Genomic Profiling of Prostate Cancers from Men with African and European Ancestry

Abstract

Purpose: African American (AFR) men have the highest mortality rate from prostate cancer (PCa) compared with men of other racial/ancestral groups. Differences in the spectrum of somatic genome alterations in tumors between AFR men and other populations have not been well-characterized due to a lack of inclusion of significant numbers in genomic studies.

Experimental design: To identify genomic alterations associated with race, we compared the frequencies of somatic alterations in PCa obtained from four publicly available datasets comprising 250 AFR and 611 European American (EUR) men and a targeted sequencing dataset from a commercial platform of 436 AFR and 3018 EUR men.

Results: Mutations in ZFHX3 as well as focal deletions in ETV3 were more frequent in tumors from AFR men. TP53 mutations were associated with increasing Gleason score. MYC amplifications were more frequent in tumors from AFR men with metastatic PCa, whereas deletions in PTEN and rearrangements in TMPRSS2-ERG were less frequent in tumors from AFR men. KMT2D truncations and CCND1 amplifications were more frequent in primary PCa from AFR men. Genomic features that could impact clinical decision making were not significantly different between the two groups including tumor mutation burden, MSI status, and genomic alterations in select DNA repair genes, CDK12, and in AR.

Conclusions: Although we identified some novel differences in AFR men compared with other populations, the frequencies of genomic alterations in current therapeutic targets for PCa were similar between AFR and EUR men, suggesting that existing precision medicine approaches could be equally beneficial if applied equitably.

Figure 1.. Mutational frequencies associated with race and Gleason score across 4 prostate cancer cohorts.

(A) Gene mutation frequencies associated with race were identified with a logistic regression model containing race, Gleason score, age, and mutation rate. Solid purple points represent genes significantly associated with race (FDR < 0.05). (B) The frequency of ZFHX3 mutations was associated race. (C) The frequency of TP53 mutations was associated with Gleason score.

Figure 2.. Copy number alterations associated with race and Gleason score across 4 prostate cancer cohorts.

(A) Gene deletion frequencies associated with race were identified with a logistic regression model containing race, Gleason score and age (AFR: 171, EUR: 626). Solid purple points represent genes significantly associated with race (FDR < 0.05). (B) The frequency of PTEN deletions was significantly lower in AFR men (FDR < 0.05). Differences between groups were most pronounced in Gleason 6 and 7 tumors. (C) The frequency of ZFHX3 deletions was significantly higher in AFR men (FDR < 0.05).

Figure 3.. Association of mutations with race and metastasis in the Foundation cohort.

(A) Comparison of alteration frequencies for each gene between AFR and EUR populations in combined samples (AFR: N = 436, EUR: N = 3,018, upper panel), localized PCa samples (AFR: N = 251, EUR: 1,940, lower left panel) and metastatic PCa samples (AFR: N = 185, EUR: 1,078, lower right panel). Alteration frequencies are overall frequencies of all classes. Solid black lines represent a 1:1 relationship between AFR and EUR patients. Open grey circles are genes with no significant differences (FDR >= 0.05) and solid purple circles are genes with significantly different alteration rates (FDR < 0.05). Gene names are labeled beside their corresponding markers in the scatter plots. (B) Frequency of major pathway alterations with significant differences between AFR (solid) and EUR (shadow) in localized or metastatic PCa samples, including KMT (lysine methyltransferase) genes, PI3K pathway genes and cell cycle pathway genes in which alterations were detected in the Foundation cohort. Gene alteration rates are shown as side-by-side bar charts consisting of a total of four color-coded alteration classes. Genes with significantly different alteration rates (FDR < 0.05) were highlighted with asterisks.

Figure 4.. Frequency of major pathway alterations and tumor mutational burdens.

(A) Frequency of major pathway alterations with no significant differences between AFR (solid) and EUR (shadow) in localized or metastatic PCa samples, including DNA repair pathway genes, RAS/MAPK pathway genes and WNT pathway genes in which alterations were detected in the Foundation cohort. Gene alteration rates are shown as side-by-side bar charts consisting of a total of four color-coded alteration classes. If the alteration frequency for a gene was 0, it was omitted in the dataset. (B) Tumor mutational burdens (TMB) in both localized and metastatic PCa (localized: n_AFR = 124, n_EUR = 852; metastatic: n_AFR = 202, n_EUR = 1695). TMBs were computed as the percentage of patients within the cohort with respect to the number of mutations detected (0~100). No significant difference was found between AFR (blue) and EUR (orange) populations.

Figure 5.. Association of ERG and PTEN alteration frequencies to ancestry percentage.

Logistic regression was used to identify associations of ERG and PTEN alteration status with percentage of AFR or EUR ancestry within each patient (N = 5,624). Solid lines represent the logistic regression curves between alteration status and ancestry percentage. The semi-transparent band around the solid lines represent the 95% confidence interval of the logistic regression curves.

Figure 6.. Top ten most frequently altered genes in AFR and EUR men.

(A) The ten most frequent alterations are shown from AFR and EUR patients in the meta-analysis cohort for tumors with low-grade disease (top; Gleason scores 6, 7) and high-grade disease (bottom; Gleason scores 8, 9, and 10). Gene alteration classes considered include non-synonymous mutations, amplifications, and deletions. (B) The ten most frequent alterations in AFR and EUR patients in the Foundation Medicine cohort for tumors with localized PCa (top) and metastatic PCa (bottom). Gene alteration classes considered include amplifications, deletions, rearrangements, point (missense) mutations and truncations.