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 2

Gene-level sCNA landscape of primary prostate tumors by genetic ancestry.

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Gene-level sCNA landscape of primary prostate tumors by genetic ancestry...
Generalized linear models (GLM) were used to compare the genomic copy number landscape of prostate tumors (n = 290) based on percent African ancestry adjusted with Gleason Grade Group (GG1 and GG2 versus GG3, GG4, and GG5), age, and preoperative PSA levels after removing genes likely to represent gCNV based on analysis of benign colon tissue. (A) Overlap between loci with sCNA varying significantly by self-reported race or by percent African ancestry (FDR < 0.05). (B) Overlap between loci with copy number alteration varying by self-reported race in normal colon tissue (FDR < 0.001) versus prostate cancer by percent African ancestry. From the 237 genes significantly associated with percent African ancestry in the prostate cohort, 94 overlapped with regions found in the comparison between self-identified race in colon normal tissue (Supplemental Table 7). (C) Estimates from GLM for each locus shown by chromosome. Each dot represents an individual locus. Red dots show loci with sCNA that vary significantly by genetic ancestry in the GLM using FDR-adjusted P < 0.1, with 94 overlapping loci with colon limma models excluded from the figure, as they represent presumptive gCNV. (D) GLM P values on the y axis are distributed by chromosome in the x axis. For ease of visualization, labels are shown for a subset of coding loci with adjusted P < 0.01, with the complete list available in Supplemental Table 6. Previously described prostate cancer driver genes are indicated with red labels for reference (regardless of significance in model).