TY - JOUR
T1 - CDKN1B Deletions are Associated with Metastasis in African American Men with Clinically Localized, Surgically Treated Prostate Cancer
AU - Faisal, Farzana A.
AU - Murali, Sanjana
AU - Kaur, Harsimar
AU - Vidotto, Thiago
AU - Guedes, Liana B.
AU - Salles, Daniela Correia
AU - Kothari, Vishal
AU - Tosoian, Jeffrey J.
AU - Han, Sumin
AU - Hovelson, Daniel H.
AU - Hu, Kevin
AU - Spratt, Daniel E.
AU - Baras, Alexander S.
AU - Tomlins, Scott A.
AU - Schaeffer, Edward M.
AU - Lotan, Tamara L.
N1 - Funding Information:
This work was supported by a Health Disparity Research Awards from the CDMRP-PCRP (W81XWH-15-1-0661 to S. Tomlins, E. Schaeffer, and T. Lotan); U01CA196390 (to E. Schaeffer), R01 CA183857 to S. Tomlins, the NIH/NCI Prostate SPOREs P50 CA58236, P50 CA186786-05 and P50 CA180995; and the NCI Cancer Center Support Grant 5P30CA006973-52. E. Schaeffer is also supported by Prostate Cancer Foundation and Polsky Urologic Cancer Institute. The authors would like to acknowledge the American Association for Cancer Research and its financial and material support in the development of the AACR Project GENIE registry, as well as members of the consortium for their commitment to data sharing. Interpretations are the responsibility of study authors.
Funding Information:
D.H. Hovelson is an employee/paid consultant for Strata Oncology. D.E. Spratt is an employee/paid consultant for Janssen, AstraZeneca, and Blue Earth. S.A. Tomlins is an employee/paid consultant for Strata Oncology, Astellas, Janssen, Almac Diagnostics, Sanofi, and Abbvie, reports receiving commercial research grants from Astellas, and holds a patent on ETS gene fusion, licensed to Hologic and Ventana. T.L. Lotan reports receiving commercial research grants from Ventana/Roche and GenomeDx. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Purpose: The potential biological determinants of aggressive prostate cancer in African American (AA) men are unknown. Here we characterize prostate cancer genomic alterations in the largest cohort to date of AA men with clinical follow-up for metastasis, with the aim to elucidate the key molecular drivers associated with poor prognosis in this population. Experimental Design: Targeted sequencing was retrospectively performed on 205 prostate tumors from AA men treated with radical prostatectomy (RP) to examine somatic genomic alterations and percent of the genome with copy-number alterations (PGA). Cox proportional hazards analyses assessed the association of genomic alterations with risk of metastasis. Results: At RP, 71% (145/205) of patients had grade group ≥3 disease, and 49% (99/202) were non–organ confined. The median PGA was 3.7% (IQR = 0.9%–9.4%) and differed by pathologic grade (P < 0.001) and stage (P = 0.02). Median follow-up was 5 years. AA men with the highest quartile of PGA had increased risks of metastasis (multivariable: HR = 13.45; 95% CI, 2.55–70.86; P = 0.002). The most common somatic mutations were SPOP (11.2%), FOXA1 (8.3%), and TP53 (3.9%). The most common loci altered at the copy number level were CDKN1B (6.3%), CHD1 (4.4%), and PTEN (3.4%). TP53 mutations and deep deletions in CDKN1B were associated with increased risks of metastasis on multivariable analyses (TP53: HR = 9.5; 95% CI, 2.2–40.6; P = 0.002; CDKN1B: HR = 6.7; 95% CI, 1.3–35.2; P = 0.026). Conclusions: Overall, PGA, somatic TP53 mutations, and a novel finding of deep deletions in CDKN1B were associated with poor prognosis in AA men. These findings require confirmation in additional AA cohorts.
AB - Purpose: The potential biological determinants of aggressive prostate cancer in African American (AA) men are unknown. Here we characterize prostate cancer genomic alterations in the largest cohort to date of AA men with clinical follow-up for metastasis, with the aim to elucidate the key molecular drivers associated with poor prognosis in this population. Experimental Design: Targeted sequencing was retrospectively performed on 205 prostate tumors from AA men treated with radical prostatectomy (RP) to examine somatic genomic alterations and percent of the genome with copy-number alterations (PGA). Cox proportional hazards analyses assessed the association of genomic alterations with risk of metastasis. Results: At RP, 71% (145/205) of patients had grade group ≥3 disease, and 49% (99/202) were non–organ confined. The median PGA was 3.7% (IQR = 0.9%–9.4%) and differed by pathologic grade (P < 0.001) and stage (P = 0.02). Median follow-up was 5 years. AA men with the highest quartile of PGA had increased risks of metastasis (multivariable: HR = 13.45; 95% CI, 2.55–70.86; P = 0.002). The most common somatic mutations were SPOP (11.2%), FOXA1 (8.3%), and TP53 (3.9%). The most common loci altered at the copy number level were CDKN1B (6.3%), CHD1 (4.4%), and PTEN (3.4%). TP53 mutations and deep deletions in CDKN1B were associated with increased risks of metastasis on multivariable analyses (TP53: HR = 9.5; 95% CI, 2.2–40.6; P = 0.002; CDKN1B: HR = 6.7; 95% CI, 1.3–35.2; P = 0.026). Conclusions: Overall, PGA, somatic TP53 mutations, and a novel finding of deep deletions in CDKN1B were associated with poor prognosis in AA men. These findings require confirmation in additional AA cohorts.
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U2 - 10.1158/1078-0432.CCR-19-1669
DO - 10.1158/1078-0432.CCR-19-1669
M3 - Article
C2 - 31969336
AN - SCOPUS:85085712446
SN - 1078-0432
VL - 26
SP - 2595
EP - 2602
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 11
ER -