Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry

Chen, Fei; Madduri, Ravi; Rodríguez, Alex A.; Darst, Burcu F.; Chou, Alisha; Sheng, Xin; Wang, Anqi; Shen, Jiayi; Saunders, Edward J.; Rhie, Suhn Kyong; Bensen, Jeannette T.; Ingles, Sue A.; Kittles, Rick A.; Strom, Sara S.; Rybicki, Benjamin A.; Nemesure, Barbara; Isaacs, William B.; Stanford, Janet L.; Zheng, Wei; Sanderson, Maureen; John, Esther M.; Park, Jong Y.; Xu, Jianfeng; Wang, Ying; Berndt, Sonja I.; Huff, Chad; Yeboah, Edward D.; Tettey, Yao; Lachance, Joseph; Tang, Wei; Rentsch, Christopher T; Cho, Kelly; McMahon, Benjamin H.; Biritwum, Richard; Adjei, Andrew A.; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Sellers, Thomas A.; Yamoah, Kosj; Murphy, Adam B.; Crawford, Dana C.; Patel, Alpa V.; Bush, William S.; Aldrich, Melinda C.; Cussenot, Olivier; Petrovics, György; Cullen, Jennifer; Neslund‐Dudas, Christine; Stern, Mariana C.; Kóte-Jarai, Zsofia; Govindasami, Koveela; Cook, Michael B.; Chokkalingam, Anand P.; Hsing, Ann W.; Goodman, Phyllis J.; Hoffmann, Thomas J.; Drake, Bettina F.; Hu, Jennifer J.; Keaton, Jacob M.; Hellwege, Jacklyn N.; Clark, Peter E.; Jalloh, Mohamed; Gueye, Serigne; Niang, Lamine; Ogunbiyi, Olufemi; Idowu, Michael O.; Popoola, Olufemi; Adebiyi, Akindele Olupelumi; Aisuodionoe-Shadrach, Oseremen I.; Ajibola, Hafees O.; Jamda, Mustapha A; Oluwole, Olabode P.; Nwegbu, Maxwell M.; Adusei, Ben; Mante, Sunny; Abrahams, Afua O.D.; Mensah, James E.; Diop, Halimatou; Eeden, Stephen K. Van Den; Blanchet, Pascal; Fowke, Jay H.; Casey, Graham; Hennis, Anselm; Lubwama, Alexander; Thompson, Ian M.; Leach, Robin J.; Easton, Douglas F.; Preuß, Michael; Loos, Ruth J. F.; Gundell, Susan M.; Wan, Peggy; Mohler, James L.; Fontham, Elizabeth T.H.; Smith, Gary J.; Taylor, Jack A.; Srivastava, Shiv; Eeles, Rosaline A.; Carpten, John D.; Kibel, Adam S.; Multigner, Luc; Parent, Marie‐Élise; Ménégaux, Florence; Cancel‐Tassin, Géraldine; Klein, Eric A.; Andrews, Caroline; Rebbeck, Timothy R.; Brureau, Laurent; Ambs, Stefan; Edwards, Todd L.; Watya, Stephen; Chanock, Stephen J.; Witte, John S.; Blot, William J.; Gaziano, J. Michael; Justice, Amy C.; Conti, David V.; Haiman, Christopher A.

doi:10.1016/j.eururo.2023.01.022

Cited by 22 publications

(5 citation statements)

References 57 publications

(31 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The cause of the racial disparity in prostate cancer is multifactorial and not yet fully elucidated, stemming from a combination of inequitable access to health resources, lack of representation in research, and epigenetic sequelae of environmental factors (e.g., stress, metabolism, diet). Although race is an inherently social category, biogeographical ancestry analyses have shown that there is a strong concordance between molecular-based ancestry groups and racial groups ( 47, 48 ). Identification of molecular expression and activity patterns that vary by racial group may provide a key to addressing outcomes related to racial disparities, as currently existing treatments have not been developed with attention to the inclusion of diverse patient populations.…”

Section: Discussionmentioning

confidence: 99%

ERBB3 Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature

Vellky,

Kirkpatrick,

Gutgesell

et al. 2024

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Despite successful clinical management of castration-sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer (CRPC) is only 32%. Combination treatment strategies to prevent disease recurrence are increasing, albeit in biomarker-unselected patients. Identifying a biomarker in CSPC to stratify patients who will progress on standard-of-care therapy could guide therapeutic strategies. Methods: Targeted deep sequencing was performed for the UI cohort (n=30), and immunostaining was performed on a patient tissue microarray (n=149). Bioinformatic analyses identified pathways associated with biomarker overexpression in the UI cohort, consolidated RNA-seq samples accessed from dbGaP (n=664), and GSE209954 (n=68). Neutralizing antibody Patritumab and ectopic HER3 overexpression were utilized for functional mechanistic experiments. Results: We identified ERBB3 overexpression in diverse CSPC patient populations, where it was associated with advanced disease at diagnosis. Bioinformatic analyses showed a positive correlation between ERBB3 expression and the androgen response pathway despite low DHT and stable expression of AR transcript in Black/African American men. At the protein level, HER3 expression was negatively correlated with intraprostatic androgen in Black/African American men. Mechanistically, HER3 promoted enzalutamide resistance in prostate cancer cell line models and HER3-targeted therapy re-sensitized therapy-resistant prostate cancer cell lines to enzalutamide. Conclusions: In diverse CSPC patient populations, ERBB3 OE was associated with high AR signaling despite low intraprostatic androgen. Mechanistic studies demonstrated a direct link between HER3 and enzalutamide resistance. ERBB3 OE as a biomarker could thus stratify patients for intensification of therapy in castration-sensitive disease, including targeting HER3 directly to improve sensitivity to AR-targeted therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

ERBB3 Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature

Vellky,

Kirkpatrick,

Gutgesell

et al. 2024

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Our analyses of variant-trait associations detected several signals that would not have been identified in a GWAS comprising solely individuals genetically similar to EUR reference populations. One example is rs72725854 at the PCAT2 locus, which has been associated with an increased risk of prostate cancer identified in prior studies (37)(38)(39). Prostate cancer is more common in self-reported Black men compared to the general population, and approaches that incorporate this variant and others into risk scores are under active investigation as a component of precision medicine-based prostate cancer screening approaches.…”

Section: Discussionmentioning

confidence: 99%

Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program

Verma,

Huffman,

Rodriguez

et al. 2024

Science

View full text Add to dashboard Cite

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third ( n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.

show abstract

“…Furthermore, they reported that by the age of 85, the cumulative incidence of prostate cancer was 7.1% in the bottom decile and 54.1% in the top decile for European American men 19 . In addition to Conti's 269 PRS, Chen et al identi ed nine novel susceptibility loci for prostate cancer that were common in African men and were strongly associated with prostate risk and aggressive prostate cancer in African ancestry 20 . Our study is the rst and largest GWAS cohort to examine Conti's 269 PRS in Han Chinese individuals and found similar predictive value as observed in European and African ancestries.…”

Section: Discussionmentioning

confidence: 99%

Predictive value of polygenic risk score for prostate cancer incidence and prognosis in the Han Chinese

Hung

Chang

Hsiao

et al. 2023

Preprint

View full text Add to dashboard Cite

Background: Although prostate cancer is a common occurrence among males, the relationship between existing risk prediction models remains unclear. The objective of this hospital-based retrospective study is to investigate the impact of polygenic risk scores (PRSs) on the incidence and prognosis of prostate cancer in the Han Chinese population. Methods: A total of 24,778 male participants including 903 patients with prostate cancer at Taichung Veterans General Hospital were enrolled in the study. PRS was calculated using 269 single nucleotide polymorphisms and their corresponding effect sizes from the polygenic score catalog. The association between PRS and the risk prostate cancer was evaluated using a logistic regression model. Results: Among the 24,778 participants, 903 were diagnosed with prostate cancer. The prevalence of prostate cancer was significantly higher in the highest quartile of PRS distribution compared to the lowest (OR=4.99, 95% CI=4.17-5.98, p<0.0001), with statistical significance across all age groups. Patients in the highest quartile were diagnosed with prostate cancer at a younger age (66.8±8.3 vs. 69.5±8.8, p=0.002). Subgroup analysis of patients with localized or stage 4 prostate cancer showed no significant differences in biochemical failure or overall survival. Conclusions: This hospital-based cohort study observed that a higher PRS was associated with increased susceptibility to prostate cancer and younger age of diagnosis. However, PRS was not found to be a significant predictor of disease stage and prognosis. These findings suggest that PRS could serve as a useful tool in prostate cancer risk assessment.

show abstract

Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry

Cited by 22 publications

References 57 publications

ERBB3 Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature

ERBB3 Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature

Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program

Predictive value of polygenic risk score for prostate cancer incidence and prognosis in the Han Chinese

Contact Info

Product

Resources

About