African Americans with Prostate Cancer Face Higher Frequency of Genetic Alterations, Aggressive Disease

Compared with prostate cancer tumors from white men, prostate cancer tumors from Black men have higher frequencies of certain genetic alterations that may be associated with aggressive disease, according to a study published in Molecular Cancer Research.¹

“Prostate cancer incidence and mortality are highest in African American men, but the exact reasons for the disparity are not fully understood,” senior author Jianfeng Xu, DrPH, vice president of Translational Research at NorthShore University Health System, said in a press release.² “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.”

In this retrospective study, researchers evaluated somatic mutations in 39 genes using deeper next-generation sequencing (NGS) with an average depth of 2522 reads for tumor DNA and genome-wide DNA copy-number alterations (CNA) in the prostate cancer of 77 African American men and compared those with the prostate cancer of 410 white men.

The study revealed that at least 35% of African American men harbor damaging mutations in APC, ATM, BRCA2, KDM6A, KMT2C, KMT2D, MED12, ZFHX3, and ZMYM3, each with 1% or more mutated copies. More specifically, ZMYM3, which regulates chromatin and DNA repair, was found to be among the most frequently mutated genes in this patient population. Overall, 11.7% of African American patients had tumors harboring mutations in ZMYM3, compared to 2.7% of tumors from white patients

In addition, to assess whether there were variations in the copy number alterations between the prostate tumors of African American and white patients, the investigators pooled data representing 171 African American patients and 860 white patients from several public databases. Distinct copy number alterations were found between African American and white patients in more aggressive, high-grade prostate tumors, though not in low-grade tumors.

High-grade tumors from African American patients were found to be more likely to have additional copies of the MYC oncogene and deletions of the LRP1B, MAP3K7, BNIP3L, and RB1 genes compared with tumors from white patients. Moreover, a gain of MYC and loss of MAP3K7 or RB1 were also associated with more advanced tumor stage.

“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,” Xu explained. “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.”

Moving forward, the investigators aim to understand how genetic alterations in African American men affect recurrence, metastasis, treatment, and prostate cancer-specific death. Additionally, they hope to develop tests which could detect such genetic changes.

References:

1. Liu W, Zheng SL, Na R, et al. Distinct Genomic Alterations in Prostate Tumors Derived from African American Men. Molecular Cancer Research. 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]. Published October 28, 2020. Accessed October 28, 2020.