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Oncologists’ Guide to Genomics

Stay current on the latest trends in genomics and molecular diagnostics for oncology.

Tuesday, December 22, 2020

Gene Alterations Linked to Prostate Cancer Disparities

By Warren Froelich

The genetic makeup of prostate tumors in African-American men exhibits a higher frequency of damaging mutations, potentially contributing to the significant disparity in prostate cancer cases and death when compared to White males.

In a retrospective study published in the online issue of Molecular Cancer Research, a journal of the American Association for Cancer Research (AACR), a research team from NorthShore University HealthSystem in Illinois found more than 35 percent of prostate tumors in African-American men harbored potentially damaging mutations in several genes, a higher frequency than White men (2020; doi: 10.1158/1541-7786.MCR-20-0648).

What's more, prostate tumors from African-American men had a higher frequency of altered genetic regions than White men, including deletions and gains that may contribute to more aggressive prostate cancer.

“These distinct genetic differences may help us understand the racial disparity in prostate cancer cases and provide the future basis for genetic testing to better predict the prognosis of tumors at time of diagnosis and inform targeted treatment options," said Jianfeng Xu, DrPH, Vice President of Translational Research at NorthShore and senior author of the study.

According to the American Cancer Society, one in seven or 14.8 percent of African-American men will develop prostate cancer in his lifetime, with one in 25 (4%) dying from their disease. Overall, African-American men are 1.8 times more likely to be diagnosed—and 2.2 times more likely to die—from prostate cancer than White men.

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

Genetic Research

Xu and first author Weenuan Liu, PhD, along with their colleagues, sought to sequence and compare DNA extracted from prostate cancer tumor tissues from African-American and White men to explore the genetic differences.

This can be challenging since the segment of DNA of interest containing the mutation only makes up a small proportion of the DNA present in the samples. The vast majority of DNA may come from normal cells, other clones of the primary tumor present in the sample, or the non-mutated copy of the gene of interest.

These challenges, along with an insufficient number of specimens for study, previously have hindered the identification of genetic factors responsible for more aggressive prostate cancer and higher mortality rates in African-American males.

To overcome this hurdle, Xu and colleagues turned to “deeper next-generation sequencing" to better separate mutated genes that drive prostate tumor growth and proliferation from all the other genetic noise.

“In deeper next-generation sequencing used in our study, we copy and read all the DNA segments greater than 2,000 times so that we can better detect the mutated segments we are interested in from all the other segments of DNA," Xu said in an interview.

Study Details

In their study, the research team focused on two types of major genetic changes: point mutations, a change in a single DNA position; and changes (deletions and gains) in a stretch of DNA affecting an entire gene or several genes, also known as “copy number alterations."

“These changes can be useful when predicting how the cancer will progress, whether it will metastasize, and how it will respond to certain drugs and treatments," Xu stated.

In the first part of the study, the NorthShore team extracted and sequenced 39 driver genes of interest in tumors and matched normal DNA from 77 African-American men with prostate cancer. After filtering out tumors containing less than 10 percent mutated genes, the team identified the top 22 mutated genes for analysis.

More than 35 percent of these patients' tumors had point mutations in several genes known to affect cancer growth and progression, including DNA repair genes ATM, BRCA2, and ZMYM3, among others.

ZMTM3, which regulates chromatin and DNA repair, was found to be among the most frequently mutated genes in patients, with nine of the 77 African-American patients (11.7%) harboring mutations in ZMYM3, compared to 2.7 percent of tumors from 410 white patients whose data was included in the Genomic Data Commons database.

“ZMYM3 promotes BRCA1 to the location of the damaged chromatin to facilitate DNA repair," said Xu. “Knockout of ZMYM3 in mice and in cells, respectively, causes defects in spindle assembly and impairs homologous recombination DNA repair leading to genomic instability."

In the second part of their study, the researchers compared the copy number alterations—where genetic material is gained or lost—in the prostate tumors of African-American men with White men. The study included a pool of 171 African-American patients and 860 White patients from several public databases. They found distinct copy number alterations between African-American and White patients in the more aggressive, high-grade prostate tumors (Gleeson score 7 or higher), but not in low-grade tumors.

High-grade tumors from African-American 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 in MYC and loss of MAP3K7 or RB1 were also associated with more advanced tumor stage.

“Taken together, these results show that there are unique differences in prostate tumors of African-American and European American (White) men that could affect how we manage and treat prostate cancer between these two groups," Xu noted.

In the future, the research team is interested in expanding its study to include more African-American men from multiple institutions. In addition, they want to collect additional clinical data such as recurrence/relapse, metastasis, treatment, and prostate cancer-specific death, and then analyze their associations with distinct genetic alterations in African-American men. And then, the team plans to develop tests to detect these genetic changes.

“We have already developed and tested the feasibility of such type of assays for Caucasian patients," Xu stated. (Prostate 2020; https://doi.org/10.1002/pros.24057).

Warren Froelich is a contributing writer.