Genomics of lethal prostate cancer at diagnosis and castration resistance

Mateo, Joaquín; Seed, George; Bertan, Claudia; Rescigno, Pasquale; Dolling, David; Figueiredo, Ines; Miranda, Susana; Rodrigues, Daniel Nava; Gürel, Bora; Clarke, Matthew; Atkin, Mark; Chandler, Rob; Messina, Carlo; Sumanasuriya, Semini; Bianchini, Diletta; Barrero, Maialen; Petermolo, Antonella; Zafeiriou, Zafeiris; Fontes, Mariane; Pérez-López, Raquel; Tunariu, Nina; Fulton, Ben; Jones, Robert J.; McGovern, Ursula; Ralph, Christy; Varughese, M.; Parikh, Omi; Jain, Suneil; Elliott, Tony; Sandhu, Shahneen; Porta, Núria; Hall, Emma; Yuan, Wei; Carreira, Suzanne

doi:10.1172/jci132031

Cited by 199 publications

(178 citation statements)

References 43 publications

Supporting

Mentioning

152

Contrasting

Order By: Relevance

“…Moreover, 28% of the tumour samples presented alterations in at least one of the 15 genes involved in the homologous recombination repair (HRR) pathway, with mutations detected both in primary tumours (27%) and metastatic lesions (32%). These data, considered together with the findings recently described by Mateo et al-who found that DDR defects were present in a similar percentage of localised tumours (diagnostic biopsies) and in biopsied samples obtained from men (n = 61) with mCRPC [96]-confirm that alterations in the HRR pathway occur early in the course of disease in certain prostate tumours. Although HRR alterations are an early event, their prevalence is markedly higher in castration-resistant disease [49,50] compared to localised PCa [89,94], suggesting a correlation between HRR mutations and more aggressive forms of PCa.…”

Section: Dna Repair Defectssupporting

confidence: 85%

Clinical Applications of Molecular Biomarkers in Prostate Cancer

Couñago

López-Campos

Díaz-Gavela

et al. 2020

Cancers

View full text Add to dashboard Cite

There is clinically relevant molecular heterogeneity in prostate cancer (PCa), but this biological diversity has had only a minimal impact on clinical practice. Treatment outcomes in patients with localised PCa are often highly variable, even among patients stratified to the same risk group or disease state based on standard clinical and pathological parameters. In recent years, the development of gene panels has provided valuable data on the differential expression of genes in patients with PCa. Nevertheless, there is an urgent need to identify and validate prognostic and predictive biomarkers that can be applied across clinical scenarios, ranging from localised disease to metastatic castration-resistant PCa. The availability of such tools would allow for precision medicine to finally reach PCa patients. In this review, we evaluate current data on molecular biomarkers for PCa, with an emphasis on the biomarkers and gene panels with the most robust evidence to support their application in routine clinical practice.

show abstract

Section: Dna Repair Defectssupporting

confidence: 85%

Clinical Applications of Molecular Biomarkers in Prostate Cancer

Couñago

López-Campos

Díaz-Gavela

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…It is considered that loss or mutation of CDK12 leads to genomic instability, which contributes to metastatic prostate cancer [68]. In addition, TP53, PTEN (phosphatase and tensin homolog) and CDK12 defects are commonly detected in metastatic castration-resistant prostate cancer (mCRPC) patients [70]. It has been shown that inactivation of CDK12, TP53 and BRCA2 affects distinct classes of structural variation in mCRPC based on a whole-genome analysis from 101 mCRPC patients [71].…”

Section: Cdk12 In Prostate Cancermentioning

confidence: 99%

CDK12: A Potent Target and Biomarker for Human Cancer Therapy

Liang

et al. 2020

Cells

View full text Add to dashboard Cite

Cyclin-dependent kinases (CDKs) are a group of serine/threonine protein kinases and play crucial roles in various cellular processes by regulating cell cycle and gene transcription. Cyclin-dependent kinase 12 (CDK12) is an important transcription-associated CDK. It shows versatile roles in regulating gene transcription, RNA splicing, translation, DNA damage response (DDR), cell cycle progression and cell proliferation. Recently, increasing evidence demonstrates the important role of CDK12 in various human cancers, illustrating it as both a biomarker of cancer and a potential target for cancer therapy. Here, we summarize the current knowledge of CDK12, and review the research advances of CDK12′s biological functions, especially its role in human cancers and as a potential target and biomarker for cancer therapy.

show abstract

“…While some data suggests that HR repair gene mutations are typically early (i.e. truncal) genomic events, we cannot rule out the possibility that some patient had their HR gene mutational status misclassified [38]. Additionally, when assessing PFS endpoints, we did not require confirmation of PSA or clinical/radiographic progression.…”

Section: Plos Onementioning

confidence: 99%

Impact of mutations in homologous recombination repair genes on treatment outcomes for metastatic castration resistant prostate cancer

et al. 2020

View full text Add to dashboard Cite

Introduction A significant proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in homologous recombination (HR) repair genes, with some of these mutations associating with increased tumor susceptibility to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy. While mutations in some HR repair genes (e.g., BRCA1/2) have been associated with a more aggressive clinical course, prior studies correlating HR mutational status with treatment response to androgen receptor (AR) signaling inhibitors (ARSIs) or taxane-based chemotherapy have yielded conflicting results. Methods We conducted a single-center retrospective analysis to assess clinical outcomes to conventional, regulatory-approved therapies in mCRPC patients with somatic (monoallelic and biallelic) and/or germline HR repair mutations compared to patients without alterations as determined by clinical-grade next-generation sequencing assays. The primary endpoint was PSA30/PSA50 response, defined as �30%/�50% prostate-specific antigen (PSA) reduction from baseline. Secondary endpoints of PSA progression-free survival (pPFS) and clinical/radiographic progression-free survival (crPFS) were estimated using Kaplan-Meier methods. Results A total of 90 consecutively selected patients were included in this analysis, of which 33 (37%) were identified to have HR repair gene mutations. Age, race, Gleason score, prior

show abstract

Genomics of lethal prostate cancer at diagnosis and castration resistance

Cited by 199 publications

References 43 publications

Clinical Applications of Molecular Biomarkers in Prostate Cancer

Clinical Applications of Molecular Biomarkers in Prostate Cancer

CDK12: A Potent Target and Biomarker for Human Cancer Therapy

Impact of mutations in homologous recombination repair genes on treatment outcomes for metastatic castration resistant prostate cancer

Contact Info

Product

Resources

About