Proteogenomic Signatures Shed Light on Prostate Cancer Recurrence Risk in Select Ancestries

Cara Schafer, PhD

The presence of select proteogenomic signatures and copy number variations differed between men with prostate cancer who were of African and European ancestry, and were associated with a higher risk of developing disease metastasis and/or recurrence, according to findings from a proteogenomic analysis presented at the 2024 AACR Annual Meeting.^1,2

Findings showed that distinct differences in copy number variations and the expression levels of proteins associated with biochemical recurrence risk were observed between the tumors of patients with African and European ancestries; these alterations were localized to chromosomes 2, 4, 7, and 8.

The NADH-ubiquinone oxidoreductase subunit proteins NDUFS8 and NDUFV3 in the oxidative phosphorylation pathway were more highly expressed in patients of African ancestry, whereas increased expression of the apolipoproteins APOB and APOC1 in the cholesterol metabolism pathway were noted in patients of European ancestry. These proteins were associated with a higher risk of disease progression.

Moreover, age-related mutation signatures were more frequently observed in patients of European ancestry, which is consistent with the older age at diagnosis of this cohort. Additionally, DNA repair deficiency signatures were higher in patients with African ancestry, which may contribute to responses with radiotherapy or other drugs targeting this pathway, such as PARP inhibitors.

“Differences in the global proteome and phospho-proteome between [patients of] African and European ancestry highlight the reprogramming of transcriptional, metabolic, and cellular functions regulating tumor cell growth and survival,” lead study author Cara Schafer, PhD, and colleagues, wrote in a poster presentation of the data. “The identified proteogenomic features correlated for copy number variant and protein abundance associated with aggressive disease have potential use as prognostic markers or treatment targets.” Schafer is an assistant professor in the Department of Surgery at the Uniformed Services University of the Health Sciences (USUHS) and a scientist at the Henry M. Jackson Foundation (HJF), in Rockville, Maryland.

Although the genomic landscape of prostate cancer is known to vary according to a patient’s ancestry, differences between genomic landscapes according to African and European ancestry have been underinvestigated.1 The Applied Proteogenomic OrganizationaL Learning and Outcomes (APOLLO) Research Network conducted a comparison of the proteogenomic landscapes of patient cohorts matched for genomically inferred African and European ancestries to identify ancestry-associated driver genes and correlated features that could be linked with an aggressive disease presentation.

To perform the analysis, investigators utilized deep whole genome sequencing and quantitative mass spectrometry–based proteomic and phosphoproteomics of tumor tissue specimens that were obtained from 57 and 55 patients with African and European ancestry, respectively. Tissue specimens were obtained from the Center for Prostate Disease Research (CPDR) at the USUHS Department of Surgery and the John P. Murtha Cancer Center at the Walter Reed National Military Medical Center. Patients included in the analysis had early-stage prostate cancer and equal access to care in the military health system. Proteogenomic signatures between tumors in each cohort were compared, and correlation analyses between proteins and gene alterations were performed. Unadjusted univariate analysis was used to evaluate time to biochemical recurrence or metastasis as a function of copy number alteration events and as function of protein levels.

“The availability of equal access to care in this military cohort was advantageous because it allowed us to limit the socioeconomic factors that might influence patient outcomes and to focus on the genomic and proteomic alterations as a molecular factor in health disparity,” Schafer added in a press release regarding this research.

The majority of patients in the CPDR prostate cancer cohort had data from whole genome sequencing and proteomics. Patients included in this cohort were between 40 and 79 years of age and had follow-up data ranging from less than 5 months to more than 20 months. Prostate-specific antigen (PSA) levels ranged from less than 4 ng/mL to more than 20 ng/mL, although most patients had PSA levels between 4 and 10. Patients had a Gleason sum between 6 and 10, and either T2, T3, or Tx stage disease. Most patients had not experienced biochemical recurrence or disease metastases.

Integrated comparative analyses of prostate cancer genomes in this matched-patient cohort showed ancestry-associated variations in somatic mutation signatures and global mutations, as well as focal regions of copy number variations. De novo somatic mutation signatures based on single-base substitutions, insertion deletions, and structural variations were also assessed and showed a greater variability in the germline genomes of patients of African vs European ancestry.

The most prevalent single nucleotide variant–mutated driver genes identified across both groups were SPOP, TP53, and FOXA1. Variations in ancestry-associated genomic metrics were observed in tumors of European vs African ancestry. SPOP single nucleotide variations were more common in those of African ancestry, whereas TP53 mutations were more frequently observed in patients with European ancestry.

Patients with African ancestry more commonly displayed amplifications at the 1p36 locus, which is associated with prostate cancer susceptibility, than their European counterparts. Deletions in the 17p13 locus, which harbors multiple driver genes including TP53, were more common in patients with European ancestry.

The most frequent driver gene copy number variations in tumors from the European ancestry cohort were at chromosomes 3p, 17p, and 18q; alterations in chromosomes 1p, 1q, 3q, 13q, and 19p were most common in the African ancestry cohort.

Over 8,800 proteins were quantified in a global proteomic analysis of tumors from 48 and 53 patients with African and European ancestry, respectively. A total of 1,452 proteins were found to be differentially expressed, 422 of which were considered to be expressed at significant levels. Of these 422 genes, 227 were more highly expressed in the European ancestry cohort vs 195 in the African ancestry cohort.

A panel of 23 proteins was validated using an independent dataset to accurately determine ETS-related gene status in tumors. Regarding the functionality of significantly differentially expressed proteins, tumors of African ancestry have more highly expressed proteins in pathways regulating xenobiotic metabolism, androgen regulation, and fatty acid degradation. In contrast, proteins in the MYC pathway were more highly expressed in tumors of European ancestry.

Lastly, a correlation analysis of protein expression and gene alterations between 6,446 genes and proteins identified 1,645 proteogenomic features which, when correlated for copy number variation and protein abundance, were associated with a more aggressive disease presentation.

“Differences in our genetic ancestry and the variations in gene mutation signatures can partly explain why some cancers are more aggressive than others and can reveal weaknesses in the cancer cells that can be used as a target for therapy,” presenting author Shyh-Han Tan, PhD, an associate professor at in the USUHS Department of Surgery and scientist at HJF, added in the press release. “Additionally, it is important to understand that although we may find a mutation more frequently in one group or the other, as long as the patient has an identifiable mutation, their cancer can be susceptible to targeted treatment. That’s the benefit of doing studies like these—it doesn’t focus on one group or the other, but everyone most affected by prostate cancer.”

Key study limitations include smaller sample size, and an imbalance between the average age at diagnosis of patients in each cohort.² Moreover, conclusions cannot be drawn about the variations in mutation profiles seen in late-stage or metastatic prostate cancer as tumor samples were obtained from patients with early-stage disease.

“These proteogenomic comparisons can help us bridge the gap in our understanding of why prostate cancer remains more deadly in men of African ancestry,” Schafer concluded in the press release.

References

1. Schafer, CC, Abulez TA, Zhang X, et al. Proteogenomic landscape of prostate cancers from patients of African and European ancestries highlight novel signatures of aggressive disease. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract LB285.
2. Proteogenomic signatures may help identify risk of prostate cancer progression in patients with African and European ancestries. News release. April 9, 2024. Accessed April 9 2024. https://www.aacr.org/about-the-aacr/newsroom/news-releases/proteogenomic-signatures-may-help-identify-risk-of-prostate-cancer-progression-in-patients-with-african-and-european-ancestries