Association of self-identified race and genetic ancestry with the immunogenomic landscape of primary prostate cancer
Thiago Vidotto, Eddie L. Imada, Farzana Faisal, Sanjana Murali, Adrianna A. Mendes, Harsimar Kaur, Siqun Zheng, Jianfeng Xu, Edward M. Schaeffer, William B. Isaacs, Karen S. Sfanos, Luigi Marchionni, Tamara L. Lotan
Thiago Vidotto, Eddie L. Imada, Farzana Faisal, Sanjana Murali, Adrianna A. Mendes, Harsimar Kaur, Siqun Zheng, Jianfeng Xu, Edward M. Schaeffer, William B. Isaacs, Karen S. Sfanos, Luigi Marchionni, Tamara L. Lotan
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Research Article Genetics

Association of self-identified race and genetic ancestry with the immunogenomic landscape of primary prostate cancer

Abstract

The genomic and immune landscapes of prostate cancer differ by self-identified race. However, few studies have examined the genome-wide copy number landscape and immune content of matched cohorts with genetic ancestry data and clinical outcomes. Here, we assessed prostate cancer somatic copy number alterations (sCNA) and tumor immune content of a grade-matched, surgically treated cohort of 145 self-identified Black (BL) and 145 self-identified White (WH) patients with genetic ancestry estimation. A generalized linear model adjusted with age, preoperative prostate-specific antigen (PSA), and Gleason Grade Group and filtered for germline copy number variations (gCNV) identified 143 loci where copy number varied significantly by percent African ancestry, clustering on chromosomes 6p, 10q, 11p, 12p, and 17p. Multivariable Cox regression models adjusted for age, preoperative PSA levels, and Gleason Grade Group revealed that chromosome 8q gains (including MYC) were significantly associated with biochemical recurrence and metastasis, independent of genetic ancestry. Finally, Treg density in BL and WH patients was significantly correlated with percent genome altered, and these findings were validated in the TCGA cohort. Taken together, our findings identify specific sCNA linked to genetic ancestry and outcome in primary prostate cancer and demonstrate that Treg infiltration varies by global sCNA burden in primary disease.

Authors

Thiago Vidotto, Eddie L. Imada, Farzana Faisal, Sanjana Murali, Adrianna A. Mendes, Harsimar Kaur, Siqun Zheng, Jianfeng Xu, Edward M. Schaeffer, William B. Isaacs, Karen S. Sfanos, Luigi Marchionni, Tamara L. Lotan

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Figure 3

Chromosome 8q gains are significantly associated with risk of prostate cancer metastasis independent of ancestry.

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Chromosome 8q gains are significantly associated with risk of prostate c...
Cox regression model adjusted with percent African ancestry, age, preoperative PSA, and tumor Gleason Grade Group (GG1 and GG2 versus GG3, GG4, and GG5) was applied to all samples from our cohort (n = 290) and showed significant associations between 8q gains and metastasis. (A) Hazard ratio shown by chromosome. Each dot represents an individual locus. Red dots indicate loci where sCNA are significantly associated with risk of metastasis using FDR-adjusted P < 0.1). (B) P values on the y axis are distributed by chromosome in the x axis. For visualization purposes, only a subset of coding genes are labeled; however, the complete list is available in Supplemental Table 9. Previously described prostate cancer driver genes are indicated with red labels for reference (regardless of significance in model). (C–E) MYC gains (>2 copies) are associated with prostate cancer metastasis in Kaplan-Meier analysis. Log-rank test was employed to identify the association between MYC gains and metastasis. (C) All patients (n = 282). (D) BL patients (n = 142). (E) WH patients (n = 140).