food insecurity. Those who were severely food insecure had greater odds of being underweight (OR = 1.36, P < .01) and lower odds of high WC (OR = 0.70, P < .01). Mediation analyses estimated that food insecurity explained 4.7%-29.7% of the relationship between social disadvantage and body composition, depending on the variables considered. CONCLUSIONS: Our results are consistent with the hypothesis that food insecurity is a mechanism linking social disadvantage and body composition among older adults in India. These analyses contribute to a better understanding of processes leading to variation in body composition, which may help enhance the design of interventions aimed at improving population nutritional status.

A Panel-Based Mutational Signature of Mismatch Repair Deficiency is Associated With Durable Response to Pembrolizumab in Metastatic Castration-Resistant Prostate Cancer.

INTRODUCTION/BACKGROUND: Immune checkpoint inhibitors (ICIs) have limited efficacy in prostate cancer (PCa). Better biomarkers are needed to predict responses to ICIs. We sought to demonstrate that a panel-based mutational signature identifies mismatch repair (MMR) deficient (MMRd) PCa and is a biomarker of response to pembrolizumab. PATIENTS AND METHODS: Clinico-genomic data was obtained for 2664 patients with PCa sequenced at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering (MSK). Clinical outcomes were collected for patients with metastatic castration-resistant PCa (mCRPC) treated with pembrolizumab at DFCI. SigMA was used to characterize tumors as MMRd or MMR proficient (MMRp). The concordance between MMRd with microsatellite instability (MSI-H) was assessed. Radiographic progression-free survival (rPFS) and overall survival (OS) were collected for patients treated with pembrolizumab. Event-time distributions were estimated using Kaplan-Meier methodology. RESULTS: Across both cohorts, 100% (DFCI: 12/12; MSK: 43/43) of MSI-H tumors were MMRd. However, 14% (2/14) and 9.1% (6/66) of MMRd tumors in the DFCI and MSK cohorts respectively were microsatellite stable (MSS), and 26% (17/66) were MSI-indeterminate in the MSK cohort. Among patients treated with pembrolizumab, those with MMRd (n = 5) versus MMRp (n = 14) mCRPC experienced markedly improved rPFS (HR = 0.088, 95% CI: 0.011-0.70; P = .0064) and OS (HR = 0.11, 95% CI: 0.014-0.80; P = .010) from start of treatment. Four patients with MMRd experienced remissions of >= 2.5 years. CONCLUSION: SigMA detects additional cases of MMRd as compared to MSI testing in PCa and identifies patients likely to experience durable response to pembrolizumab.

Outcomes of First-Line Abiraterone Acetate or Enzalutamide for Older Adults With Metastatic Castration-Resistant Prostate Cancer According to Use of Upfront Docetaxel for Metastatic Castration-Sensitive Prostate Cancer in an International Multicenter Registry: A SPARTACUSS-Meet-URO 26 Study.

BACKGROUND: Managing metastatic castration-resistant prostate cancer (mCRPC) in men aged ≥ 75 is challenging due to limited data. Regardless of age, in real-world clinical practice, most mCRPC still derive from failure of androgen deprivation therapy (ADT) with or without docetaxel (D) for metastatic castration-sensitive prostate cancer (mCSPC). As abiraterone acetate plus prednisone (AA) and enzalutamide (Enza) are common first-line treatments for mCRPC. The impact of prior use of D for mCSPC on the efficacy and safety of AA or Enza in this older population remains unclear. METHODS: A cohort of patients aged ≥ 75 years starting AA or Enza as first-line therapy for mCRPC from January 2015 to April 2019 was identified from the registries of 10 institutions. Patients were categorized into 2 groups based on previous use of D for mCSPC. Primary endpoints were cancer-specific survival (CSS) from AA or Enza start, CSS from ADT onset, and safety. We used Kaplan-Meier method to estimate the endpoints distribution, including median values with 95% confidence intervals (95% CI). RESULTS: Of the 337 patients identified, 24 (7.1%) received ADT+D and 313 (92.9%) received ADT alone for mCSPC. Median follow-up from AA/Enza start was 18.8 months. Median CSS from ADT or AA/Enza was not significantly different between ADT+D and ADT alone cohorts (71.9 vs. 52.7 months, P = .97; 25.4 vs. 27.2 months, P = .89, respectively). No statistically significant difference in adverse events (AEs) of any grade rate (58.3% vs. 52.1%, respectively; P = .67) or grade ≥ 3 (12.5% vs. 15.7%, respectively; P = 1.0) was found between ADT+D and ADT alone cohorts. CONCLUSIONS: Despite the innate limitations of a retrospective design and relatively small size of the ADT+D cohort, this analysis suggests that elderly men receiving AA or Enza as first-line therapy for mCRPC have similar survival outcomes and tolerability, regardless of previous D for mCSPC.

Detecting Small Cell Transformation in Patients with Advanced EGFR Mutant Lung Adenocarcinoma through Epigenomic cfDNA Profiling.

PURPOSE: Histologic transformation to small cell lung cancer (SCLC) is a mechanism of treatment resistance in patients with advanced oncogene-driven lung adenocarcinoma (LUAD) that currently requires histologic review for diagnosis. Herein, we sought to develop an epigenomic cell-free DNA (cfDNA)-based approach to noninvasively detect small cell transformation in patients with EGFR mutant (EGFRm) LUAD. EXPERIMENTAL DESIGN: To characterize the epigenomic landscape of transformed (t)SCLC relative to LUAD and de novo SCLC, we performed chromatin immunoprecipitation sequencing (ChIP-seq) to profile the histone modifications H3K27ac, H3K4me3, and H3K27me3; methylated DNA immunoprecipitation sequencing (MeDIP-seq); assay for transposase-accessible chromatin sequencing; and RNA sequencing on 26 lung cancer patient-derived xenograft (PDX) tumors. We then generated and analyzed H3K27ac ChIP-seq, MeDIP-seq, and whole genome sequencing cfDNA data from 1 mL aliquots of plasma from patients with EGFRm LUAD with or without tSCLC. RESULTS: Analysis of 126 epigenomic libraries from the lung cancer PDXs revealed widespread epigenomic reprogramming between LUAD and tSCLC, with a large number of differential H3K27ac (n = 24,424), DNA methylation (n = 3,298), and chromatin accessibility (n = 16,352) sites between the two histologies. Tumor-informed analysis of each of these three epigenomic features in cfDNA resulted in accurate noninvasive discrimination between patients with EGFRm LUAD versus tSCLC [area under the receiver operating characteristic curve (AUROC) = 0.82-0.87]. A multianalyte cfDNA-based classifier integrating these three epigenomic features discriminated between EGFRm LUAD versus tSCLC with an AUROC of 0.94. CONCLUSIONS: These data demonstrate the feasibility of detecting small cell transformation in patients with EGFRm LUAD through epigenomic cfDNA profiling of 1 mL of patient plasma.

Co-occurring BRCA2/SPOP Mutations Predict Exceptional Poly (ADP-ribose) Polymerase Inhibitor Sensitivity in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND AND OBJECTIVE: BRCA2 mutations in metastatic castration-resistant prostate cancer (mCRPC) confer sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. However, additional factors predicting PARP inhibitor efficacy in mCRPC are needed. Preclinical studies support a relationship between speckle-type POZ protein (SPOP) inactivation and PARP inhibitor sensitivity. We hypothesized that SPOP mutations may predict enhanced PARP inhibitor response in BRCA2-altered mCRPC. METHODS: We conducted a multicenter retrospective study involving 13 sites. We identified 131 patients with BRCA2-altered mCRPC treated with PARP inhibitors, 14 of which also carried concurrent SPOP mutations. The primary efficacy endpoint was prostate-specific antigen (PSA) response rate (≥50% PSA decline). The secondary endpoints were biochemical progression-free survival (PSA-PFS), clinical/radiographic progression-free survival (PFS), and overall survival (OS). These were compared by multivariable Cox proportional hazard models adjusting for age, tumor stage, baseline PSA level, Gleason sum, prior therapies, BRCA2 alteration types, and co-occurring mutations. KEY FINDINGS AND LIMITATIONS: Baseline characteristics were similar between groups. PSA responses were observed in 60% (70/117) of patients with BRCA2mut/SPOPwt disease and in 86% (12/14) of patients with BRCA2mut/SPOPmut disease (p = 0.06). The median time on PARP inhibitor treatment was 24.0 mo (95% confidence interval [CI] 19.2 mo to not reached) in this group versus 8.0 mo (95% CI 6.1-10.9 mo) in patients with BRCA2 mutation alone (p = 0.05). In an unadjusted analysis, patients with BRCA2mut/SPOPmut disease experienced longer PSA-PFS (hazard ratio [HR] 0.33 [95% CI 0.15-0.72], p = 0.005) and clinical/radiographic PFS (HR 0.4 [95% CI 0.18-0.86], p = 0.02), and numerically longer OS (HR 0.4 [95% CI 0.15-1.12], p = 0.08). In a multivariable analysis including histology, Gleason sum, prior taxane, prior androgen receptor pathway inhibitor, stage, PSA, BRCA2 alteration characteristics, and other co-mutations, patients with BRCA2mut/SPOPmut disease experienced longer PSA-PFS (HR 0.16 [95% CI 0.05-0.47], adjusted p = 0.001), clinical/radiographic PFS (HR 0.28 [95% CI 0.1-0.81], adjusted p = 0.019), and OS (HR 0.19 [95% CI 0.05-0.69], adjusted p = 0.012). In a separate cohort of patients not treated with a PARP inhibitor, there was no difference in OS between patients with BRCA2mut/SPOPmut versus BRCA2mut/SPOPwt disease (HR 0.97 [95% CI 0.40-2.4], p = 0.94). In a genomic signature analysis, Catalog of Somatic Mutations in Cancer (COSMIC) SBS3 scores predictive of homologous recombination repair (HRR) defects were higher for BRCA2mut/SPOPmut than for BRCA2mut/SPOPwt disease (p = 0.04). This was a retrospective study, and additional prospective validation cohorts are needed. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this retrospective analysis, PARP inhibitors appeared more effective in patients with BRCA2mut/SPOPmut than in patients with BRCA2mut/SPOPwt mCRPC. This may be related to an increase in HRR defects in coaltered disease. PATIENT SUMMARY: In this study, we demonstrate that co-alteration of both BRCA2 and SPOP predicts superior clinical outcomes to treatment with poly (ADP-ribose) polymerase (PARP) inhibitors than BRCA2 alteration without SPOP mutation.

Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes.

Advanced prostate cancers comprise distinct phenotypes, but tumor classification remains clinically challenging. Here, we harnessed circulating tumor DNA (ctDNA) to study tumor phenotypes by ascertaining nucleosome positioning patterns associated with transcription regulation. We sequenced plasma ctDNA whole genomes from patient-derived xenografts representing a spectrum of androgen receptor active (ARPC) and neuroendocrine (NEPC) prostate cancers. Nucleosome patterns associated with transcriptional activity were reflected in ctDNA at regions of genes, promoters, histone modifications, transcription factor binding, and accessible chromatin. We identified the activity of key phenotype-defining transcriptional regulators from ctDNA, including AR, ASCL1, HOXB13, HNF4G, and GATA2. To distinguish NEPC and ARPC in patient plasma samples, we developed prediction models that achieved accuracies of 97% for dominant phenotypes and 87% for mixed clinical phenotypes. Although phenotype classification is typically assessed by IHC or transcriptome profiling from tumor biopsies, we demonstrate that ctDNA provides comparable results with diagnostic advantages for precision oncology. SIGNIFICANCE: This study provides insights into the dynamics of nucleosome positioning and gene regulation associated with cancer phenotypes that can be ascertained from ctDNA. New methods for classification in phenotype mixtures extend the utility of ctDNA beyond assessments of somatic DNA alterations with important implications for molecular classification and precision oncology. This article is highlighted in the In This Issue feature, p. 517.

Recruitment and retention of Latino immigrant families in prevention research.

The development and testing of culturally competent interventions relies on the recruitment and retention of ethnic minority populations. Minority immigrants are a population of keen interest given their widespread growth, needs, and contributions to communities in which they settle, and particularly recent immigrants from Mexico and Central and South American countries. However, recruitment and retention strategies for entirely immigrant samples are rarely discussed in the literature. The current article describes lessons learned from two family-focused longitudinal prevention research studies of Latino immigrants in Oregon-the Adolescent Latino Acculturation Study (ALAS) and the Latino Youth and Family Empowerment Project-II (LYFE-II). Social, legal, economic, and political contexts are considered that shape Latino immigrants' experiences in their home countries as well as in the United States. The implications of these contexts for effective recruitment and retention strategies are discussed.

Child and adolescent affective and behavioral distress and elevated adult body mass index.

Obesity rates throughout the world have risen rapidly in recent decades, and are now a leading cause of morbidity and mortality. Several studies indicate that behavioral and affective distress in childhood may be linked to elevated adult body mass index (BMI). The present study utilizes data from a 20-year longitudinal study to examine the relations between symptoms of conduct disorder, attention-deficit/hyperactivity disorder, and depression during late childhood and mid-adolescence and BMI during emerging adulthood. Data were analyzed using multiple regression. Results suggest that childhood and adolescent problems may influence adult BMI through direct impacts on adolescent overweight, a condition which then persists into adulthood.

Addition of Germline Testing to Tumor-Only Sequencing Improves Detection of Pathogenic Germline Variants in Men With Advanced Prostate Cancer.

PURPOSE: Guidelines recommend somatic and germline testing for men with advanced prostate cancer (PCa). Barriers to widespread implementation result in underutilization of germline testing. Somatic testing alone risks missing pathogenic germline variants (PGVs). We sought to determine whether the addition of germline testing to tumor-only sequencing improves detection of PGVs in men with advanced PCa. Secondarily, we sought to define the added value of combining somatic and germline testing to optimize detection of clinically actionable alterations. PATIENTS AND METHODS: We analyzed results of independent germline testing and tumor-only sequencing from 100 men with advanced PCa from a prospective clinical trial (ClinicalTrials.gov identifier: NCT03328091). The primary outcome was the proportion of PGVs not reported with tumor-only sequencing. The secondary outcome was the association of locus-specific loss of heterozygosity for PGVs in homologous recombination genes with clinical-genomic features. RESULTS: In the 100 men who underwent germline testing and tumor-only sequencing, 24 PGVs were identified, 17 of which were clinically actionable, in 23 patients. Tumor-only sequencing failed to report four (17%) of the PGVs. One additional PGV (4.2%) had variant allele frequency on tumor-sequencing below the threshold for follow-up germline testing. When integrating tumor-only sequencing with germling testing results, 33% of patients harbored clinically actionable alterations. Rates of locus-specific loss of heterozygosity were higher for BRCA2 PGVs in castration-resistant PCa than PGVs in other homologous recombination genes in hormone-sensitive PCa (P = .029). CONCLUSION: Tumor-only sequencing failed to report more than 20% of PGVs in men with advanced PCa. These findings strongly support guideline recommendations for universal germline and somatic testing in this population. Combining tumor and germline sequencing doubled the chance of detecting a clinically actionable alteration.