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Molecular Cancer Research
Molecular Cancer Research
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Cancer “-omics”

Distinct Genomic Alterations in Prostate Tumors Derived from African American Men

Wennuan Liu, S. Lilly Zheng, Rong Na, Lin Wei, Jishan Sun, Johnie Gallagher, Jun Wei, W. Kyle Resurreccion, Sarah Ernst, Karen S. Sfanos, William B. Isaacs and Jianfeng Xu
Wennuan Liu
1Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois.
2Departments of Surgery, NorthShore University HealthSystem, Evanston, Illinois.
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  • ORCID record for Wennuan Liu
S. Lilly Zheng
1Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois.
2Departments of Surgery, NorthShore University HealthSystem, Evanston, Illinois.
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Rong Na
1Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois.
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Lin Wei
1Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois.
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Jishan Sun
1Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois.
2Departments of Surgery, NorthShore University HealthSystem, Evanston, Illinois.
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Johnie Gallagher
1Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois.
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Jun Wei
1Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois.
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W. Kyle Resurreccion
1Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois.
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Sarah Ernst
3Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.
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Karen S. Sfanos
3Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.
4Department of Urology and Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland.
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William B. Isaacs
4Department of Urology and Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland.
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Jianfeng Xu
1Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois.
2Departments of Surgery, NorthShore University HealthSystem, Evanston, Illinois.
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  • For correspondence: u@northshore.org
DOI: 10.1158/1541-7786.MCR-20-0648 Published December 2020
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Abstract

We aim to understand, from acquired genetic alterations in tumors, why African American (AA) men are more likely to develop aggressive prostate cancer. By analyzing 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 (CNA) in prostate cancer in a total of 171 AA/black men and comparing with those in 860 European American (EA)/white men, we here present several novel findings. First, >35% of AA men harbor damaging mutations in APC, ATM, BRCA2, KDM6A, KMT2C, KMT2D, MED12, ZFHX3, and ZMYM3, each with >1% of mutated copies. Second, among genes with >10% of mutated copies in tumor cells, ZMYM3 is the most frequently mutated gene in AA prostate cancer. In a patient's tumor with >96% frameshift mutations of ZMYM3, we find allelic imbalances in 10 chromosomes, including losses of five and gains of another four chromosomes, suggesting its role in maintaining genomic integrity. Third, when compared to prostate cancer in EA/white men, a higher frequency of CNAs of MYC, THADA, NEIL3, LRP1B, BUB1B, MAP3K7, BNIP3L and RB1, and a lower frequency of deletions of RYBP, TP53, and TMPRSS2-ERG are observed in AA/black men. Finally, for the above genes with higher frequency of CNAs in AA than in EA, deletion of MAP3K7, BNIP3L, NEIL3 or RB1, or gain of MYC significantly associates with both higher Gleason grade and advanced pathologic stage in AA/black men. Deletion of THADA associates with advanced pathologic stage only.

Implications: A higher frequency of damaging mutation in ZMYM3 causing genomic instability along with higher frequency of altered genomic regions including deletions of MAP3K7, BNIP3L, RB1, and NEIL3, and gain of MYC appear to be distinct somatically acquired genetic alterations that may contribute to more aggressive prostate cancer in AA/black men.

This article is featured in Highlights of This Issue, p. 1757

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2020;18:1815–24

  • Received July 23, 2020.
  • Revision received August 11, 2020.
  • Accepted August 26, 2020.
  • Published first October 28, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 18 (12)
December 2020
Volume 18, Issue 12
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Distinct Genomic Alterations in Prostate Tumors Derived from African American Men
Wennuan Liu, S. Lilly Zheng, Rong Na, Lin Wei, Jishan Sun, Johnie Gallagher, Jun Wei, W. Kyle Resurreccion, Sarah Ernst, Karen S. Sfanos, William B. Isaacs and Jianfeng Xu
Mol Cancer Res December 1 2020 (18) (12) 1815-1824; DOI: 10.1158/1541-7786.MCR-20-0648

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Distinct Genomic Alterations in Prostate Tumors Derived from African American Men
Wennuan Liu, S. Lilly Zheng, Rong Na, Lin Wei, Jishan Sun, Johnie Gallagher, Jun Wei, W. Kyle Resurreccion, Sarah Ernst, Karen S. Sfanos, William B. Isaacs and Jianfeng Xu
Mol Cancer Res December 1 2020 (18) (12) 1815-1824; DOI: 10.1158/1541-7786.MCR-20-0648
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