Determinants of widespread metastases and of metastatic tropism in patients with prostate cancer: A genomic analysis of primary and metastatic tumors Journal Article
| Authors: | Alshalalfa, M.; Goglia, A. G.; Swami, N.; Nguyen, B.; Hougen, H. Y.; Khan, A.; Kishan, A. U.; Punnen, S.; Nguyen, P. L.; Mahal, B. A.; Dee, E. C. |
| Article Title: | Determinants of widespread metastases and of metastatic tropism in patients with prostate cancer: A genomic analysis of primary and metastatic tumors |
| Abstract: | Introduction: Emerging evidence suggests that metastasis is better described as a spectrum of disease rather than a binary state. A greater understanding of the genomic features that determine extent and location of metastatic spread may inform risk stratification and monitoring. Here, we identify genomic alterations from primary prostate carcinomas that are predictive of wide-spread metastatic potential. Methods: Genomic and clinical data from 1,312 patients with primary prostate carcinoma were extracted from the MSK-MET cohort through cBioPortal. Metastatic site counts and overall survival (OS) data were publicly available and used as the primary outcomes. Primary tumor samples were profiled using the MSK-IMPACT targeted sequencing platform. We focused on 58 genes frequently altered in prostate cancer. Cox proportional hazard analyses defined hazard ratios (HRs) and 95% confidence intervals (CIs) for overall mortality in patients with different metastatic outcomes. Results: Out of the 1,312 patients in our cohort, 939 (71%) developed metastases, of whom 113 (8.6%) had metastases to 5 or more distinct anatomical sites (defining wide-spread metastases, WSM). Bone was the most common site of metastasis (36%), and 80% of patients with liver metastases had 4 or more additional sites of metastasis. Among patients with metastasis, increasing number of metastatic sites was associated with increased risk of death (HR: 1.8, 95%CI: 1.63–1.99, P < 0.001). Alterations in the following genes were enriched in tumors from patients with WSM vs. others: TP53 (40% vs. 20%, P < 0.0001), FOXA1-amplification (8% vs. 3%, P = 0.02), AR-amplification (4.4% vs. 1%, P = 0.01), RB1-deletion (5.3% vs. 0.7%, P = 0.001), and BRCA2-deletion (4.4% vs. 0.7%, P = 0.01). Univariable survival analysis showed all these alterations were predictive of OS (P < 0.05). On multivariable analysis, only TP53 mutations, and FOXA1 and AR amplifications were independent prognostic factors. FOXA1 (n = 37) and AR (n = 13) amplifications were mutually exclusive and patients with these experienced very poor OS (HR: 3.57, 95%CI:2.26–5.6, P < 0.001]. Conclusions: We identified genomic alterations (TP53 mutations, FOXA1/AR amplification, RB1/BRCA2 deletion) from primary prostate carcinomas that are predictive of wide-spread metastases and poor outcome. © 2023 Elsevier Inc. |
| Keywords: | adult; controlled study; survival analysis; primary tumor; gene sequence; major clinical study; overall survival; gene deletion; mutation; bone metastasis; hepatocyte nuclear factor 3alpha; gene amplification; cohort analysis; pathology; retrospective study; prediction; risk factor; cancer mortality; prostate cancer; prostatic neoplasms; tumor suppressor gene; liver metastasis; prostate tumor; carcinoma; genomics; metastasis potential; prostate carcinoma; cancer genomics; fatality; tropism; clinical outcome; rb1 gene; metastatic prostate cancer; humans; human; male; article; tumor-related gene; tumor suppressor p53 binding protein 1; foxa1-amplification; tp53-mutation; wide-spread metastasis |
| Journal Title: | Urologic Oncology: Seminars and Original Investigations |
| Volume: | 41 |
| Issue: | 5 |
| ISSN: | 1078-1439 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2023-05-01 |
| Start Page: | 253.e21 |
| End Page: | 253.e26 |
| Language: | English |
| DOI: | 10.1016/j.urolonc.2023.02.006 |
| PUBMED: | 37003878 |
| PROVIDER: | scopus |
| PMCID: | PMC10559314 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus |
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