Pan-cancer analysis of CDK12 alterations identifies a subset of prostate cancers with distinct genomic and clinical characteristics Journal Article


Authors: Nguyen, B.; Mota, J. M.; Nandakumar, S.; Stopsack, K. H.; Weg, E.; Rathkopf, D.; Morris, M. J.; Scher, H. I.; Kantoff, P. W.; Gopalan, A.; Zamarin, D.; Solit, D. B.; Schultz, N.; Abida, W.
Article Title: Pan-cancer analysis of CDK12 alterations identifies a subset of prostate cancers with distinct genomic and clinical characteristics
Abstract: Background: CDK12 genomic alterations occur in several tumor types, but little is known about their oncogenic role and clinical significance. Objective: To describe the landscape of CDK12 alterations across solid cancers and the clinical features of CDK12-altered prostate cancer. Design, setting, and participants: A single-center retrospective study of 26743 patients across 25 solid tumor types who underwent tumor sequencing was performed. Clinicopathologic features and outcomes were assessed in prostate cancer. Outcome measurements and statistical analysis: CDK12 alterations and their association with genomic characteristics are described. For prostate cancer patients, overall survival and time to castration resistance were assessed using univariable and multivariable Cox regression analysis. Results and limitations: CDK12 alterations were identified in 404/26743 patients (1.5%) overall, but were most frequent in prostate (100/1875, 5.3%) and ovarian cancer (43/1034, 4.2%), in which they were associated with a high prevalence of truncating variants and biallelic inactivation. CDK12 alterations defined a genomic subtype of prostate cancer with a unique copy-number alteration profile and involvement of distinct oncogenic pathway alterations, including cell-cycle pathway genes. CDK12-altered prostate cancer was associated with somewhat more aggressive clinical features and shorter overall survival (median 64.4 vs 74.9 mo; p = 0.032) independent of standard clinical factors and tumor copy-number alteration burden (adjusted hazard ratio 1.80, 95% confidence interval 1.12–2.89; p = 0.024). The study is limited by its retrospective nature. Conclusions: CDK12 alteration is a rare event across solid cancers but defines a clinically distinct molecular subtype of prostate cancer associated with unique genomic alterations and slightly more aggressive clinical features. Patient summary: CDK12 gene alterations occur rarely across tumor types, but more frequently in prostate cancer, where they are associated with genomic instability, cell-cycle pathway gene alterations, and somewhat worse clinical outcomes, warranting further investigation of therapeutic targeting of this disease subset. CDK12 genomic alterations occur across solid tumors but are most frequent in prostate cancer, where they define a disease subset characterized by a unique pattern of genomic alterations and slightly worse clinical outcomes. These features warrant novel investigational therapeutic approaches. © 2020 European Association of Urology
Keywords: protein kinase b; adult; cancer survival; aged; tumor biology; unclassified drug; gene mutation; gene sequence; major clinical study; overall survival; somatic mutation; gene deletion; missense mutation; clinical feature; cancer patient; pancreas cancer; follow up; glioma; endometrium cancer; colorectal cancer; cell cycle; gastrointestinal stromal tumor; melanoma; ovary cancer; breast cancer; hepatocyte nuclear factor 3alpha; transforming growth factor beta; prevalence; genetic association; notch receptor; medical record review; retrospective study; bladder cancer; phosphatidylinositol 3 kinase; protein p53; renal cell carcinoma; carcinogenesis; cancer hormone therapy; prostate cancer; gleason score; gene rearrangement; clonal variation; human genome; myc protein; protein mcl 1; enzyme inactivation; mesothelioma; soft tissue sarcoma; genomics; ras protein; thyroid cancer; heterozygosity loss; cancer of unknown primary site; salivary gland cancer; abiraterone acetate; gene dosage; point mutation; cyclin d1; cyclin dependent kinase; beta catenin; germ cell tumor; uterus sarcoma; bone cancer; small cell lung cancer; castration resistant prostate cancer; appendix cancer; non small cell lung cancer; molecular pathology; abiraterone; clinical outcome; hepatobiliary system cancer; transcription factor nrf2; fibroblast growth factor 4; enzalutamide; human; male; female; priority journal; article; cdk12; hippo signaling; solid malignant neoplasm; tgf beta signaling; clinical sequencing; cyclin dependent kinase 12; fibroblast growth factor 19; fibroblast growth factor 3; protein kinase mer
Journal Title: European Urology
Volume: 78
Issue: 5
ISSN: 0302-2838
Publisher: Elsevier Science, Inc.  
Date Published: 2020-11-01
Start Page: 671
End Page: 679
Language: English
DOI: 10.1016/j.eururo.2020.03.024
PUBMED: 32317181
PROVIDER: scopus
PMCID: PMC7572747
DOI/URL:
Notes: Article -- Export Date: 2 November 2020 -- Source: Scopus
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MSK Authors
  1. Michael Morris
    582 Morris
  2. David Solit
    780 Solit
  3. Dmitriy Zamarin
    201 Zamarin
  4. Anuradha Gopalan
    417 Gopalan
  5. Dana Elizabeth Rathkopf
    275 Rathkopf
  6. Howard Scher
    1130 Scher
  7. Wassim Abida
    157 Abida
  8. Nikolaus D Schultz
    491 Schultz
  9. Emily Steinberger Weg
    12 Weg
  10. Philip Wayne Kantoff
    198 Kantoff
  11. Bastien Nguyen
    31 Nguyen
  12. Jose Mauricio Mota
    13 Mota