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Study Finds Distinct Genomic Alterations May Contribute to More Aggressive Prostate Cancer in Black Men


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A study by Liu et al published in Molecular Cancer Research investigated why Black men appear to be more likely to develop aggressive prostate cancer than White men. Researchers found that prostate tumors in Black men had higher frequencies of distinct genetic alterations, which may contribute to more aggressive disease and a higher mortality rate. Understanding these differences in acquired genetic alterations in prostate tumors may help to guide personalized clinical management of prostate cancer in Black patients, according to the study authors.

With the exception of nonmelanoma skin cancer, prostate cancer is the most common cancer among men in the United States and one of the leading causes of cancer death among men of all races. Among Black men, the incidence of prostate cancer is 60% higher—and mortality is more than double—the rate seen in White men.

Study Methodology

Researchers analyzed somatic mutations in 39 genes using deeper next-generation sequencing with an average depth of 2,522 reads for tumor DNA and genome-wide DNA copy-number alterations in prostate cancer in 171 Black men. They then compared the findings with those found in prostate cancer in 860 White men.

Results

The study authors found that more than 35% of Black men harbored damaging mutations in several genes, including APC, ATM, BRCA2, KDM6A, KMT2C, KMT2D, MED12, ZFHX3, and ZMYM3, each with more than 1% of mutated copies. Among genes with more than 10% of mutated copies in tumor cells, ZMYM3 was the most frequently mutated gene found in Black men.

In a patient’s tumor with more than 96% frameshift mutations in ZMYM3, the researchers found allelic imbalances in 10 chromosomes, including losses of 5 and gains of another 4 chromosomes, suggesting its role in maintaining genomic integrity.

KEY POINTS

  • Black men with prostate cancer had higher frequencies of certain genetic alterations that may be associated with more aggressive disease and possibly higher mortality rates than prostate cancer in White patients.
  • High-grade tumors in Black patients were more likely to have additional copies of the MYC oncogene and deletions of the LRP1B, MAP3K7, BNIP3L, and RB1 genes, than tumors from White patients. Gain of MYC and loss of MAP3K7 or RB1 were also associated with more advanced tumor stage.

When compared with prostate cancer in White men, the researchers found a higher frequency of copy-number alterations of the MYC, THADA, NEIL3, LRP1B, BUB1B, MAP3K7, BNIP3L, and RB1 genes and a lower frequency of deletions of the RYBP, TP53, and TMPRSS2-ERG sequences in their Black counterparts.

They also found copy-number alterations between Black and White patients who had the more aggressive, high-grade prostate tumors (Gleason score of 7 or higher), but not in those who had low-grade tumors. High-grade tumors in Black men were more likely to have additional copies of the MYC oncogene and deletions of the LRP1B, MAP3K7, BNIP3L, and RB1 genes than tumors in White men. 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 [Black] 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 at NorthShore University HealthSystem and senior author of this study, in a statement. “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.”

Disclosure: For full disclosures of the study authors, visit mcr.aacrjournals.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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