The biology of a prostate tumor may be influenced by its genetics

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Sample collection sites and genetic mix analysis. a, At clinical sites across Nigeria, 45 samples were collected. B, Admixture v1.3.0 was used to estimate progeny lineage, based on reference sets from 1000 genomes in stage III superpopulations. Prior to analysis, rare variants were classified (eg, 70% of African ancestry were classified as AA; 402 TCGA samples contained >60% European admixtures. These samples were sorted by European proportion, and the top 50 samples were ranked on They are EA and were used in this study The mean European percentage for this group was 99.996%.Germline C variants within the NG and TCGA groups were compared with the stage III 1000 superpopulations using principal component analysis.NG samples clustered strongly with African superpopulations. High population density, European samples clustered with the European Census.Credit: Cancer Research Communications (2022). DOI: 10.1158 / 2767-9764.CRC-22-0136

Certain genetic variants found in prostate tumors in men of African descent have been associated with African descent, according to two studies presented at the 15th AACR Conference on the Science of Cancer Health Disparities in Racial, Ethnic, and Medically Disadvantaged Minorities, September 16-19. .

One study was simultaneously published in the journal Cancer Research Communications.

In the United States, black men have the highest rate Prostate cancerAssociated deaths. Most studies looking at disparities focus on race, which is typically self-reported and determined by skin color and sociocultural traits, explained Clayton Yates, lead author on both studies, director of the Center for Biomedical Research at Tuskegee University, and chair of AACR Minorities at Cancer Research Council.

However, Yates argued, addressing health disparities will also require an understanding of the contributions of genes Ancestral to me tumor biology. He explained that insights into genetic ancestry could aid precision medicine efforts by revealing potential therapeutic targets specific to patients of African descent.

In the first study, Esraa Al-Hussein, MBBS, MSc, graduate student at the Yates Research Laboratory and AACR NextGen Star, and colleagues examined the effect of the African strain on the expression of inflammatory immune gene signatures that correlate with higher immune capacities and an aggressive prostate. Cancers in men of African descent.

Al-Hussein and colleagues previously reported that prostate tumors in African American men have two times greater activation of inflammatory signals, which may contribute to the more aggressive disease typically observed in these patients.

However, Al-Hussein noted that the higher rate of prostate cancer-related deaths among men of African descent is not limited to those living in the United States. “Men of African descent have the highest rates of prostate cancer-related mortality worldwide, suggesting a possible ancestral basis for these divergent outcomes,” she said.

To determine the role of African ancestry in prostate cancer, Al-Hussein and colleagues sequenced prostate tumors from 72 patients in the United States who had not undergone cancer treatment. Of these patients, 16 reported their ethnicity as African American, 25 reported as European, 1 was Asian, and 30 reported no race. Using reference databases, Al-Hussein determined that most patients who identified as African Americans had genetic markers consistent with men of African descent, specifically those from the Bantu (Sub-Saharan) and/or Yoruba (Nigerian) populations.

Compared with tumors of patients of European descent, tumors of patients of African ancestry were more likely to harbor mutations in SPOP, which is tumor suppressor gene mutated in about 10-15% of all prostate cancers. Al-Hussein noted that the SPOP mutation has previously been associated with aggressive prostate cancer. Furthermore, Al-Hussein found that SPOP mutation in patients of African descent is associated with increased expression of the pro-inflammatory immune gene signature, increased immune cell infiltration into the tumor, and increased expression of the immune checkpoint proteins PD-L1 and PD-1.

“We are the first to show that the African genetic lineage is associated with a SPOP mutation, which leads to increased immunity, regulation of the immune inflammatory signature, and tumor infiltration of immune cells expressing markers of fatigue, providing a potential mechanism for higher prostate cancer–mortality in African men.” “These findings have implications for prostate cancer treatment and could lead to new treatment strategies using anti-inflammatory drugs and immunomodulators to reduce disease burden among men of African descent.”

“While most prostate tumors do not have immune cell infiltration, our findings show that prostate tumors with a SPOP mutation have very high levels of immune cell infiltration,” Yates noted. “This is an exciting finding that may help identify patients who may benefit from immunotherapy, which is particularly important given that African Americans are often underrepresented in clinical trials evaluating such treatments.”

In the second study, which was published at the same time in Cancer Research CommunicationsYates and colleagues, including first author Jason White, MS, MD, compared DNA sequences from prostate tumors of Nigerian, African-American, and European-American patients. The study was completed in collaboration with the Transatlantic Prostate Cancer Consortium (CaPTC).

“Our goal was to understand the genetic contributions of prostate cancer among Nigerian men, something that had not been studied before,” Yates said. “We performed sequencing to determine if there were unique mutations associated with the Nigerian population that differed from those in tumors from African Americans or European Americans, as well as to identify any similarities between these populations.”

Yates, White and colleagues sequenced 45 advanced treatment-stage prostate tumors and 11 unmatched non-neoplastic prostate samples collected from Nigerian patients. They compared these sequences to existing data from African American and European American prostate tumors in the Cancer Genome Atlas database.

They found that genetic variants were similar between Nigerian and African American prostate tumors, with specific variants in the BRCA1 DNA repair gene among the most common variants identified in both groups. Furthermore, the researchers determined that the frequency of BRCA1 mutations increased with higher proportions of African genetic ancestry and decreased with lower proportions of African ancestry.

“We identified unique variants in the BRCA1 gene that are not normally tested in the clinic, and these variants were specific to African ancestry,” Yates said. “On the other hand, tumors from European Americans had differences in different DNA repair genes that were not observed in tumors from African Americans or Nigerian patients. This suggests that there are different types that contribute to prostate cancer in European Americans compared to African men.” “

Yates explained that these findings may have implications for treating prostate cancer in patients of African descent. “The BRCA variants currently tested in cancer were identified from a non-minority population and do not include the variants of African ancestry that we identified,” he said, adding that this effectively excludes many African Americans from BRCA-targeting cancer therapies.

“Testing these additional variables will help identify additional patients who are eligible for BRCA-targeted therapies and may provide some predictive value as well,” he added. Yates noted that future studies will aim to understand how specific variables contribute to the development and progression of prostate cancer.

White, who presented the research on Nigerians, explains that these studies combined highlight the contributions of African ancestry to prostate cancer genes and may explain some of the racial/ethnic disparities in outcomes among prostate cancer patients. Prostate tumors At the AACR Inequality Meeting. He added that epigenetic and societal factors are also important contributors to cancer health disparities.

Limitations of both studies included small sample sizes, a dearth of vital samples from racial/ethnic minorities, and under-representation of Africans in genetic studies and in existing databases, Al-Hussein noted.

Genetic mutation linked to higher prostate cancer risk in African American families

more information:
Jason A. White et al, Whole-exome sequencing of Nigerian prostate tumors from the Trans-Atlantic Prostate Cancer Consortium (CaPTC) reveals DNA repair genes associated with African ancestry, Cancer Research Communications (2022). DOI: 10.1158 / 2767-9764.CRC-22-0136

the quote: Prostate tumor biology may be influenced by genetic origin (2022, September 19) Retrieved September 19, 2022 from

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