Konrad H. Stopsack’s research while affiliated with Massachusetts General Hospital and other places

To assess the contribution of rare coding germline genetic variants to prostate cancer risk and severity, we perform here a meta-analysis of 37,184 prostate cancer cases and 331,329 male controls from five cohorts with germline whole exome or genome sequencing data, and one cohort with imputed array data. At the gene level, our case-control collapsing analysis confirms associations between rare damaging variants in four genes and increased prostate cancer risk: SAMHD1, BRCA2 and ATM at the study-wide significance level (P < 1×10⁻⁸), and CHEK2 at the suggestive threshold (P < 2.6×10⁻⁶). Our case-only analysis, reveals that rare damaging variants in AOX1 are associated with more aggressive disease (OR = 2.60 [1.75–3.83], P = 1.35×10⁻⁶), as well as confirming the role of BRCA2 in determining disease severity. At the single-variant level, our study reveals that a rare missense variant in TERT is associated with substantially reduced prostate cancer risk (OR = 0.13 [0.07–0.25], P = 4.67×10⁻¹⁰), and confirms rare non-synonymous variants in a further three genes associated with reduced risk (ANO7, SPDL1, AR) and in three with increased risk (HOXB13, CHEK2, BIK). Altogether, this work provides deeper insights into the genetic architecture and biological basis of prostate cancer risk and severity, with potential implications for clinical risk prediction and therapeutic strategies.

Purpose Mismatch repair (MMR) deficiency and microsatellite instability are predictive biomarkers for immunotherapy response. The best approach to identify patients with such tumors is unclear in prostate cancer. Methods This study included 1,016 men diagnosed with primary prostate cancer during prospective follow-up of the Health Professionals Follow-up Study and Physicians’ Health Study. The highest-grade/index lesions from radical prostatectomy (95%) or transurethral resections of the prostate were mounted on tissue microarrays. Scoring of immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6, and PMS2 required a nontumor internal positive control for designating deficiency. Validation was done on full sections and with PCR-based quantification of microsatellite repeats. Results Tumor stage was predominantly pathologically localized with a full distribution of Gleason scores. MMR tumor scoring could be performed with available internal positive control tissue in 75% to 90% of cases, depending on the MMR protein. Of the 903 tumors evaluable for MSH2 protein loss, 4 tumors had loss of MSH2 (prevalence, 0.4%; 95% confidence interval, 0.2%–1.1%), and 3 of 708 evaluable tumors had concomitant loss of MSH6 (prevalence, 0.4%; 95% confidence interval, 0.1%–1.2%). No tumor had loss of MLH1 or PMS2. The four MMR-deficient cases had higher Gleason scores, and three had non-zero microsatellite repeats. Conclusions In this nationwide prospective study, MMR deficiency was rare in primary, surgically treated prostate cancer. The low prevalence and the need for an internal positive control for this assay are feasibility concerns for unselected routine immunohistochemistry-based screening for MMR deficiency on limited tissue specimens, such as prostate biopsies.

Background: Men with prostate cancer have a high risk for cardiovascular disease (CVD), including coronary heart and cerebrovascular disease, following cancer diagnosis. Clonal hematopoiesis (CH) is associated with coronary heart disease (CHD) in the general population. We hypothesized that a higher burden of CH among men with non-metastatic prostate cancer is associated with an increased risk of CHD. Methods: This is a nested case-cohort study among men diagnosed with non-metastatic prostate cancer and free of CVD at cancer diagnosis within the prospective Health Professionals Follow-up Study. Men had to be free from prostate cancer and CVD at blood draw and at cancer diagnosis to be included. Men diagnosed with prostate cancer were followed for incident CHD events, defined as fatal and non-fatal myocardial infarction, coronary artery bypass graft surgery, and percutaneous coronary intervention infarction, over up to 10 years after cancer diagnosis. DNA was sequenced for putative CH driver mutations in the 9 most common CH-defining genes with a custom targeted panel (VariantPlex, Invitae, Inc.) at ultra-high depth (mean, 19,664X). CH variant calling used a novel ensemble calling approach, ArCH, validated with in-silico tumor dilutions and blinded technical replicates, which had high accuracy for variant allele frequency (VAFs) as low as 0.1%. Hazard ratios (HRs) with 95% confidence intervals (95% CI) were computed using proportional hazard regression models with Prentice case-cohort weights. Results: In a sample of 562 men with prostate cancer and free from CVD at cancer diagnosis, men had a median age at cancer diagnosis of 70 years and 48% were never smokers. 95% were diagnosed with stage I and II, and 70% had a Gleason score of ≤3+4. The median time between blood draw and cancer diagnosis was 7 years (interquartile range (IQR): 3, 12). There were 116 events over 10 years of follow-up after cancer diagnosis. 59% of men had no CH or very small clones (VAF ≤0.5%), 25% had VAFs 0.5-2%, 12% had VAFs 2-10%, and 3% had VAFs ≥10%. 61% of men had variants in epigenetic modifier genes (DNMT3A, TET2, ASXL1), and 3% had variants in DNA repair genes (PPM1D, TP53, CHEK2). CH ≥10% VAF was associated with an increased risk of CHD events following cancer diagnosis compared to no CH or very small clones after adjusting for age at blood draw and at cancer diagnosis (VAF ≤0.5%) (HR 2.94, 95% CI 1.04-8.33). After further adjustment for smoking status at blood draw the association was essentially unchanged (HR 2.90, 95% CI 1.02-8.23). The association between CH and CHD risk tended to become stronger with increasing VAFs compared to VAFs ≤0.5% (VAF 0.5-2%: HR 0.92, 95% CI 0.46-1.82; VAF 2-10%: HR 1.20, 95% CI 0.57-2.52). Results for epigenetic modifiers and DNA repair genes were not individually statistically significant. Conclusions: Results from this prospective cohort suggest that a higher burden of CH is associated with CHD and may be a potential biomarker for CHD risk among men with prostate cancer. Citation Format: Caroline Himbert, Irenaeus C. C. Chan, Yuan Ma, Kenneth J Mukamal, Lorelei A Mucci, Philip W Kantoff, Kelly L Bolton, Konrad H Stopsack. Clonal hematopoiesis as biomarker for 10-year risk of coronary heart disease in men with prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A013.

The most common somatic alteration in primary prostate cancer is the TMPRSS2:ERG gene fusion, which may be caused or promoted by distinct etiologic factors. The objective of this systematic review was to assess epidemiologic evidence on etiologic factors for prostate cancer by tumor TMPRSS2:ERG fusion status in human populations. Of 3071 publications identified, 19 cohort or case–control studies from six distinct study populations were included in this systematic review. Etiologic factors included germline genetic variants, circulating hormones, and dietary and lifestyle factors. Taller height, higher total and free testosterone levels, and fewer trinucleotide repeats in AR were possibly associated with higher risk of TMPRSS2:ERG‐positive prostate cancer. Excess body weight, greater vigorous physical activity, higher lycopene intake, and the use of calcium channel blockers were associated with lower risk of TMPRSS2:ERG‐positive prostate cancer. Diabetes and family history of prostate cancer were associated with both TMPRSS2:ERG‐positive and TMPRSS2:ERG‐negative prostate cancer. Prostate cancer germline variants had suggestive differential associations with TMPRSS2:ERG‐positive or TMPRSS2:ERG‐negative prostate cancer. However, results were based on few distinct study populations and generally had low precision, underscoring the need for replication. In conclusion, prostate cancer with TMPRSS2:ERG fusion is an etiologically distinct subtype that may be, in part, preventable by addressing modifiable and hormonally acting etiologic factors that align with the established mechanistic role of TMPRSS2:ERG in androgen, insulin, antioxidant, and growth factor pathways.

Purpose: Deleterious germline variants in certain DNA repair genes are risk factors for developing aggressive prostate cancer. The objective was to quantify their prognostic impact after prostate cancer diagnosis. Methods: Men with prostate cancer, predominantly of European ancestry, were included from four cohorts with long-term follow-up. Pathogenic or likely pathogenic germline variants in 26 DNA repair genes were assessed in relation to metastasis-free survival in high-risk, localized prostate cancer and to overall survival in metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). Results: Among 3,525 patients initially diagnosed with non-metastatic prostate cancer, 2,594 had high-risk localized prostate cancer, 429 mCSPC, and 502 mCRPC at inclusion. BRCA2 variant carriers did not have worse metastasis-free survival in high-risk localized prostate cancer (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.69, 1.46) or overall survival in mCSPC (HR 0.46, 95% CI 0.14, 1.45) or mCRPC (HR 0.60, 95% CI 0.31, 1.17) compared to non-carriers of DNA repair variants. Among 868 additional patients with de novo metastatic (M1) prostate cancer, BRCA2 variant carriers tended to have worse overall survival (HR 1.59, 95% CI 1.01, 2.51). BRCA2 prognostic associations were not explained by radiation, PARP inhibitor, or platinum therapy. Results for other genes were limited in precision because variants were less common. Conclusions: Among patients with high-risk or metastatic prostate cancer who were initially diagnosed with and treated for non-metastatic tumors, germline DNA repair variants in BRCA2 do not confer a substantially worse prognosis.

Higher levels of aneuploidy, characterized by imbalanced chromosome numbers, are associated with lethal progression in prostate cancer. However, how aneuploidy contributes to prostate cancer aggressiveness remains poorly understood. In this study, we assessed in patients which genes on chromosome 8q, one of the most frequently gained chromosome arms in prostate tumors, were most strongly associated with long-term risk of cancer progression to metastases and death from prostate cancer (lethal disease) in 403 patients and found the strongest candidate was cohesin subunit gene, RAD21 , with an odds ratio of 3.7 (95% CI 1.8, 7.6) comparing the highest vs. lowest tertiles of mRNA expression and adjusting for overall aneuploidy burden and Gleason score, both strong prognostic factors in primary prostate cancer. Studying prostate cancer driven by the TMPRSS2-ERG oncogenic fusion, found in about half of all prostate tumors, we found that increased RAD21 alleviated toxic oncogenic stress and DNA damage caused by oncogene expression. Data from both organoids and patients indicate that increased RAD21 thereby enables aggressive tumors to sustain tumor proliferation, and more broadly suggests one path through which tumors benefit from aneuploidy.