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  • br the highest IG score Other

    2022-07-25


    the highest IG score. Other subsets such as PTEN mutation, ETV4 fusion, and SPOPL CNA also ranked high with regard to IG score but were not considered as important as PTEN CNA.
    Tumors with wild type and those with PTEN Ac-YVAD-CMK showed considerable differences between high- and low-heterogeneity groups (P = .0027; Fisher's exact test) (Figure 3B). Interestingly, PCs with PTEN deletion possessed an overwhelmingly large proportion of multiclone tumors. Based on this result, we think that the PTEN deletion is one of the key markers associated with ITH.
    We also analyzed the clonality among diploid, homozygous, and heterozygous PTEN deletion (Figure 3C). Our analysis revealed that multiclone PCs are notably enriched in heterozygous PTEN deletion compared to diploid or homozygous deletion (P = .001). In some 
    types of PCs, PTEN heterozygous and homozygous deletions have different characteristics such as Gleason score [14], and our study suggested different ITH patterns in the two studied groups. However, further clinical and biological investigation is warranted.
    Functional Enrichment of Tumors with PTEN Deletion and ITH
    PTEN CNA was positively correlated with mRNA expression (Figure 4A). As expected, the gene expression of genes with homozygous and heterozygous PTEN deletion was lower than that with diploid and gain. Moreover, we studied the kinds of genes differentially affecting clonality according to PTEN deletion. In order to identify genes associated with both PTEN deletion and clonality, we extracted DEGs for six possible combinations for PTEN deletion
    Figure 2. Correlations between ITH and several factors in prostate cancer samples. (A) Bar plot of average PSA values according to number of clones. (B) Box plot of TMB according to number of clones. (C) Box plot of contribution scores of CD8 T-cell signature according to number of clones.
    46 Tumor Heterogeneity in Prostate Cancer Yun et al. Translational Oncology Vol. 12, No. 1, 2019
    Table 1. Demographic and Clinical Characteristics of Prostate Cancer Patients
    Characteristic Oligoclone (n = 35) Multiclone (n = 50) P Value
    Tumor cellularity (pathology)
    Pathologic stage
    Ethnicity
    (+ and −) and clonality (oligo and multi). Among them, only two combinations had significantly differentially expressed genes (Figure 4B). One was the test for PTEN Del (+) & multiclone vs. PTEN Del (−) & oligoclone. The other was the test for PTEN Del (+) & multiclone vs. PTEN Del (−) & multiclone. Several differently expressed genes such as PTEN, CDC42EP5, RNLS, GP2, NETO2, and AMPD3 were correlated with tumor heterogeneity in the presence of PTEN deletion (≥2-fold 
    change, adjusted P value b.05). In other words, high heterogeneity of a tumor with PTEN deletion may be dominantly driven by the expression of those genes.
    According to previous studies, several pathways such as WNT, PI3CA, and androgen receptor signaling are known to regulate the progression of prostate cancer [15]. Particularly, the PI3CA pathway was significantly affected by tumor heterogeneity (Figure 4, C and D). It is assumed that the altered PI3CA pathway is closely related to higher ITH with PTEN deletion.
    Discussion
    In this study, we presented genomic and transcriptomic factors associated with the degree of ITH. Deletion of PTEN tumor suppressor gene occurs at high frequency in prostate cancer and is associated with clinical outcome and aggressive metastatic potential [16,17]. Although many studies regarding PTEN deletion in prostate cancer have been reported, the association with ITH has not been clarified. We demonstrated that it was frequently observed in tumors with high heterogeneity. It is still questionable whether the alteration of PTEN directly or indirectly causes tumor heterogeneity during prostate cancer progression.
    Previous studies have reported that most PTEN deletions of primary tumors were concordantly found in metastatic sites [5,6,18]. It is highly possible that PTEN deletions are early occurring mutations as they tend to be observed in multiple lesions. A study on ERG rearrangements and PTEN deletions in prostate cancer indicated that they are early events during tumor progression [14]. That prior study has reported that PTEN heterozygous deletions showed higher frequency than homozygous deletions in diverse tissues obtained from benign prostate tissue to high-grade prostatic intraepithelial neoplasia and prostate cancer. In our study, both types