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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, pre-operative PSA, and 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, pre-operative PSA levels, and Grade Group revealed that chromosome 8q gains (including MYC) were significantly associated with biochemical recurrence and metastasis, independent of genetic ancestry. Finally, regulatory T-cell 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 regulatory T-cell infiltrate varies by global sCNA burden in primary disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221219 | GEO | 2023/05/31

REPOSITORIES: GEO

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Project description:Many human cancers present as multi-focal lesions. Understanding the clonal origin of multi-focal cancers is of both etiological and clinical importance. The molecular basis of multi-focal prostate cancer has previously been explored using only a limited number of isolated markers and, although independent origin is widely believed, the clonal origin of multi-focal prostate cancer is still debatable. We attempted to address clonal origin using a genome-wide copy-number analysis of individual cancer and high-grade prostatic intraepithelial neoplasia (HGPIN) lesions. Using Affymetrix array 6.0 copy-number analysis, we compared the genomic changes detected in 54 individual cancer and HGPIN lesions, isolated from 20 clinically localized prostate cancer cases. Identical genomic copy-number changes, shared by all same-case cancer foci, were detected in all 16 informative multi-tumor cases. In addition, both HGPIN lesions in the two multi-HGPIN cases available shared identical genomic changes. Commonly known genomic alterations, including losses at 6q15, 8p21.3-8p21.2, 10q23.2-10q23.31, 13q21.31-13q21.32, 16q22.3, 16q23.2-16q23.3 and 21q22.2-21q22.3 regions and gain of 8q24.3 were the most frequently detected changes in this multi-focal prostate cancer study, occurring in all same-case foci in at least one case. Microarray data were confirmed by fluorescence in situ hybridization in selected foci. Our high-resolution genome-wide copy-number data suggest that many multi-focal cases derive from a single prostate cancer precursor clone and that this precursor may give rise to separate HGPIN foci, which through clonal expansion may progress to multi-focal invasive prostate cancer. These findings, which demonstrate the monoclonal origin of multi-focal prostate cancer, should significantly enhance our understanding of prostate carcinogenesis and potentially improve clinical management of the disease. Copy number analysis of Affymetrix SNP 6.0 array was performed for a total of 48 cancer and HGPIN lesions from 18 prostate cancer cases. All samples have case-matched normal controls. PL = high grade PIN from left side, PR = high grade PIN from right side, PM = high grade PIN from middle of the tissue, TL = tumour from left side, TR = tumour from right side.

Project description:The incidence of oesophageal adenocarcinoma (OeC) has been increasing rapidly in most Western countries during the last few decades. Although multimodal treatment combining pre-operative chemotherapy with radical surgical resection has become the standard of care in the UK for all patients with locally advanced resectable disease, the 5-year survival rate in this patient group is less than 25%. Only 30% of all patients will benefit from pre-operative chemotherapy. Hence, there is an urgent clinical need to identify genomic markers that allow stratification of patients for a more individualised therapy approach. The goal of this study is to use whole genome high-resolution array CGH to examine the DNA copy number profile of a subset of OeC patients recruited into the OE02 trial and establish it’s relationship with clinicopathological variables including pathological tumor regression and patient survival. High-resolution array CGH analysis was conducted on 84 formalin fixed paraffin embedded resection samples obtained from subjects enrolled in the Oe02 trial. We compared the DNA copy number profiles between patients treated with chemotherapy and surgery and those treated with surgery alone. DNA copy number entropy was assessed to identify differences in overall copy number aberrations between the two treatment groups. Furthermore, the association between DNA copy number aberrations and tumor regression grade was investigated. The genetic make-up of OeCs investigated in the current study proved to be highly complex reducing our ability to determine the background normal copy number level in a tumor sample. Using DNA copy number entropy as a measure to compare sample profiles, we identified significant treatment arm specific DNA copy number aberration patterns predominantly in chromosome 1 and 5. High DNA copy number entropy was associated with longer overall survival. Differential DNA copy number entropy was observed between the two treatment groups, and the positions of the driving DNA regions were identified. To our surprise, the differences between the treatment groups went unnoticed when a standard test was applied. We also found that the DNA copy number entropy was strongly correlated with patients’ overall survival and clinicopathological characteristics. To the best of our knowledge, this is the first study in OeC quantitatively showed that the tumor heterogeneity was reduced by chemotherapy. And, the observed tumor heterogeneity was shown to has prognostic value. However, further research is needed to narrow down these regions to a few driving genes/probes that may aid in predicting whether a new patient will benefit from chemotherapy.

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

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