Increased Somatically Acquired Alterations May Lead to More Aggressive Prostate Cancer, Mortality in Black Patients

Jianfeng Xu, DrPH

A higher incidence of somatically acquired genetic alterations, including damaging mutations in ZMYM3 leading to genomic instability, as well as deletions in MAP3K7, BNIP3L, RB1, and NEIL3, and gain of MYC, may lead to more aggressive prostate cancer in Black/African American men, according to findings published in Molecular Cancer Research.¹

“Our findings suggest that distinct genetic alterations in the prostate cancers of African American men, in comparison to White men, may contribute to more aggressive prostate cancer and could lead to a higher mortality rate,” said Jianfeng Xu, DrPH, vice president of Translational Research and director of the Program for Personalized Cancer Care at NorthShore University HealthSystem, and a research professor at the University of Chicago Pritzker School of Medicine.² “If confirmed in other studies, these results will not only help to understand the racial disparity of prostate cancer but could also help guide personalized clinical management, such as predicting prognosis and guiding targeted therapy.”

In the analysis, investigators utilized pathologic tumor specimens and matched benign tissues from 83 African American patients diagnosed with prostate cancer. Of these, 81 matched tumor-normal pairs were successfully sequenced, minus 4 pairs that had a maximum depth of less than 50 reads for normal DNA.

“Among the 22 tumors sequenced using Agilent HaloPlex HS enrichment, we identified a total of 233 mutations, with an average of 10.6 exon mutations per tumor,” wrote the authors. “On the other hand, we detected a total of 8567 exon mutations among the 55 tumors sequenced using the NimbleGen SeqCap EZ Library SR enrichment from Roche, with an average of 156 mutations per tumor in these 39 genes. Combining the results from these two platforms together, we found that the percentages of tumors harboring somatically acquired mutations were much higher than those expected in these genes, even after filtering out the ones with ≤ 1% of the mutated copies in the tumor.”

Data showed that more than 35% of African American/Black patients had damaging mutations in APC, ATM, BRCA2, KDM6A, KMT2C, KMT2D, MED12, ZFHX3, and ZMYM3, in which there was more than 1% of mutated copies. ZMYM3 was the most frequently mutated gene in African American patients among genes with more than 10% of mutated copies in tumor cells. For patients who had ZMYM3-mutated tumors with 96% frameshift, 10 chromosomes were found to have allelic imbalances, including losses of 5 and gains of 4 chromosomes.

When compared with White men, African American/Black men were found to have a higher frequency of copy number alterations (CNA) in several genes, including MYC, THADA, NEIL3, LRP1B, BUB1B, MAP3K7, BNIP3L, and RB1.

There was also a lower frequency of deletions in RYBP (12%), TP53 (11%), and TMPRSS2-ERG within this patient subgroup vs European Ancestry/White men (21%, 20%, and 50%, respectively). The higher frequency of CNAs; deletion of MAP3K7, BNIP3L, NEIL3, or RB1; or gain of MYC seen in African American patients were significantly associated with advanced pathologic stage and Gleason grade.

“Prostate cancer incidence and mortality are highest in African American men, but the exact reasons for the disparity are not fully understood,” Xu said. “The disparity is likely due to multiple factors, including socioeconomic differences and biology. We suspect that differences in the genetic changes that occur within tumors may play a critical role.”

Additional findings showed that ZMYM3 and FOXA1 exon mutations occurred more commonly in African American/Black patients (11.7% and 11.7%, respectively) compared with European Ancestry/White patients (2.7% and 5.4%). The most common CNA seen in the 80 African American/Black patients within the Prostate Cancer Biorepository Network (PCBN) cohort was 6q deletion, including MAP3K7, which occurred in approximately 49% of patients. Overall, African American/Black patients were found to have a significantly higher incidence of damaging mutations (77%) compared with European Ancestry/White patients (58%).

When examining the incidence of CNAs in prostate cancer between European Ancestry/White and Black/African American patients, investigators found that Black/African American patients had a notably higher rate of MAP3K7 deletion at 6q15 (P = .0247), as well as lower rates of losses at PTEN at 10q23.31 (P <.0001), TP53 at 17p13.1 (P = .0002), TMPRSS2-ERG at 21q22.2–22.3 (P <.0001), and SERPINB5 at 18q21.33 (P = .009) compared with European Ancestry/White patients.

While there were no notable differences in the incidence of CNAs in all 13 genes in Gleason 6 or lower tumors between the 2 subgroups, Black/African American men had higher incidences of MYC gain in Gleason 7 and 8 (P = .0142 and P = .021, respectively), LRP1B loss in Gleason 8 (P = .0163), and deletions of MAP3K7, BNIP3L, and RB1 in Gleason 9 or higher compared with European Ancestry/White men (P = .0019; P = .0036; P = .0274, respectively).

Finally, investigators examined how CNAs in prostate cancer are unique to African American patients related to Gleason grade and pathologic stage.

“Compared with tumors with GG ≤2, the rates of deletions of LRP1B at 2q22.1-2 (P = 4.37E-05), BNIP3L at 8p21.2 (P = 3.37E-04), BUB1B at 15q15.1 (P = .001), and NEIL3 at 4q34.3 (P = .0086) were each significantly higher in tumors with Gleason grade ≥3,” the authors noted.

Both the deletion of MAP3K7 or RB1 along with gain of MYC were notably indicative of a higher Gleason grade, as well as more advanced pathologic stage (odds ratio [OR] = 2.72; 95% CI, 1.45-5.11; P = .002; OR = 3.36; 95% CI, 1.75-6.46; P = 2.76E-4; OR = 2.84; 95% CI, 1.39-5.81; P = .004, respectively).

References

1. Liu W, Zheng SL, Rong N, et al. Distinct genomic alterations in prostate tumors derived from African American men. Mol Cancer Res. 2020;18:1815-1824. doi:10.1158/1541-7786.MCR-20-0648
2. Genetic alterations may contribute to greater prostate cancer incidence and mortality among African American men. News release. American Association for Cancer Research. October 28, 2020. Accessed October 28, 2020. https://bit.ly/3oAszVi