MP66-10 CHARACTERIZATION OF SUSCEPTIBILITY LOCI IN HEREDITARY PROSTATE CANCER FAMILIES USING COPY NUMBER VARIATION AND LINKAGE ANALYSIS

232 Background: Family history is one of the most significant predictor of prostate cancer risk. With approximately 10% of prostate cancer cases attributable to inheritable genetic factors. However, disease gene identification for prostate cancer has been extremely challenging due to both disease and genetic heterogeneity. Therefore, the goal of this study was to employ an array of genetic tools in order to characterize germline variants in seven high-risk families with prostate cancer. Methods: To overcome the effects of ethnic disparity, genetic heterogeneity, incomplete penetrance, and missing heritability, we utilized a comprehensive approach that combines both array comparative genomic hybridization (aCGH) analysis and linkage analysis to identify genetic components of prostate cancer. Seven prostate cancer cases were studied using aCGH to search for germ-line copy number variants (CNVs) associated with hereditary prostate cancer. The study subjects were from 7 large, high-risk, clinically homogenous families with European ancestry from Southern Louisiana. Genotyping for linkage analyses was done using Illumina Infinium II SNP HumanLinkage-12 panel. Results: Three novel regions of CNVs were identified: 16q23, 11q22, and 2q22 in all 7 prostate cancer cases from high-risk families. Both model-based and model-free linkage analyses were performed on 4 of the most informative families (≥5 prostate cancer patients per family). Suggestive evidence of linkage was obtained at 2q14 (HLOD score of 1.94). Using aCGH, a 68 kb duplication was observed in this region in all 7 hereditary prostate cancer cases. Conclusions: These genetic findings, which were identified in multiple large, well-characterized families, provide new insight into hereditary prostate cancer. A combination of future fine mapping of the 2q14 region in a larger cohort of patients, confirmation of these novel CNVs in additional subjects, and use of next-generation sequencing approaches to search for potential disease-associated genetic alterations are needed to provide further characterization of these prostate cancer associated susceptibility loci.

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Characterization of germline copy number variation in high-risk African American families with prostate cancer

The Prostate ◽

10.1002/pros.22602 ◽

2012 ◽

Vol 73 (6) ◽

pp. 614-623 ◽

Cited By ~ 16

Author(s):

Elisa M. Ledet ◽

Xiaofeng Hu ◽

Oliver Sartor ◽

Walter Rayford ◽

Marilyn Li ◽

...

Keyword(s):

Prostate Cancer ◽

African American ◽

High Risk ◽

Copy Number Variation ◽

Copy Number ◽

African American Families ◽

Number Variation ◽

American Families

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High copy number variations, particular transcription factors, and low immunity contribute to the stemness of prostate cancer cells

Journal of Translational Medicine ◽

10.1186/s12967-021-02870-x ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Zao Dai ◽

Ping Liu

Keyword(s):

Prostate Cancer ◽

Transcription Factors ◽

Copy Number Variation ◽

Cancer Cells ◽

Immune Cells ◽

Copy Number ◽

Tumor Metastasis ◽

Prostate Cancer Cells ◽

Immune Microenvironment ◽

Number Variation

Abstract Background Tumor metastasis is the main cause of death of cancer patients, and cancer stem cells (CSCs) is the basis of tumor metastasis. However, systematic analysis of the stemness of prostate cancer cells is still not abundant. In this study, we explore the effective factors related to the stemness of prostate cancer cells by comprehensively mining the multi-omics data from TCGA database. Methods Based on the prostate cancer transcriptome data in TCGA, gene expression modules that strongly relate to the stemness of prostate cancer cells are obtained with WGCNA and stemness scores. Copy number variation of stemness genes of prostate cancer is calculated and the difference of transcription factors between prostate cancer and normal tissues is evaluated by using CNV (copy number variation) data and ATAC-seq data. The protein interaction network of stemness genes in prostate cancer is constructed using the STRING database. Meanwhile, the correlation between stemness genes of prostate cancer and immune cells is analyzed. Results Prostate cancer with higher Gleason grade possesses higher cell stemness. The gene set highly related to prostate cancer stemness has higher CNV in prostate cancer samples than that in normal samples. Although the transcription factors of stemness genes have similar expressions, they have different contributions between normal and prostate cancer tissues; and particular transcription factors enhance the stemness of prostate cancer, such as PUM1, CLOCK, SP1, TCF12, and so on. In addition, the lower tumor immune microenvironment is conducive to the stemness of prostate cancer. CD8 + T cells and M1 macrophages may play more important role in the stemness of prostate cancer than other immune cells in the tumor microenvironment. Finally, EZH2 is found to play a central role in stemness genes and is negatively correlated with resting mast cells and positively correlated with activated memory CD4 + T cells. Conclusions Based on the systematic and combined analysis of multi-omics data, we find that high copy number variation, specific transcription factors, and low immune microenvironment jointly contribute to the stemness of prostate cancer cells. These findings may provide us new clues and directions for the future research on stemness of prostate cancer.

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