Subclonal Complete Loss of CDKN1B as a Common Genomic Alteration in Prostate Cancer: Associations with Race and Prostate Cancer Outcomes

2026 · doi:10.64898/2026.03.03.709424
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This study evaluated the prevalence of intratumoral (subclonal) complete loss of the p27 protein, using immunohistochemistry for p27 in a large cohort of primary radical prostatectomy tumors (n=412) and metastases, comparing self-identified African American and European American individuals, and integrating p27 CDKN1B mRNA in situ hybridization and sequencing of laser-captured cancer regions. Subclonal complete p27 loss was found in 18.1% of African American versus 12.2% of European American cases and was tightly correlated with CDKN1B mRNA loss and biallelic genomic loss. The authors report that complete p27 loss associated with more advanced pathologic features and, in univariate and multivariate Cox analyses, with biochemical recurrence and metastasis after primary treatment, particularly among African American participants, with a caveat that key significance of clinicopathologic associations was limited to that subgroup. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Background Homozygous biallelic inactivation of CDKN1B is thought to be rare in cancer. Herein we evaluate the prevalence of intratumoral (subclonal) complete p27 protein loss (IPPL) in primary prostate cancer. Experimental Design We used immunohistochemistry (IHC) for p27 in a large cohort of whole tissue sections from radical prostatectomy (n=412) and metastases from self-identified African American (AA) and European American (EA) individuals. IPPL was evaluated alongside CDKN1B mRNA in-situ hybridization and next generation sequencing of laser captured cancer regions. Cox proportional hazards analyses assessed the association of IPPL with biochemical recurrence and development of metastases after radical prostatectomy. Results IPPL was detected in 18.1% of AA versus 12.2% of EA cases and was tightly correlated with CDKN1B mRNA loss and biallelic genomic loss. IPPL was associated with ≥pT3 pathologic stage and pN1 disease, however these associations were only significant among AA participants. IPPL was further associated in both univariate and multivariate analyses with the development of biochemical recurrence and metastasis after primary treatment, specifically in AA individuals. The prevalence of p27 genomic alterations in metastatic disease is higher than that of primary prostate cancer in publicly available datasets as well as our analysis of autopsy cases via IHC, indicating that complete p27 loss may be selected for in metastatic disease. Conclusions Subclonal biallelic loss of CDKN1B resulting in complete p27 protein loss is one of the most commonly occurring biallelic tumor suppressor genomic alterations in primary prostate cancer, and could contribute to worse prostate cancer outcomes, specifically in AA males.
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Abstract

Background Homozygous biallelic inactivation of CDKN1B is thought to be rare in cancer. Herein we evaluate the prevalence of intratumoral (subclonal) complete p27 protein loss (IPPL) in primary prostate cancer. Experimental Design We used immunohistochemistry (IHC) for p27 in a large cohort of whole tissue sections from radical prostatectomy (n=412) and metastases from self-identified African American (AA) and European American (EA) individuals. IPPL was evaluated alongside CDKN1B mRNA in-situ hybridization and next generation sequencing of laser captured cancer regions. Cox proportional hazards analyses assessed the association of IPPL with biochemical recurrence and development of metastases after radical prostatectomy.

Results

IPPL was detected in 18.1% of AA versus 12.2% of EA cases and was tightly correlated with CDKN1B mRNA loss and biallelic genomic loss. IPPL was associated with ≥pT3 pathologic stage and pN1 disease, however these associations were only significant among AA participants. IPPL was further associated in both univariate and multivariate analyses with the development of biochemical recurrence and metastasis after primary treatment, specifically in AA individuals. The prevalence of p27 genomic alterations in metastatic disease is higher than that of primary prostate cancer in publicly available datasets as well as our analysis of autopsy cases via IHC, indicating that complete p27 loss may be selected for in metastatic disease.

Conclusions

Subclonal biallelic loss of CDKN1B resulting in complete p27 protein loss is one of the most commonly occurring biallelic tumor suppressor genomic alterations in primary prostate cancer, and could contribute to worse prostate cancer outcomes, specifically in AA males. Competing Interest Statement The authors have declared no competing interest. Footnotes Grant support: Prostate Cancer Foundation Challenge Award 19CHAS03; Department of Defense, Prostate Cancer Research Program (PCRP) Award W81XWH-17-1-0286; NIH R01 1R01CA288760 Conflicts of Interest: None

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