CDKN1B Deletions are Associated with Metastasis in African American Men with Clinically Localized, Surgically Treated Prostate Cancer

Farzana A. Faisal; Sanjana Murali; Harsimar Kaur; Thiago Vidotto; Liana B. Guedes; Daniela Correia Salles; Vishal Kothari; Jeffrey J. Tosoian; Sumin Han; Daniel H. Hovelson; Kevin Hu; Daniel E. Spratt; Alexander S. Baras; Scott A. Tomlins; Edward M. Schaeffer; Tamara L. Lotan

doi:10.1158/1078-0432.CCR-19-1669

CDKN1B Deletions are Associated with Metastasis in African American Men with Clinically Localized, Surgically Treated Prostate Cancer

Farzana A. Faisal, Sanjana Murali, Harsimar Kaur, Thiago Vidotto, Liana B. Guedes, Daniela Correia Salles, Vishal Kothari, Jeffrey J. Tosoian, Sumin Han, Daniel H. Hovelson, Kevin Hu, Daniel E. Spratt, Alexander S. Baras, Scott A. Tomlins, Edward M. Schaeffer, Tamara L. Lotan^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	2595-2602
Number of pages	8
Journal	Clinical Cancer Research
Volume	26
Issue number	11
DOIs	https://doi.org/10.1158/1078-0432.CCR-19-1669
State	Published - Jun 1 2020

Funding

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. 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.

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General Medicine

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10.1158/1078-0432.CCR-19-1669

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Faisal, F. A., Murali, S., Kaur, H., Vidotto, T., Guedes, L. B., Salles, D. C., Kothari, V., Tosoian, J. J., Han, S., Hovelson, D. H., Hu, K., Spratt, D. E., Baras, A. S., Tomlins, S. A., Schaeffer, E. M., & Lotan, T. L. (2020). CDKN1B Deletions are Associated with Metastasis in African American Men with Clinically Localized, Surgically Treated Prostate Cancer. Clinical Cancer Research, 26(11), 2595-2602. https://doi.org/10.1158/1078-0432.CCR-19-1669

@article{b11f62adf29e499e96431a4e263aad03,

title = "CDKN1B Deletions are Associated with Metastasis in African American Men with Clinically Localized, Surgically Treated Prostate Cancer",

abstract = "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.",

author = "Faisal, {Farzana A.} and Sanjana Murali and Harsimar Kaur and Thiago Vidotto and Guedes, {Liana B.} and Salles, {Daniela Correia} and Vishal Kothari and Tosoian, {Jeffrey J.} and Sumin Han and Hovelson, {Daniel H.} and Kevin Hu and Spratt, {Daniel E.} and Baras, {Alexander S.} and Tomlins, {Scott A.} and Schaeffer, {Edward M.} and Lotan, {Tamara L.}",

note = "Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

year = "2020",

month = jun,

day = "1",

doi = "10.1158/1078-0432.CCR-19-1669",

language = "English (US)",

volume = "26",

pages = "2595--2602",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "11",

}

Faisal, FA, Murali, S, Kaur, H, Vidotto, T, Guedes, LB, Salles, DC, Kothari, V, Tosoian, JJ, Han, S, Hovelson, DH, Hu, K, Spratt, DE, Baras, AS, Tomlins, SA, Schaeffer, EM & Lotan, TL 2020, 'CDKN1B Deletions are Associated with Metastasis in African American Men with Clinically Localized, Surgically Treated Prostate Cancer', Clinical Cancer Research, vol. 26, no. 11, pp. 2595-2602. https://doi.org/10.1158/1078-0432.CCR-19-1669

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.

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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UR - http://www.scopus.com/inward/citedby.url?scp=85085712446&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-19-1669

DO - 10.1158/1078-0432.CCR-19-1669

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AN - SCOPUS:85085712446

SN - 1078-0432

VL - 26

SP - 2595

EP - 2602

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 11

ER -

CDKN1B Deletions are Associated with Metastasis in African American Men with Clinically Localized, Surgically Treated Prostate Cancer

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