Elsevier

European Urology

Volume 78, Issue 5, November 2020, Pages 671-679
European Urology

Platinum Priority – Prostate Cancer
Editorial by XXX on pp. x–y of this issue
Pan-cancer Analysis of CDK12 Alterations Identifies a Subset of Prostate Cancers with Distinct Genomic and Clinical Characteristics

https://doi.org/10.1016/j.eururo.2020.03.024Get rights and content

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.

Introduction

Genomic alterations in CDK12 have been observed in various cancer types [1], [2], [3], [4] but their oncogenic function and clinical relevance are poorly understood. CDK12 encodes a cyclin-dependent serine/threonine kinase involved in the regulation of the cell cycle and of DNA repair by homologous recombination (HR). Specifically, it has been shown that CDK12 loss of function suppresses the expression of several HR genes, at least in part, via intronic polyadenylation [5], [6], [7], [8]. Growing evidence suggests that biallelic CDK12 loss determines a distinct phenotype of ovarian and prostate cancer characterized by high genomic instability and tandem duplications [9], [10], [11].

It has been reported that CDK12 alterations occur in 4–11% of prostate cancer cases and are more frequent in the metastatic castration-resistant setting (mCRPC) [3], [9], [12]. Despite preclinical work suggesting that CDK12 loss or inhibition could impair genes in the HR repair pathway, recent evidence has shown that PARP inhibitors have limited efficacy in mCRPC patients harboring a CDK12 alteration [13], [14]. However, Wu and colleagues [9] recently demonstrated that CDK12 loss determines a novel molecular subtype of prostate cancer associated with a higher proportion of fusion neoantigens and potentially high immune infiltration and response to anti–PD1/PD-L1 agents.

In this study we sought to survey the landscape of CDK12 mutations across different cancer types. We identified prostate cancer as the cancer type with the highest prevalence of CDK12 oncogenic alterations and the largest proportion of truncating variants, with biallelic inactivation occurring frequently, and characterized the genomic architecture of CDK12-altered prostate carcinomas. We describe clinicopathologic characteristics and clinical outcomes for patients with prostate cancers harboring CDK12 alterations. Our work adds to recent publications [15], [16] by integrating pan-cancer genomic analysis from a clinical sequencing assay, identifying distinct genomic alterations associated with CDK12-altered prostate cancer, and describing clinical features of the largest set of prostate cancer patients with CDK12 alterations identified using a single assay.

Section snippets

Study design and patients

All patients in the study underwent tumor sequencing performed using the Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets (MSK-IMPACT) clinical sequencing assay, a hybridization capture-based, next-generation sequencing platform, with 341, 410, or 468 genes (all panels included CDK12) [17], [18]. After excluding 1965 cases with high microsatellite instability (MSI) cases, defined as an MSI sensor [19] score >10, and/or high tumor mutation burden (TMB) cases,

Landscape of CDK12 alterations across cancer types

We assessed the prevalence of CDK12 alterations among 26743 patients across 25 solid cancer types profiled using the MSK-IMPACT clinical sequencing test. A total of 404 patients (1.5%) had tumors with at least one CDK12 alteration. Prostate (n = 100/1875, 5.3%) and ovarian (n = 43/1034, 4.2%) cancers were the types with the highest frequencies of CDK12 oncogenic alterations (Fig. 1A), including somatic point mutations, rearrangements, and deep deletions. Using MutSigCV [22], we found that CDK12 was

Discussion

We analyzed the prevalence and types of somatic CDK12 alterations across >26000 tumors spanning 25 cancer types and found that prostate and ovarian cancers were the malignancies with the highest prevalence of CDK12 alterations, similar to a recent report [15]. The overall prevalence of CDK12 alterations in prostate cancer was 5.3%, which falls within the previously reported range [3], [15]. The majority of CDK12 alterations in these cancers were oncogenic and clonal and resulted in biallelic

Conclusions

In summary, our results suggest that CDK12 loss of function defines a distinct subset of disease associated with unique genomic alterations and somewhat worse clinical outcomes, and highlights the need for novel therapies targeting CDK12-altered prostate cancer.


Author contributions: Wassim Abida had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Nguyen, Mota, Nandakumar, Gopalan,

CRediT authorship contribution statement

Bastien Nguyen: Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing - original draft, Writing - review & editing. Jose Mauricio Mota: Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review & editing. Subhiksha Nandakumar: Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing - review & editing. Konrad H. Stopsack: Methodology, Validation, Writing - review & editing. Emily Weg: Writing -

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      Citation Excerpt :

      Alterations in the CDK12 genome have been observed in various cancers, but little is known about its oncogenic function and clinical relevance. A large number of clinical studies have found that among the tumors caused by CDK12 mutations, prostate cancer, colon cancer, and ovarian cancer are the most common [62–65]. Analysis of metastatic castration-resistant prostate cancer (mCRPC) samples identified a new subtype of prostate cancer caused by biallelic deletion of CDK12 [66].

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