The Cancer Spectrum Theory.

SUMMARY: Biological characteristics of tumors are heterogeneous, forming spectra in terms of several factors such as age at onset, anatomic spatial localization, tumor subtyping, and the degree of tumor aggressiveness (encompassing a neoplastic property spectrum). Instead of blindly using dichotomized approaches, the application of the multicategorical and continuous analysis approaches to detailed cancer spectrum data can contribute to a better understanding of the etiology of cancer, ultimately leading to effective prevention and precision oncology. We provide examples of cancer spectra and emphasize the importance of integrating the cancer spectrum theory into large-scale population cancer research.

Multivitamin use after diagnosis and prostate cancer survival among men with nonmetastatic prostate cancer.

BACKGROUND: Multivitamin use is common among cancer patients. Whether post-diagnostic multivitamin supplementation is beneficial for prostate cancer survival is largely unknown, and some evidence even suggests potential harm. METHODS: We prospectively assessed post-diagnostic multivitamin use in relation to prostate cancer survival among 4756 men with nonmetastatic prostate cancer at diagnosis in the Health Professionals Follow-up Study (1986-2016). Cox regression models were used to evaluate the association between post-diagnostic multivitamin use and frequency and risk of lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality. RESULTS: We observed 438 lethal prostate cancer and 2609 deaths during a median follow-up of 11 years. Compared to non-users, post-diagnostic multivitamin use was not associated with risk of lethal prostate cancer (HR [95% CI], 0.98 [0.74-1.30]) or all-cause mortality (1.00 [0.88-1.12]), after adjustment for potential confounders. Similarly, null associations were observed across various categories of use frequency. Compared to non-users, men who used multivitamins regularly (6-9 tablets/week) after cancer diagnosis had similar risk of lethal prostate cancer (0.96 [0.72-1.28]) and all-cause mortality (0.99 [0.88-1.12]). CONCLUSIONS: We found no evidence that post-diagnostic multivitamin use among men with nonmetastatic prostate cancer was associated with better or worse survival in a well-nourished population.

ArCH: improving the performance of clonal hematopoiesis variant calling and interpretation.

MOTIVATION: The acquisition of somatic mutations in hematopoietic stem and progenitor stem cells with resultant clonal expansion, termed clonal hematopoiesis (CH), is associated with increased risk of hematologic malignancies and other adverse outcomes. CH is generally present at low allelic fractions, but clonal expansion and acquisition of additional mutations leads to hematologic cancers in a small proportion of individuals. With high depth and high sensitivity sequencing, CH can be detected in most adults and its clonal trajectory mapped over time. However, accurate CH variant calling is challenging due to the difficulty in distinguishing low frequency CH mutations from sequencing artifacts. The lack of well-validated bioinformatic pipelines for CH calling may contribute to lack of reproducibility in studies of CH. RESULTS: Here, we developed ArCH, an Artifact filtering Clonal Hematopoiesis variant calling pipeline for detecting single nucleotide variants and short insertions/deletions by combining the output of four variant calling tools and filtering based on variant characteristics and sequencing error rate estimation. ArCH is an end-to-end cloud-based pipeline optimized to accept a variety of inputs with customizable parameters adaptable to multiple sequencing technologies, research questions, and datasets. Using deep targeted sequencing data generated from six acute myeloid leukemia patient tumor: normal dilutions, 31 blood samples with orthogonal validation, and 26 blood samples with technical replicates, we show that ArCH improves the sensitivity and positive predictive value of CH variant detection at low allele frequencies compared to standard application of commonly used variant calling approaches. AVAILABILITY AND IMPLEMENTATION: The code for this workflow is available at: https://github.com/kbolton-lab/ArCH.

Healthy dietary patterns and risk of prostate cancer in men at high genetic risk.

Prostate cancer has high heritability. Healthy lifestyle has been associated with lower lethal prostate cancer risk among men at increased genetic susceptibility, but the role of healthy dietary patterns remains unknown. We prospectively followed 10,269 genotyped men in the Health Professionals Follow-up Study (1993-2019). Genetic risk was quantified using an established polygenic risk score (PRS). Five dietary patterns were investigated: healthy eating index, Mediterranean, diabetes risk-reducing, hyperinsulinemic and inflammatory diet. Overall and lethal prostate cancer rates (metastatic disease/prostate cancer-specific death) were analyzed using multivariable Cox proportional hazards models. During 26 years of follow-up, 2133 overall and 253 lethal prostate cancer events were documented. In the highest PRS quartile, higher adherence to a diabetes risk-reducing diet was associated with lower rates of overall (top vs. bottom quintile HR [95% CI], 0.74 [0.58-0.94]) and lethal prostate cancer (0.43 [0.21-0.88]). A low insulinemic diet was associated with similar lower rates (overall, 0.76 [0.60-0.95]; lethal, 0.46 [0.23-0.94]). Other dietary patterns showed weaker, but similar associations. In the highest PRS quartile, men with healthy lifestyles based on body weight, physical activity, and low insulinemic diet had a substantially lower rate (0.26 [0.13-0.49]) of lethal prostate cancer compared with men with unhealthy lifestyles, translating to a lifetime risk of 3.4% (95% CI, 2.3%-5.0%) among those with healthy lifestyles and 9.5% (5.3%-16.7%) among those with unhealthy lifestyles. Our findings indicate that lifestyle modifications lowering insulin resistance and chronic hyperinsulinemia could be relevant in preventing aggressive prostate cancer among men genetically predisposed to prostate cancer.

Marital Status, Living Arrangement, and Survival among Individuals with Advanced Prostate Cancer in the International Registry for Men with Advanced Prostate Cancer.

BACKGROUND: Studies have shown improved survival among individuals with cancer with higher levels of social support. Few studies have investigated social support and overall survival (OS) in individuals with advanced prostate cancer in an international cohort. We investigated the associations of marital status and living arrangements with OS among individuals with advanced prostate cancer in the International Registry for Men with Advanced Prostate Cancer (IRONMAN). METHODS: IRONMAN is enrolling participants diagnosed with advanced prostate cancer (metastatic hormone-sensitive prostate cancer, mHSPC; castration-resistant prostate cancer, CRPC) from 16 countries. Participants in this analysis were recruited between July 2017 and January 2023. Adjusting for demographics and tumor characteristics, the associations were estimated using Cox regression and stratified by disease state (mHSPC, CRPC), age (<70, ≥70 years), and continent of enrollment (North America, Europe, Other). RESULTS: We included 2,119 participants with advanced prostate cancer, of whom 427 died during up to 5 years of follow-up (median 6 months). Two-thirds had mHSPC. Most were married/in a civil partnership (79%) and 6% were widowed. Very few married participants were living alone (1%), while most unmarried participants were living alone (70%). Married participants had better OS than unmarried participants [adjusted HR: 1.44; 95% confidence interval (CI): 1.02-2.02]. Widowed participants had the worst survival compared with married individuals (adjusted HR: 1.89; 95% CI: 1.22-2.94). CONCLUSIONS: Among those with advanced prostate cancer, unmarried and widowed participants had worse OS compared with married participants. IMPACT: This research highlighted the importance of social support in OS within this vulnerable population.

SLCO1B3 and SLCO2B1 genotypes, androgen deprivation therapy, and prostate cancer outcomes: a prospective cohort study and meta-analysis.

Solute carrier organic anion (SLCO) transporters (OATP transporters) are involved in cellular uptake of drugs and hormones. Germline variants in SLCO1B3 and SLCO2B1 have been implicated in prostate cancer progression and therapy response, including to androgen deprivation and statin medications, but results have appeared heterogeneous. We conducted a cohort study of five single-nucleotide polymorphisms (SNPs) in SLCO1B3 and SLCO2B1 with prior evidence among 3208 men with prostate cancer who participated in the Health Professionals Follow-up Study or the Physicians' Health Study, following participants prospectively after diagnosis over 32 years (median, 14 years) for development of metastases and cancer-specific death (lethal disease, 382 events). Results were suggestive of, but not conclusive for, associations between some SNPs and lethal disease and differences by androgen deprivation and statin use. All candidate SNPs were associated with SLCO mRNA expression in tumor-adjacent prostate tissue. We also conducted a systematic review and harmonized estimates for a dose-response meta-analysis of all available data, including 9 further studies, for a total of 5598 patients and 1473 clinical events. The A allele of the exonic SNP rs12422149 (14% prevalence), which leads to lower cellular testosterone precursor uptake via SLCO2B1, was associated with lower rates of prostate cancer progression (hazard ratio per A allele, 0.80; 95% confidence interval, 0.69-0.93), with little heterogeneity between studies (I2, 0.27). Collectively, the totality of evidence suggests a strong association between inherited genetic variation in SLCO2B1 and prostate cancer prognosis, with potential clinical use in risk stratification related to androgen deprivation therapy.

Modifiable risk factors for subsequent lethal prostate cancer among men with an initially negative prostate biopsy.

BACKGROUND: Previously suggested modifiable risk factors for prostate cancer could have resulted from detection bias because diagnosis requires a biopsy. We investigated modifiable risk factors for a subsequent cancer diagnosis among men with an initially negative prostate biopsy. METHODS: In total, 10,396 participants of the Health Professionals Follow-up Study with an initial negative prostate biopsy after 1994 were followed for incident prostate cancer until 2017. Potential risk factors were based on previous studies in the general population. Outcomes included localised, advanced, and lethal prostate cancer. RESULTS: With 1851 prostate cancer cases (168 lethal) diagnosed over 23 years of follow-up, the 20-year risk of any prostate cancer diagnosis was 18.5% (95% CI: 17.7-19.3). Higher BMI and lower alcohol intake tended to be associated with lower rates of localised disease. Coffee, lycopene intake and statin use tended to be associated with lower rates of lethal prostate cancer. Results for other risk factors were less precise but compatible with and of similar direction as for men in the overall cohort. CONCLUSIONS: Risk factors for future prostate cancer among men with a negative biopsy were generally consistent with those for the general population, supporting their validity given reduced detection bias, and could be actionable, if confirmed.

Germline Sequencing Analysis to Inform Clinical Gene Panel Testing for Aggressive Prostate Cancer.

Importance: Germline gene panel testing is recommended for men with advanced prostate cancer (PCa) or a family history of cancer. While evidence is limited for some genes currently included in panel testing, gene panels are also likely to be incomplete and missing genes that influence PCa risk and aggressive disease. Objective: To identify genes associated with aggressive PCa. Design, Setting, and Participants: A 2-stage exome sequencing case-only genetic association study was conducted including men of European ancestry from 18 international studies. Data analysis was performed from January 2021 to March 2023. Participants were 9185 men with aggressive PCa (including 6033 who died of PCa and 2397 with confirmed metastasis) and 8361 men with nonaggressive PCa. Exposure: Sequencing data were evaluated exome-wide and in a focused investigation of 29 DNA repair pathway and cancer susceptibility genes, many of which are included on gene panels. Main Outcomes and Measures: The primary study outcomes were aggressive (category T4 or both T3 and Gleason score ≥8 tumors, metastatic PCa, or PCa death) vs nonaggressive PCa (category T1 or T2 and Gleason score ≤6 tumors without known recurrence), and metastatic vs nonaggressive PCa. Results: A total of 17 546 men of European ancestry were included in the analyses; mean (SD) age at diagnosis was 65.1 (9.2) years in patients with aggressive PCa and 63.7 (8.0) years in those with nonaggressive disease. The strongest evidence of association with aggressive or metastatic PCa was noted for rare deleterious variants in known PCa risk genes BRCA2 and ATM (P ≤ 1.9 × 10-6), followed by NBN (P = 1.7 × 10-4). This study found nominal evidence (P < .05) of association with rare deleterious variants in MSH2, XRCC2, and MRE11A. Five other genes had evidence of greater risk (OR≥2) but carrier frequency differences between aggressive and nonaggressive PCa were not statistically significant: TP53, RAD51D, BARD1, GEN1, and SLX4. Deleterious variants in these 11 candidate genes were carried by 2.3% of patients with nonaggressive, 5.6% with aggressive, and 7.0% with metastatic PCa. Conclusions and Relevance: The findings of this study provide further support for DNA repair and cancer susceptibility genes to better inform disease management in men with PCa and for extending testing to men with nonaggressive disease, as men carrying deleterious alleles in these genes are likely to develop more advanced disease.

Germline Genetic Variants Associated with Somatic TMPRSS2:ERG Fusion Status in Prostate Cancer: A Genome-Wide Association Study.

BACKGROUND: The prostate cancer subtype defined by the presence of TMPRSS2:ERG has been shown to be molecularly and epidemiologically distinct. However, few studies have investigated germline genetic variants associating with TMPRSS2:ERG fusion status. METHODS: We performed a genome-wide association study with 396 TMPRSS2:ERG(+) cases, 390 TMPRSS2:ERG(-) cases, and 2,386 cancer-free controls from the Physicians' Health Study (PHS), the Health Professionals Follow-up Study (HPFS), and a Seattle-based Fred Hutchinson (FH) Cancer Center Prostate Cancer Study. We applied logistic regression models to test the associations between ∼5 million SNPs with TMPRSS2:ERG fusion status accounting for population stratification. RESULTS: We did not identify genome-wide significant variants comparing the TMPRSS2:ERG(+) to the TMPRSS2:ERG(-) prostate cancer cases in the meta-analysis. When comparing TMPRSS2:ERG(+) prostate cancer cases with controls without prostate cancer, 10 genome-wide significant SNPs on chromosome 17q24.3 were observed in the meta-analysis. When comparing TMPRSS2:ERG(-) prostate cancer cases with controls without prostate cancer, two SNPs on chromosome 8q24.21 in the meta-analysis reached genome-wide significance. CONCLUSIONS: We observed SNPs at several known prostate cancer risk loci (17q24.3, 1q32.1, and 8q24.21) that were differentially and exclusively associated with the risk of developing prostate tumors either with or without the gene fusion. IMPACT: Our findings suggest that tumors with the TMPRSS2:ERG fusion exhibit a different germline genetic etiology compared with fusion negative cases.

The Imperative for Population-based Cancer Registration of All Metastatic Cancers.

Metastases are the main cause of morbidity and mortality from solid tumors. Surprisingly, population-based cancer registries in various countries, including the National Cancer Institute's Surveillance, Epidemiology, and End Results program in the United States, only capture data on individuals diagnosed with cancers that are metastatic at diagnosis (M1). Metastatic recurrences of previously diagnosed, initially nonmetastatic tumors are missed. Devasia and colleagues specify an illness-death model for chronic disease and estimate that in prostate cancer, which has a large pool of primary disease that may or may not progress to metastases, about half of all metastatic cancers arise as recurrences from initially nonmetastatic disease. Capturing all incident metastatic cancer cases across all tumor types in population-based cancer registries, not only based on initial stage at diagnosis, would be critical to better understand the disparities in metastatic disease burden and the effectiveness of primary prevention, screening, and therapies for primary and metastatic disease. See related article by Devasia et al., p. 659.

Influence of Neighborhood Social and Natural Environment on Prostate Tumor Histology in a Cohort of Male Health Professionals.

Adverse neighborhood social and natural (green space) environments may contribute to the etiology of prostate cancer (CaP), but mechanisms are unclear. We examined associations between neighborhood environment and prostate intratumoral inflammation in 967 men diagnosed with CaP with available tissue samples from 1986-2009 in the Health Professionals Follow-up Study. Exposures were linked to work or residential addresses in 1988. We estimated indices of neighborhood socioeconomic status (nSES) and segregation (Index of Concentration at the Extremes (ICE)) using US Census tract-level data. Surrounding greenness was estimated using seasonal averaged Normalized Difference Vegetation Index (NDVI) data. Surgical tissue underwent pathological review for acute and chronic inflammation, corpora amylacea, and focal atrophic lesions. Adjusted odds ratios (aORs) for inflammation (ordinal) and focal atrophy (binary) were estimated using logistic regression. No associations were observed for acute or chronic inflammation. Each interquartile-range increase in NDVI within 1,230 m of the participant's work or home address (aOR = 0.74, 95% confidence interval (CI): 0.59, 0.93), in ICE-income (aOR = 0.79, 95% CI: 0.61, 1.04), and in ICE-race/income (aOR = 0.79, 95% CI: 0.63, 0.99) was associated with lower odds of postatrophic hyperplasia. Interquartile-range increases in nSES (aOR = 0.76, 95% CI: 0.57, 1.02) and ICE-race/income (aOR = 0.73, 95% CI: 0.54, 0.99) were associated with lower odds of tumor corpora amylacea. Histopathological inflammatory features of prostate tumors may be influenced by neighborhood.

Experience with the US health care system for Black and White patients with advanced prostate cancer.

OBJECTIVE: The purpose of this study was to assess differences in reported information about treatment, integration into care, and respect by self-identified Black and White individuals with advanced prostate cancer in the United States. PATIENTS AND METHODS: This is a prospective cohort study of 701 participants (20% identifying as Black) enrolled in the International Registry for Men with Advanced Prostate Cancer at 37 US sites from 2017 to 2022. Participants were asked six questions from the Cancer Australia National Cancer Control Indicators about their experience with care at study enrollment. Prevalence differences by self-reported race were estimated using marginal standardization of logistic-normal mixed effects models (adjusted for age at enrollment and disease state at enrollment), and 95% CIs were estimated using parametric bootstrapping. RESULTS: Most participants reported a high quality of care for each question. Black participants generally reported higher care quality compared with White participants. Black participants reported more frequently that they were offered a written assessment and care plan (71%) compared with White participants (58%; adjusted difference, 13 percentage points; 95% CI, 4-23). Black participants also reported more frequently being given the name of nonphysician personnel who would support them (64%) than White participants (52%; adjusted difference, 10; 95% CI, 1-20). Prevalence differences did not differ by disease state at enrollment. CONCLUSIONS: Black participants generally reported a higher quality of care compared with White participants. This study calls attention to the need to study potential mediating factors and interpersonal aspects of care in this population to improve survivorship.

Associations between Etiologic or Prognostic Tumor Tissue Markers and Neighborhood Contextual Factors in Male Health Professionals Diagnosed with Prostate Cancer.

BACKGROUND: There is growing evidence that unfavorable neighborhood contexts may influence prostate cancer progression. Whether these associations may be explained in part by differences in tumor-level somatic alterations remain unclear. METHODS: Data on tumor markers (PTEN, p53, ERG, and SPINK1) were obtained from 1,157 participants with prostate cancer in the Health Professionals Follow-up Study. Neighborhood greenness, socioeconomic status, and the income Index of Concentration at Extremes were obtained from satellite and census data and linked to participants' address at diagnosis and at study enrollment. Exposures were scaled to an interquartile range and modeled as tertiles. Bivariate associations between tertiles of neighborhood factors and tumor markers were assessed in covariate adjusted logistic regression models to estimate ORs and 95% confidence intervals. RESULTS: There was no association between any of the neighborhood contextual factors and PTEN, p53, ERG, or SPINK1 in bivariate or multivariable adjusted models. Results were generally consistent when modeling exposure using exposure at diagnosis or at study enrollment. CONCLUSIONS: In this multilevel study of men with prostate cancer, we found no evidence of associations between neighborhood context and tumor tissue markers. IMPACT: Our results provide some of the first empirical data in support of the hypothesis that prostate cancer risk conferred by tumor tissue markers may arise independently of underlying neighborhood context. Prospective studies in more diverse populations are needed to confirm these findings.

Physical Activity, Sedentary Behavior, and Risk of Coronavirus Disease 2019.

INTRODUCTION: Data on the associations of prepandemic physical activity and sedentary behavior with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) severity, particularly milder illness, have been limited. METHODS: We used data from 43,913 participants within the Nurses' Health Study II and Health Professionals Follow-Up Study who responded to periodic COVID-related surveys from May 2020 through March 2021. History of physical activity from the prepandemic period was assessed as the metabolic equivalents of task (MET)-hours per week of various activities of different intensity and sedentary behavior assessed from reports of time spent sitting from questionnaires completed 2016-2017. Multivariable logistic regression models were fitted to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for risk of SARS-CoV-2 infection and COVID-19 severity, as well as predicted COVID-19 defined using a validated symptom-based algorithm. RESULTS: Higher levels of prepandemic physical activity were associated with a lower risk for SARS-CoV-2 infection. Compared to participants with <3 MET-hours per week, the multivariable-adjusted OR was 0.86 (95% CI: 0.74, 0.99; P trend =.07) for those with ≥27 MET-hours per week. Higher physical activity levels were also associated with lower risk of symptomatic SARS-CoV-2 infection (OR: 0.84; 95% CI: 0.72, 0.99; P trend = .05) and predicted COVID-19 (OR: 0.87; 95% CI: 0.78, 0.97; P trend = .01). Longer time sitting at home watching TV (OR: 0.85; 95% CI: 0.73, 0.97) or for other tasks (OR: 0.78; 95% CI: 0.66, 0.92) was associated with a lower risk of SARS-CoV-2 infection. CONCLUSIONS: Our findings support a protective association between prepandemic physical activity and lower risk and severity of COVID-19.

Promoting Reproducibility and Integrity in Observational Research: One Approach of an Epidemiology Research Community.

To increase research reproducibility, sharing of study data, analysis code, and use of standardized reporting are increasingly advocated. However, beyond reproducibility, few initiatives have addressed the integrity of how research is conducted before manuscripts are submitted. We describe a decades-long experience with a comprehensive approach based in an academic research community around prospective cohort studies that is aimed at promoting a culture of integrity in observational research. The approach includes prespecifying hypotheses and analysis plans, which are discussed in the research community and posted; presentation and discussion of analysis results; mandatory analysis code review by a programmer; review of concordance between analysis output and manuscripts by a technical reviewer; and checks of adherence to the process, including compliance with institutional review board requirements and reporting stipulations by the National Institutes of Health. The technical core is based in shared computing and analytic environments with long-term archiving. More than simply a list of rules, our approach promotes research integrity through integrated educational elements, making it part of the "hidden curriculum," by fostering a sense of belonging, and by providing efficiency gains to the research community. Unlike reproducibility checklists, such long-term investments into research integrity require substantial and sustained funding for research personnel and computing infrastructure. Our experiences suggest avenues for how institutions, research communities, and funders involved in observational research can strengthen integrity within the research process.

Analysis of BRCA2 Copy Number Loss and Genomic Instability in Circulating Tumor Cells from Patients with Metastatic Castration-resistant Prostate Cancer.

BACKGROUND: BRCA2 alterations predict for a response to poly-ADP-ribose polymerase inhibition in metastatic castration-resistant prostate cancer (mCRPC). However, detection is hindered by insufficient tumor tissue and low sensitivity of cell-free DNA for detecting copy number loss. OBJECTIVE: To evaluate the BRCA2 loss detection using single-cell, shallow whole-genome sequencing (sWGS) of circulating tumor cells (CTCs) in patients with mCRPC. DESIGN, SETTING, AND PARTICIPANTS: We analyzed CTC samples collected concurrently with tumor biopsies intended for clinical sequencing in patients with progressing mCRPC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Differences in proportions were evaluated using the chi-square test. Correlations between assays were analyzed in linear regression models. Associations between alterations and genomic instability were assessed on the single-cell level using mixed-effect negative binomial models. RESULTS AND LIMITATIONS: We identified 138 patients with concurrent CTC and biopsy samples. CTC sWGS generated copy number profiles in a similar proportion of patients to biopsy samples (83% vs 78%, p = 0.23), but was more effective than bone biopsies (79% vs 50%; p = 0.009). CTC sWGS detected BRCA2 loss in more patients than tissue at the ≥1 (42% vs 16%; p < 0.001) and ≥2 (27% vs 16%; p = 0.028) CTC thresholds. The overall prevalence of BRCA2 loss was not increased in CTCs using sample-level composite z scores (p = 0.4), but was significantly increased compared with a lower-than-expected prevalence in bone samples (21% vs 3%, p = 0.014). Positive/negative predictive values for CTC BRCA2 loss were 89%/96% using the ≥1 CTC threshold and 67%/92% using the composite z score. CTC BRCA2 loss was associated with higher genomic instability in univariate (1.4-fold large-scale transition difference, 95% confidence interval [CI]: 1.2-1.6; p < 0.001) and multivariable analysis (1.4-fold difference, 95% CI: 1.2-1.6; p < 0.001). CONCLUSIONS: Copy number profiles can reliably be generated using CTC sWGS, which detected a majority of tissue-confirmed BRCA2 loss and "CTC-only" losses. BRCA2 losses were supported by increases in genomic instability. PATIENT SUMMARY: Current testing strategies have limitations in their ability to detect BRCA2 loss, a relatively common alteration in prostate cancer that is used to identify patients who may benefit from targeted therapy. In this paper, we evaluated whether we could detect BRCA2 loss in individual tumor cells isolated from patient blood samples and found this method to be suitable for further analysis.

Transcriptomes of Prostate Cancer with TMPRSS2:ERG and Other ETS Fusions.

The most common somatic event in primary prostate cancer is a fusion between the androgen-related TMPRSS2 gene and the ERG oncogene. Tumors with these fusions, which occur early in carcinogenesis, have a distinctive etiology. A smaller subset of other tumors harbor fusions between TMPRSS2 and members of the ETS transcription factor family other than ERG. To assess the genomic similarity of tumors with non-ERG ETS fusions and those with fusions involving ERG, this study derived a transcriptomic signature of non-ERG ETS fusions and assessed this signature and ERG-related gene expression in 1,050 men with primary prostate cancer from three independent population-based and hospital-based studies. Although non-ERG ETS fusions involving ETV1, ETV4, ETV5, or FLI1 were individually rare, they jointly accounted for one in seven prostate tumors. Genes differentially regulated between non-ERG ETS tumors and tumors without ETS fusions showed similar differential expression when ERG tumors and tumors without ETS fusions were compared (differences explained: R2 = 69-77%), including ETS-related androgen receptor (AR) target genes. Differences appeared to result from similarities among ETS tumors rather than similarities among non-ETS tumors. Gene sets associated with ERG fusions were consistent with gene sets associated with non-ERG ETS fusions, including fatty acid and amino acid metabolism, an observation that was robust across cohorts. IMPLICATIONS: Considering ETS fusions jointly may be useful for etiologic studies on prostate cancer, given that the transcriptome is profoundly impacted by ERG and non-ERG ETS fusions in a largely similar fashion, most notably genes regulating metabolic pathways.

A Healthy Lifestyle in Men at Increased Genetic Risk for Prostate Cancer.

BACKGROUND: Prostate cancer is the most heritable cancer. There is a need to identify possible modifiable factors for men at an increased risk of prostate cancer due to genetic factors. OBJECTIVE: To examine whether men at an increased genetic risk of prostate cancer can offset their risk of disease or disease progression by adhering to a healthy lifestyle. DESIGN, SETTING, AND PARTICIPANTS: We prospectively followed 12 411 genotyped men in the Health Professionals Follow-up Study (1993-2019) and the Physicians' Health Study (1983-2010). Genetic risk of prostate cancer was quantified using a polygenic risk score (PRS). A healthy lifestyle was defined by healthy weight, vigorous physical activity, not smoking, and a healthy diet. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall and lethal prostate cancer events (metastatic disease/prostate cancer-specific death) were analyzed using time-to-event analyses estimating hazard ratios (HRs) and lifetime risks. RESULTS AND LIMITATIONS: During 27 yr of follow-up, 3005 overall prostate cancer and 435 lethal prostate cancer events were observed. The PRS enabled risk stratification not only for overall prostate cancer, but also for lethal disease with a four-fold difference between men in the highest and lowest quartiles (HR, 4.32; 95% confidence interval [CI], 3.16-5.89). Among men in the highest PRS quartile, adhering to a healthy lifestyle was associated with a decreased rate of lethal prostate cancer (HR, 0.55; 95% CI, 0.36-0.86) compared with having an unhealthy lifestyle, translating to a lifetime risk of 1.6% (95% CI, 0.8-3.1%) among the healthy and 5.3% (95% CI, 3.6-7.8%) among the unhealthy. Adhering to a healthy lifestyle was not associated with a decreased risk of overall prostate cancer. CONCLUSIONS: Our findings suggest that a genetic predisposition for prostate cancer is not deterministic for a poor cancer outcome. Maintaining a healthy lifestyle may provide a way to offset the genetic risk of lethal prostate cancer. PATIENT SUMMARY: This study examined whether the genetic risk of prostate cancer can be attenuated by a healthy lifestyle including a healthy weight, regular exercise, not smoking, and a healthy diet. We observed that adherence to a healthy lifestyle reduced the risk of metastatic disease and prostate cancer death among men at the highest genetic risk. We conclude that men at a high genetic risk of prostate cancer may benefit from adhering to a healthy lifestyle.