Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy

Krug, Karsten; Jaehnig, Eric J.; Satpathy, Shankha; Blumenberg, Lili M.; Karpova, Alla; Anurag, Meenakshi; Miles, George; Mertins, Philipp; Geffen, Yifat; Tang, Lihao; Heiman, David I.; Cao, Song; Maruvka, Yosef E.; Lei, Jonathan T.; Huang, Chen; Kothadia, Ramani B.; Colaprico, Antonio; Birger, Chet; Wang, Jarey; Dou, Yongchao; Wen, Bo; Shi, Zhiao; Liao, Yuxing; Wiznerowicz, Maciej; Wyczalkowski, Matthew A.; Chen, Xi Steven; Kennedy, Jacob J.; Paulovich, Amanda G.; Thiagarajan, Mathangi; Kinsinger, Christopher R.; Hiltke, Tara; Boja, Emily S.; Mesri, Mehdi; Robles, Ana I.; Rodriguez, Henry; Westbrook, Thomas F.; Li, Ding; Getz, Gad; Clauser, Karl R.; Fenyö, David; Ruggles, Kelly V.; Zhang, Bing; Mani, D. R.; Carr, Steven A.; Ellis, Matthew J.; Gillette, Michael A.; Avanessian, Shayan C.; Cai, Shuang; Chan, Daniel W.; Chen, Xian; Edwards, Nathan; Hoofnagle, Andrew N.; Kane, M. Harry; Ketchum, Karen A.; Kuhn, Eric; Levine, Douglas A.; Li, Shunqiang; Liebler, D.C.; Liu, Tao; Luo, Jingqin; Madhavan, Subha; Maher, Chris G; McDermott, Jason; McGarvey, Peter B.; Oberti, Mauricio; Pandey, Akhilesh; Payne, Samuel H.; Ransohoff, David F.; Rivers, Robert; Rodland, Karin D.; Rudnick, Paul; Sanders, Melinda E.; Shaw, Kenna Mills; Shih, Ie‐Ming; Slebos, Robbert J.C.; Smith, Richard; Snyder, M; Stein, Stephen E.; Tabb, David L.; Thangudu, Ratna R.; Thomas, Stefani N.; Wang, Yue; White, Forest M.; Whiteaker, Jeffrey R.; Whiteley, Gordon A.; Zhang, Hui; Zhang, Zhen; Zhao, Yingming; Zhu, Heng; Zimmerman, Lisa J.

doi:10.1016/j.cell.2020.10.036

Cited by 307 publications

(347 citation statements)

References 149 publications

(221 reference statements)

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“…Proteogenomics (the combination of genomics with proteomics) is also beginning to be utilized to toxicity and resistance to therapies and determine precision oncology strategies. The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) has published several seminal manuscripts on various cancer types including pediatric brain cancer (56)(57)(58)(59)(60). We have found proteogenomics to be useful in identifying key pathways involved in metastatic progression to the brain (61).…”

Section: Future Directionsmentioning

confidence: 99%

Brain Tumor Biobank Development for Precision Medicine: Role of the Neurosurgeon

et al. 2021

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Neuro-oncology biobanks are critical for the implementation of a precision medicine program. In this perspective, we review our first year experience of a brain tumor biobank with integrated next generation sequencing. From our experience, we describe the critical role of the neurosurgeon in diagnosis, research, and precision medicine efforts. In the first year of implementation of the biobank, 117 patients (Female: 62; Male: 55) had 125 brain tumor surgeries. 75% of patients had tumors biobanked, and 16% were of minority race/ethnicity. Tumors biobanked were as follows: diffuse gliomas (45%), brain metastases (29%), meningioma (21%), and other (5%). Among biobanked patients, 100% also had next generation sequencing. Eleven patients qualified for targeted therapy based on identification of actionable gene mutations. One patient with a hereditary cancer predisposition syndrome was also identified. An iterative quality improvement process was implemented to streamline the workflow between the operating room, pathology, and the research laboratory. Dedicated tumor bank personnel in the department of neurosurgery greatly improved standard operating procedure. Intraoperative selection and processing of tumor tissue by the neurosurgeon was integral to increasing success with cell culture assays. Currently, our institutional protocol integrates standard histopathological diagnosis, next generation sequencing, and functional assays on surgical specimens to develop precision medicine protocols for our patients. This perspective reviews the critical role of neurosurgeons in brain tumor biobank implementation and success as well as future directions for enhancing precision medicine efforts.

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Section: Future Directionsmentioning

confidence: 99%

Brain Tumor Biobank Development for Precision Medicine: Role of the Neurosurgeon

et al. 2021

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“…Breast cancer (BRCA) with high aggressiveness is one of the most common malignant tumors that seriously endanger women's health (1). However, the mechanism of its occurrence and development is not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

ATP2C2 Has Potential to Define Tumor Microenvironment in Breast Cancer

Liu

Wei

et al. 2021

Front. Immunol.

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Tumor microenvironment (TME) is vital for the occurrence and development of breast cancer (BRCA). However, it remains challenging to understand the dynamic modulation of the stromal and immune components comprehensively in TME. Herein, we used ESTIMATE and CIBERSORT algorithm to estimate the number of stromal and immune components and the abundance of tumor-infiltrating immune cells (TICs) in 582 BRCA cases from gene expression omnibus (GEO) database. We employed three regression models including univariable Cox proportion, LASSO regression model and multivariate Cox regression, and identified 7 immune-specific genes related to BRCA survival. Of 7 genes, ATPase Secretory Pathway Ca2+ Transporting 2 (ATP2C2) attracts our attention for significantly predicting prognosis of BRCA patients. Further analysis indicated that ATP2C2 expression was closely related to the clinicopathological features (age, T- and N-staging) and negatively correlated with patients’ survival in BRCA. Gene Set Enrichment Analysis (GSEA) was performed to reveal pathway enrichment between ATP2C2high and ATP2C2low groups. The low ATP2C2 expression groups’ genes were mainly enriched for immune-related activities, while those in the ATP2C2 high-expression group were largely enriched in metabolic-related pathways. Notably, Pearson’s correlation analysis identified that ATP2C2 expression was positively correlated with T follicular helper (Tfh) cells, and negatively correlated with gamma delta (γδ) T cell, suggesting that ATP2C2 might be accountable for the maintenance of immune-dominant status for TME. To sum up, this study comprehensively analyzed the TME and shed light on prognostic immune-related biomarkers for BRCA. In particular, ATP2C2 might be helpful for predicting the prognosis of BRCA patients, which provided an extra insight for BRCA treatment.

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“…Normalized proteomic data (log2 ratio) from six CPTAC datasets [LUAD, BRCA, OV, UCEC, COAD, ccRCC (clear cell renal cell carcinoma)] and their clinical data were downloaded from CPTAC Portal (cptac-dataportal.georgetown.edu), LinkedOmics (www.linkedomics.org), or original published papers 21,[68][69][70][71][72][73] .…”

Section: Analysis Of Mettl Protein Expression In Tumor and Normal Sammentioning

confidence: 99%

Bioinformatic analysis of methyltransferase-like protein family reveals clinical and functional outcomes in human cancer

Campeanu

Jiang

Liu

et al. 2021

Preprint

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Human methyltransferase-like (METTL) proteins transfer methyl groups to nucleic acids, proteins, lipids, and other small molecules, subsequently playing important roles in various cellular processes. In this study, we performed integrated genomic, transcriptomic, proteomic, and clinicopathological analyses of 34 METLLs in a large cohort of primary tumor and cell line data. We identified a subset of METTL genes, notably METTL1, METTL7B, and NTMT1, with high frequencies of genomic amplification and/or up-regulation at both the mRNA and protein levels in a spectrum of human cancers. Higher METTL1 expression was associated with high-grade tumors and poor disease prognosis. Loss-of-function analysis in tumor cell lines indicated the biological importance of METTL1, an m7G methyltransferase, in cancer cell growth and survival. Furthermore, functional annotation and pathway analysis of METTL1-associated proteins revealed that, in addition to the METTL1 cofactor WDR4, RNA regulators and DNA packaging complexes may be functionally interconnected with METTL1 in human cancer. Finally, we generated a crystal structure model of the METTL1-WDR4 heterodimeric complex that provides the basis for further development of novel inhibitors. Our results provide a framework for further study of the functional consequences of METTL alterations in human cancer and for development of small inhibitors that target cancer-promoting METTLs.

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Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy

Cited by 307 publications

References 149 publications

Brain Tumor Biobank Development for Precision Medicine: Role of the Neurosurgeon

Brain Tumor Biobank Development for Precision Medicine: Role of the Neurosurgeon

ATP2C2 Has Potential to Define Tumor Microenvironment in Breast Cancer

Bioinformatic analysis of methyltransferase-like protein family reveals clinical and functional outcomes in human cancer

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