Analysis of CDK12 alterations in a pan-cancer database.
biomarkers
cancer genetics
clinical cancer research
genomics
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
revised:
13
10
2021
received:
08
08
2021
accepted:
19
11
2021
pubmed:
14
12
2021
medline:
19
4
2022
entrez:
13
12
2021
Statut:
ppublish
Résumé
CDK12 inactivation leading to increased neoantigen burden has been hypothesized to sensitize tumors to immune checkpoint inhibition. Pan-cancer data regarding the frequency of CDK12 alterations are limited. We aimed to characterize CDK12 alterations across all cancer types through real-world clinical-grade sequencing. This was a single-center retrospective analysis of 4994 cancer patients who underwent tissue or blood genomic profiling, including CDK12 assessment, conducted as part of routine care from December 2012 to January 2020. Prevalence, clinical characteristics, and treatment outcomes of patients with tumors with pathogenic CDK12 alterations were described. In all, 39 (0.78%, n = 39/4994) patients had pathogenic CDK12 alterations. Among CDK12-altered tumors, the most common organ site was prostate (n = 9, 23.1%) followed by colorectal (n = 5, 12.8%). Adenocarcinoma was the most common histology (n = 26, 66.7%). Median follow-up from time of diagnosis was 4.02 years. Median overall survival from time of metastasis was 4.43 years (95% CI: 3.11-5.74). Ten patients with CDK12-altered tumors received at least one immune checkpoint inhibitor-containing regimen. The majority of patients (n = 6/10, 60%) experienced an objective response. Progression-free survival for patients who had metastatic disease and received a checkpoint inhibitor-containing regimen was 1.16 years (95% CI: 0.32-2.00). CDK12 alterations are rare events across hematologic and solid tumor malignancies. They represent a clinically distinct molecular cancer subtype which may have increased responsiveness to checkpoint inhibition. Prospective studies are warranted to investigate checkpoint inhibition in CDK12-altered tumors.
Sections du résumé
BACKGROUND
CDK12 inactivation leading to increased neoantigen burden has been hypothesized to sensitize tumors to immune checkpoint inhibition. Pan-cancer data regarding the frequency of CDK12 alterations are limited. We aimed to characterize CDK12 alterations across all cancer types through real-world clinical-grade sequencing.
METHODS
This was a single-center retrospective analysis of 4994 cancer patients who underwent tissue or blood genomic profiling, including CDK12 assessment, conducted as part of routine care from December 2012 to January 2020. Prevalence, clinical characteristics, and treatment outcomes of patients with tumors with pathogenic CDK12 alterations were described.
RESULTS
In all, 39 (0.78%, n = 39/4994) patients had pathogenic CDK12 alterations. Among CDK12-altered tumors, the most common organ site was prostate (n = 9, 23.1%) followed by colorectal (n = 5, 12.8%). Adenocarcinoma was the most common histology (n = 26, 66.7%). Median follow-up from time of diagnosis was 4.02 years. Median overall survival from time of metastasis was 4.43 years (95% CI: 3.11-5.74). Ten patients with CDK12-altered tumors received at least one immune checkpoint inhibitor-containing regimen. The majority of patients (n = 6/10, 60%) experienced an objective response. Progression-free survival for patients who had metastatic disease and received a checkpoint inhibitor-containing regimen was 1.16 years (95% CI: 0.32-2.00).
CONCLUSION
CDK12 alterations are rare events across hematologic and solid tumor malignancies. They represent a clinically distinct molecular cancer subtype which may have increased responsiveness to checkpoint inhibition. Prospective studies are warranted to investigate checkpoint inhibition in CDK12-altered tumors.
Identifiants
pubmed: 34898046
doi: 10.1002/cam4.4483
pmc: PMC8817093
doi:
Substances chimiques
CDK12 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinases
EC 2.7.11.22
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
753-763Subventions
Organisme : NCI NIH HHS
ID : P30 CA023100
Pays : United States
Informations de copyright
© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
Références
Oncologist. 2019 Dec;24(12):1526-1533
pubmed: 31292271
Cell. 2018 Jul 26;174(3):758-769.e9
pubmed: 30033370
Front Oncol. 2019 Jun 14;9:493
pubmed: 31259151
Genes Dev. 2011 Oct 15;25(20):2158-72
pubmed: 22012619
J Chronic Dis. 1987;40(5):373-83
pubmed: 3558716
Cancer Med. 2022 Feb;11(3):753-763
pubmed: 34898046
N Engl J Med. 2012 Apr 12;366(15):1382-92
pubmed: 22452356
Sci Adv. 2020 Apr 29;6(18):
pubmed: 32917631
Cancer Cell. 2019 Nov 11;36(5):545-558.e7
pubmed: 31668947
Nature. 2014 Jul 31;511(7511):616-20
pubmed: 25043025
Cell Rep. 2016 Nov 22;17(9):2367-2381
pubmed: 27880910
Cell. 2018 Jul 12;174(2):433-447.e19
pubmed: 29909985
Cell. 2018 Jun 14;173(7):1770-1782.e14
pubmed: 29906450
Eur Urol. 2020 Nov;78(5):671-679
pubmed: 32317181
Nature. 2018 Dec;564(7734):141-145
pubmed: 30487607
N Engl J Med. 2018 Sep 13;379(11):1087-1089
pubmed: 30207914
Transcription. 2019 Apr;10(2):91-110
pubmed: 30319007
Cancer Res. 2014 Jan 1;74(1):287-97
pubmed: 24240700
Eur Urol. 2020 Mar;77(3):333-341
pubmed: 31640893
JCO Precis Oncol. 2020;4:370-381
pubmed: 32462107
Front Oncol. 2018 Oct 02;8:421
pubmed: 30333958
Arch Toxicol. 2018 Sep;92(9):2845-2857
pubmed: 29992508
N Engl J Med. 2020 May 28;382(22):2091-2102
pubmed: 32343890