TY - JOUR
T1 - Novel RNA-Affinity Proteogenomics Dissects Tumor Heterogeneity for Revealing Personalized Markers in Precision Prognosis of Cancer
AU - Wang, Li
AU - Wrobel, John A.
AU - Xie, Ling
AU - Li, Dong Xu
AU - Zurlo, Giada
AU - Shen, Huali
AU - Yang, Pengyuan
AU - Wang, Zefeng
AU - Peng, Yibing
AU - Gunawardena, Harsha P.
AU - Zhang, Qing
AU - Chen, Xian
N1 - Funding Information:
This work was supported by grants NC Tracs TTSA Phase I TTSA021P1, Chinese 973 fund 2013CB910802, NIH grant 1U19AI109965, and 1U24CA160035-01 from the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium (CPTAC), awarded to X.C. and NSFC grant nos. 31570823 and 3161101092 awarded to Z.W. The authors also thank Dr. Howard Fried for editorial assistance. This invention is protected by US Provisional Patent Application Serial No. 62/481,383 that was filed by University of North Carolina-Chapel Hill. X.C. is the founder of TransChromix, LLC.
Funding Information:
This work was supported by grants NC Tracs TTSA Phase I TTSA021P1 , Chinese 973 fund 2013CB910802 , NIH grant 1U19AI109965 , and 1U24CA160035-01 from the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium (CPTAC), awarded to X.C. and NSFC grant nos. 31570823 and 3161101092 awarded to Z.W. The authors also thank Dr. Howard Fried for editorial assistance. This invention is protected by US Provisional Patent Application Serial No. 62/481,383 that was filed by University of North Carolina-Chapel Hill. X.C. is the founder of TransChromix, LLC.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/5/17
Y1 - 2018/5/17
N2 - To discriminate the patient subpopulations with different clinical outcomes within each breast cancer (BC) subtype, we introduce a robust, clinical-practical, activity-based proteogenomic method that identifies, in their oncogenically active states, candidate biomarker genes bearing patient-specific transcriptomic/genomic alterations of prognostic value. First, we used the intronic splicing enhancer (ISE) probes to sort ISE-interacting trans-acting protein factors (trans-interactome) directly from a tumor tissue for subsequent mass spectrometry characterization. In the retrospective, proteogenomic analysis of patient datasets, we identified those ISE trans-factor-encoding genes showing interaction-correlated expression patterns (iCEPs) as new BC-subtypic genes. Further, patient-specific co-alterations in mRNA expression of select iCEP genes distinguished high-risk patient subsets/subpopulations from other patients within a single BC subtype. Function analysis further validated a tumor-phenotypic trans-interactome contained the drivers of oncogenic splicing switches, representing the predominant tumor cells in a tissue, from which novel personalized biomarkers were clinically characterized/validated for precise prognostic prediction and subsequent individualized alignment of optimal therapy. The interpatient tumor-phenotypic heterogeneity hinders discovery of biomarkers for individualized prognosis. Wang and colleagues introduce an alternative splicing activity-based proteogenomic method that dissects tumor heterogeneity for de novo discovery of individualized prognostic biomarkers. The resulting biomarkers distinguish high-risk patient subpopulations from other patients within each single breast cancer subtype.
AB - To discriminate the patient subpopulations with different clinical outcomes within each breast cancer (BC) subtype, we introduce a robust, clinical-practical, activity-based proteogenomic method that identifies, in their oncogenically active states, candidate biomarker genes bearing patient-specific transcriptomic/genomic alterations of prognostic value. First, we used the intronic splicing enhancer (ISE) probes to sort ISE-interacting trans-acting protein factors (trans-interactome) directly from a tumor tissue for subsequent mass spectrometry characterization. In the retrospective, proteogenomic analysis of patient datasets, we identified those ISE trans-factor-encoding genes showing interaction-correlated expression patterns (iCEPs) as new BC-subtypic genes. Further, patient-specific co-alterations in mRNA expression of select iCEP genes distinguished high-risk patient subsets/subpopulations from other patients within a single BC subtype. Function analysis further validated a tumor-phenotypic trans-interactome contained the drivers of oncogenic splicing switches, representing the predominant tumor cells in a tissue, from which novel personalized biomarkers were clinically characterized/validated for precise prognostic prediction and subsequent individualized alignment of optimal therapy. The interpatient tumor-phenotypic heterogeneity hinders discovery of biomarkers for individualized prognosis. Wang and colleagues introduce an alternative splicing activity-based proteogenomic method that dissects tumor heterogeneity for de novo discovery of individualized prognostic biomarkers. The resulting biomarkers distinguish high-risk patient subpopulations from other patients within each single breast cancer subtype.
KW - RNA-protein interactions
KW - affinity proteomics
KW - breast cancer
KW - dissection of tumor heterogeneity
KW - patient-specific prognostic markers
KW - proteogenomics
KW - quantitative proteomics
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U2 - 10.1016/j.chembiol.2018.01.016
DO - 10.1016/j.chembiol.2018.01.016
M3 - Article
C2 - 29503206
AN - SCOPUS:85042591529
SN - 2451-9456
VL - 25
SP - 619-633.e5
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 5
ER -