signature=89fa36136ea2bd6e2c6ca71591ef43cc,Multigene Profiling of CTCs in mCRPC Identifies a Clinica...

最新推荐文章于 2022-05-08 21:30:28 发布

weixin_39712705

最新推荐文章于 2022-05-08 21:30:28 发布

阅读量1k

点赞数

文章标签： signature=89fa36136ea2bd6e2c6ca71591ef43cc

研究通过检测mCRPC患者血液中的循环肿瘤细胞（CTC），发现WNT5a、AURKA和BMP7基因表达与整体生存显著相关，构建的miCTC评分模型超越了传统Halabi基因组。这一发现为理解晚期前列腺癌分子景观及精准治疗提供了新的工具。

摘要由CSDN通过智能技术生成

doi: 10.1158/1541-7786.MCR-17-0539.

Epub 2018 Feb 16.

Multigene Profiling of CTCs in mCRPC Identifies a Clinically Relevant Prognostic Signature

Affiliations

Expand

Affiliations

1 Department of Urology, University of Michigan, Ann Arbor, Michigan.

2 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.

3 Michigan Center for Translational Pathology, Department of Pathology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.

4 Department of Urology, Inje University, Haeundae Paik Hospital, Busan, Korea.

5 Department of Hematology/Oncology, Department of Urology, University of Michigan, Ann Arbor, Michigan.

6 Department of Urology, Mayo Clinic, Rochester, Minnesota.

7 Department of Radiation Oncology, Helen Diller Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California.

8 Department of Urology, Medical University of Vienna, Vienna, Austria.

9 Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, University of Michigan, Ann Arbor, Michigan.

10 Michigan Center for Translational Pathology, Department of Pathology, Comprehensive Cancer Center, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan.

11 Departments of Pathology and Urology, Comprehensive Cancer Center, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.

12 Department of Urology, University of Michigan, Ann Arbor, Michigan. tomorgan@med.umich.edu.

# Contributed equally.

Free PMC article

Item in Clipboard

Multigene Profiling of CTCs in mCRPC Identifies a Clinically Relevant Prognostic Signature

Udit Singhalet al.

Mol Cancer Res.

2018 Apr.

Free PMC article

Show details

Display options

Format

Abstract

PubMed

PMID

doi: 10.1158/1541-7786.MCR-17-0539.

Epub 2018 Feb 16.

Affiliations

1 Department of Urology, University of Michigan, Ann Arbor, Michigan.

2 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.

3 Michigan Center for Translational Pathology, Department of Pathology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.

4 Department of Urology, Inje University, Haeundae Paik Hospital, Busan, Korea.

5 Department of Hematology/Oncology, Department of Urology, University of Michigan, Ann Arbor, Michigan.

6 Department of Urology, Mayo Clinic, Rochester, Minnesota.

7 Department of Radiation Oncology, Helen Diller Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California.

8 Department of Urology, Medical University of Vienna, Vienna, Austria.

9 Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, University of Michigan, Ann Arbor, Michigan.

10 Michigan Center for Translational Pathology, Department of Pathology, Comprehensive Cancer Center, Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan.

11 Departments of Pathology and Urology, Comprehensive Cancer Center, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.

12 Department of Urology, University of Michigan, Ann Arbor, Michigan. tomorgan@med.umich.edu.

# Contributed equally.

Item in Clipboard

Full text linksCite

Display options

FormatAbstractPubMedPMID

Abstract

The trend toward precision-based therapeutic approaches dictated by molecular alterations offers substantial promise for men with metastatic castration-resistant prostate cancer (mCRPC). However, current approaches for molecular characterization are primarily tissue based, necessitating serial biopsies to understand changes over time and are limited by the challenges inherent to extracting genomic material from predominantly bone metastases. Therefore, a circulating tumor cell (CTC)-based assay was developed to determine gene expression across a panel of clinically relevant and potentially actionable prostate cancer-related genes. CTCs were isolated from the whole blood of mCRPC patients (n = 41) and multiplex qPCR was performed to evaluate expression of prostate cancer-related target genes (n = 78). A large fraction of patients (27/41, 66%) had detectable CTCs. Increased androgen receptor (AR) expression (70% of samples) and evidence of Wnt signaling (67% of samples) were observed. The TMPRSS2:ERG fusion was expressed in 41% of samples, and the aggressive prostate cancer-associated long noncoding RNA SChLAP1 was upregulated in 70%. WNT5a [HR 3.62, 95% confidence interval (CI), 1.63-8.05, P = 0.002], AURKA (HR 5.56, 95% CI, 1.79-17.20, P = 0.003), and BMP7 (HR 3.86, 95% CI, 1.60-9.32, P = 0.003) were independently predictive of overall survival (FDR < 10%) after adjusting for a panel of previously established prognostic variables in mCRPC (Halabi nomogram). A model including Halabi, WNT5a, and AURKA expression, termed the miCTC score, outperformed the Halabi nomogram alone (AUC = 0.89 vs. AUC = 0.70). Understanding the molecular landscape of CTCs has utility in predicting clinical outcomes in patients with aggressive prostate cancer and provides an additional tool in the arsenal of precision-based therapeutic approaches in oncology.Implications: Analysis of CTC gene expression reveals a clinically prognostic "liquid biopsy" signature in patients with metastatic castrate-resistance prostate cancer. Mol Cancer Res; 16(4); 643-54. ©2018 AACR.

Conflict of interest statement

Conflicts of interest: S.A.T. has consulted for Ventana Medical Systems, Astellas/Medivation, Janssen, Sanofi, and Almac Diagnostics; has research funding from Thermo Fisher Scientific and GenomeDX; travel expenses from Thermo Fisher Scientific; patents on ETS gene fusions in prostate cancer, of which the diagnostic field of use has been licensed to Hologic/Gen-Probe Inc., who has sublicensed some rights to Ventana Medical Systems/Roche.

Figures

Fig. 1. CTC gene expression analysis reveals…

Fig. 1. CTC gene expression analysis reveals WNT5a, AURKA, and BMP7 are independently associated with…

Fig. 1. CTC gene expression analysis reveals WNT5a, AURKA, and BMP7 are independently associated with overall survival in mCRPC

(A) A heatmap representation of the top 20 independently predictive genes as determined by Cox proportional hazards model. Each column represents a different sample and each row represents a separate gene. The heatmap color spectrum corresponds to lower relative expression (white) and higher relative expression (red). The left colored column represents the associated functional pathway for each separate gene (B) WNT5a, BMP7, and AURKA (highlighted in blue) are independently associated with overall survival with p <0.05 and FDR <10% when adjusting for Halabi variables.

Fig. 2. A score combining Halabi, WNT5a…

Fig. 2. A score combining Halabi, WNT5a and AURKA improves prediction of overall survival at…

Fig. 2. A score combining Halabi, WNT5a and AURKA improves prediction of overall survival at 6 months over Halabi alone

(A) Survival status at 6 months based on normalized expression of WNT5a, AURKA, and BMP7 in 39 (26 CTC positive) patients with mCRPC. The hypergeometric distribution was used to test whether deaths were over-represented in the top 25% of patients. Deaths were significantly over-represented at the 1% level for all three genes (p<0.001). (B) Receiver operating characteristic (ROC) curve compares accuracy of WNT5a, AURKA, and BMP7 expression for predicting overall survival at 6 months. (C) ROC curve compares accuracy of Halabi score alone (AUC=0.70) vs. miCTC score (AUC=0.89) combining Halabi score, WNT5a, and AURKA expression. (D) Kaplan- Meier curves depicting overall survival in patients with high vs. low miCTC score. Left curve represents entire mCRPC patient cohort (CTC+/−), right curve represents only CTC positive mCRPC patients.

Fig. 3. Concordance of CTC gene expression…

Fig. 3. Concordance of CTC gene expression by qPCR with known tissue-based RNA-seq expression

(A)…

Fig. 3. Concordance of CTC gene expression by qPCR with known tissue-based RNA-seq expression

(A) Global analysis of expression for select genes in CTCs of 7 patients after isolation and qPCR via platform with known RNA-seq data from MI-ONCOSEQ (spearman correlation = 0.38, p=0.0002) (B) AR (r2=0.57), KLK2 (r2=0.51), and PSA (r2=0.64) show concordance of expression between CTC qPCR and RNA-seq from MI-ONCOSEQ of 7 patients (C) Analysis of expression of AURKA and WNT5a by RNA-seq in an external cohort* (D) calculated miCTC score in external cohort of patients with primary and metastatic prostate cancer* (numbers within each pie represent number of samples with that specific miCTC score), *primary tumor samples obtained from TCGA, metastatic samples from SU2C

Fig. 4. miCTC score predicts long-term outcomes…

Fig. 4. miCTC score predicts long-term outcomes in patients with high-risk prostate cancer

Kaplan-Meier curves…

Fig. 4. miCTC score predicts long-term outcomes in patients with high-risk prostate cancer

Kaplan-Meier curves showing high risk (miCTC ≥2) and increasing miCTC score is associated with decreased (A) biochemical recurrence free survival (p=0.004) (B) metastasis free survival (p=0.005) (C) overall survival (p=0.002) (D) and prostate cancer specific survival (p=0.04) in high-risk, clinically localized prostate cancer (Mayo Clinic)

Similar articles

Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castration-resistant prostate cancer: A report from the PETRUS prospective study.

Massard C, Oulhen M, Le Moulec S, Auger N, Foulon S, Abou-Lovergne A, Billiot F, Valent A, Marty V, Loriot Y, Fizazi K, Vielh P, Farace F.

Massard C, et al.

Oncotarget. 2016 Aug 23;7(34):55069-55082. doi: 10.18632/oncotarget.10396.

Oncotarget. 2016.

PMID: 27391263

Free PMC article.

Gene expression analysis of bone metastasis and circulating tumor cells from metastatic castrate-resistant prostate cancer patients.

Cho WJ, Oliveira DS, Najy AJ, Mainetti LE, Aoun HD, Cher ML, Heath E, Kim HR, Bonfil RD.

Cho WJ, et al.

J Transl Med. 2016 Mar 15;14:72. doi: 10.1186/s12967-016-0829-5.

J Transl Med. 2016.

PMID: 26975354

Free PMC article.

Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer.

Sharp A, Welti JC, Lambros MBK, Dolling D, Rodrigues DN, Pope L, Aversa C, Figueiredo I, Fraser J, Ahmad Z, Lu C, Rescigno P, Kolinsky M, Bertan C, Seed G, Riisnaes R, Miranda S, Crespo M, Pereira R, Ferreira A, Fowler G, Ebbs B, Flohr P, Neeb A, Bianchini D, Petremolo A, Sumanasuriya S, Paschalis A, Mateo J, Tunariu N, Yuan W, Carreira S, Plymate SR, Luo J, de Bono JS.

Sharp A, et al.

Eur Urol. 2019 Nov;76(5):676-685. doi: 10.1016/j.eururo.2019.04.006. Epub 2019 Apr 27.

Eur Urol. 2019.

PMID: 31036442

Clinical Utility of Circulating Tumor Cells in Advanced Prostate Cancer.

Zhang T, Armstrong AJ.

Zhang T, et al.

Curr Oncol Rep. 2016 Jan;18(1):3. doi: 10.1007/s11912-015-0490-9.

Curr Oncol Rep. 2016.

PMID: 26700506

Review.

Development and Application of Liquid Biopsies in Metastatic Prostate Cancer.

Morrison GJ, Goldkorn A.

Morrison GJ, et al.

Curr Oncol Rep. 2018 Mar 23;20(4):35. doi: 10.1007/s11912-018-0683-0.

Curr Oncol Rep. 2018.

PMID: 29572775

Free PMC article.

Review.

Cited by

articles

Blood-Derived Biomarkers of Diagnosis, Prognosis and Therapy Response in Prostate Cancer Patients.

Balázs K, Antal L, Sáfrány G, Lumniczky K.

Balázs K, et al.

J Pers Med. 2021 Apr 13;11(4):296. doi: 10.3390/jpm11040296.

J Pers Med. 2021.

PMID: 33924671

Free PMC article.

Review.

Longitudinal CTCs gene expression analysis on metastatic castration-resistant prostate cancer patients treated with docetaxel reveals new potential prognosis markers.

Pereira-Veiga T, González-Conde M, León-Mateos L, Piñeiro-Cid R, Abuín C, Muinelo-Romay L, Martínez-Fernández M, Brea Iglesias J, García González J, Anido U, Aguín-Losada S, Cebey V, Costa C, López-López R.

Pereira-Veiga T, et al.

Clin Exp Metastasis. 2021 Apr;38(2):239-251. doi: 10.1007/s10585-021-10075-1. Epub 2021 Feb 26.

Clin Exp Metastasis. 2021.

PMID: 33635497

Free PMC article.

Coupled liquid biopsy and bioinformatics for pancreatic cancer early detection and precision prognostication.

Hou J, Li X, Xie KP.

Hou J, et al.

Mol Cancer. 2021 Feb 16;20(1):34. doi: 10.1186/s12943-021-01309-7.

Mol Cancer. 2021.

PMID: 33593396

Free PMC article.