Overexpression of MUC1 and Genomic Alterations in Its Network Associate with Prostate Cancer Progression. |
| Authors: |
Lin, Xiaozeng Gu, Yan Kapoor, Anil Wei, Fengxiang Aziz, Tariq Ojo, Diane Jiang, Yanzhi Bonert, Michael Shayegan, Bobby Yang, Huixiang Al-Nedawi, Khalid Major, Pierre Tang, Damu
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| Citation: |
Lin X, etal., Neoplasia. 2017 Nov;19(11):857-867. doi: 10.1016/j.neo.2017.06.006. Epub 2017 Sep 18. |
| RGD ID: |
13504750 |
| Pubmed: |
PMID:28930697 (View Abstract at PubMed) |
| PMCID: |
PMC5605493 (View Article at PubMed Central) |
| DOI: |
DOI:10.1016/j.neo.2017.06.006 (Journal Full-text) |
We investigate the association of MUC1 with castration-resistant prostate cancer (CRPC), bone metastasis, and PC recurrence. MUC1 expression was studied in patient-derived bone metastasis and CRPCs produced by prostate-specific PTEN-/- mice and LNCaP xenografts. Elevations in MUC1 expression occur in CRPC. Among nine patients with hormone-naïve bone metastasis, eight express MUC1 in 61% to 100% of PC cells. Utilizing cBioPortal PC genomic data, we organized a training (n=300), testing (n=185), and validation (n=194) cohort. Using the Cox model, a nine-gene signature was derived, including eight genes from a MUC1-related network (APC, CTNNB1/ß-catenin, GALNT10, GRB2, LYN, SIGLEC1, SOS1, and ZAP70) and FAM84B. Genomic alterations in these genes reduce disease-free survival (DFS) in the training (P=.00161), testing (P=.00699), entire (training+testing, P=5.557e-5), and a validation cohort (P=3.326e-5). The signature independently predicts PC recurrence [hazard ratio (HR)=1.731; 95% confidence interval (CI): 1.104-2.712; P=.0167] after adjusting for known clinical factors and stratifies patients with high risk of PC recurrence using the median (HR 2.072; 95% CI: 1.245-3.450, P=.0051) and quartile 3 (HR 3.707, 95% CI: 1.949-7.052, P=6.51e-5) scores. Several novel ß-catenin mutants are identified in PCs leading to a rapid onset of death and recurrence. Genomic alterations in APC and CTNNB1/ß-catenin reduce DFS in two independent PC cohorts (n=485, P=.0369; n=84, P=.0437). The nine-gene signature also associates with reductions in overall survival (P=.0458) and DFS (P=.0163) in melanoma patients (n=367). MUC1 upregulation is associated with CRPC and bone metastasis. A nine-gene signature derived from a MUC1 network predicts PC recurrence.
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| Genes (Rattus norvegicus) |
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| Grb2 (growth factor receptor bound protein 2) |
| Genes (Mus musculus) |
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| Grb2 (growth factor receptor bound protein 2) |
| Genes (Homo sapiens) |
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| GRB2 (growth factor receptor bound protein 2) |
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