[ad_1]
Researchers from Baylor College of Medicine, the Broad Institute of MIT and Harvard have applied powerful proteogenomics approaches to better understand the biological complexity of breast cancer.
Proteogenomics is a tumor profiling approach that combines next-generation DNA and RNA sequencing (NGS), a high-throughput methodology that enables rapid base pair sequencing in DNA or RNA samples, with mass spectrometry-based proteomics to provide in-depth and unbiased quantification of proteins and post-translational modifications such as phosphorylation.
Proteogenomics helps create a better understanding of the molecular profile of human cell types, which leads to a (better) understanding of its role in normal physiology and disease. [1] Proteogenomics has significantly contributed to the (re) annotation of the genome, thanks to which new coding sequences (CDS) are identified and confirmed. [2]
Using this approach, the researchers were able to propose more precise diagnostics for known treatment goals, identify new tumor susceptibilities for translation into aggressive cancer treatments, and implicate new mechanisms involved in breast cancer treatment resistance.
The study appears in the November 18, 2020 edition of Cell.[3]
Proteogenomics combines laboratory techniques for next-generation DNA and RNA sequencing with mass spectrometry-based analyzes for the deep and unbiased quantification of proteins and protein modifications in cancer cells, together with computational methods for integrated analysis of these data.
Such proteogenomic approaches have been widely applied to study tumors by researchers from the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (NCI-CPTAC), a national effort to accelerate understanding of the molecular basis of cancer through the application of proteome and genome analysis or proteogenomics.
Launched in 2011, CPTAC pioneered integrated proteogenomic analysis of colorectal, breast and ovarian cancer to reveal new information on these cancers, such as identification of proteomic-centric subtypes, prioritization of driver mutations using correlative analysis of copy number alterations and protein abundance and understanding pathways relevant to cancer through post-translational modifications.
Breast cancer
“Importantly, our analysis included the identification of phosphorylation and acetylation, protein modifications that reveal information about the activity of individual proteins. Protein acetylation had not been analyzed before in breast cancer. These new approaches promise biological insights into difficult-to-treat breast cancers and the ability to dissect response heterogeneity, “said co-correspondent author Matthew Ellis, MD, BChir, BSc., Ph.D., FRCP, oncologist and breast cancer professor, and director of the Lester and Sue Smith Breast Center at Baylor College of Medicine, McNair Scholar at Baylor and Susan G. Komen Scholar.
Simultaneous analysis of changes in the genetic code and resulting alterations in protein function provides a much more complete picture of what is happening in breast cancer tumors than analyzing each component in isolation.
More accurate data
Breast cancer researchers’ initial proteogenomics analysis using residual samples from the Cancer Genome Atlas provided proof of principle that proteogenomics represented a breakthrough in breast cancer profiling.
The current study represents an important step forward as it included tissue samples collected using protocols that specifically preserve protein modifications, analyzed many more samples, performed genomic and proteomic characterization on exactly the same tissue fragments, and added the profile of the acetylation of proteins to proteins. phosphorylation, DNA and RNA measurements.
Proteogenomic analytical techniques have matured substantially in recent years and these cutting-edge approaches have been applied to this dataset.
Researchers completed proteogenomic analyzes of 122 treatment-naïve primary breast cancer samples. Their measurements generated an enormous amount of data – approximately 38,000 protein phosphorylation sites and nearly 10,000 protein acetylation sites per tumor, as well as whole exome and RNA sequencing – that require advanced computational methods to analyze and integrate the information.
“Complex analyzes such as these are now routinely performed on large-scale proteogenomic datasets and we are developing tools to automate the process,” noted DR Mani, Ph.D., corresponding co-author and principal computational scientist at Broad.
“We describe here the proteogenomic characterization of the largest set to date of breast cancer samples that were collected specifically for these types of analyzes, maximizing the fidelity and accuracy of the results,” Ellis explained.
“Every cancer cell has literally hundreds of genomic changes. Mostly we don’t understand their significance either clinically or biologically. The approach we illustrate allows for a deeper and more complete understanding of breast cancer for each individual, “he added.
Identification of drug targets
For example, analyzes revealed that some breast cancer subtypes have certain targetable enzymes called kinases that are more heavily phosphorylated than other cancers, suggesting greater activity and therefore the potential to target.
These analyzes included newly identified drug targets such as CDK4 / 6 and its regulatory background, as well as programmed cell death receptors and ligands that are the targets of new immunotherapy drugs.
The integrated analyzes also identified new series of estrogen receptor positive breast cancers that could be treated with these agents. This is significant because these agents are currently limited to estrogen receptor negative disease.
Further analyzes have yielded completely new information on the metabolic vulnerabilities of ER + and ER- breast cancer.
“Our comprehensive acetylproteome analysis, the first in breast cancers, has revealed new details about the specific metabolism of the breast cancer subtype,” said co-correspondent author Steven A. Carr, Ph.D., director of proteomics at Broad.
Improve diagnosis and treatment
The researchers hope their findings will motivate breast cancer scientists to explore the therapeutic or diagnostic potential of the new biological alterations they identified in this study. They are also optimistic that their findings will encourage an effort to translate proteogenomics into a cancer profiling approach that can be routinely used in the clinic to improve diagnosis and treatment.
“We believe that approaches to proteogenomics will continue to help us identify new candidate therapeutic targets, better understand the immune landscape of breast cancer and other cancers, gain insight into response and resistance, and final progress towards our personalized cancer care goal. noted co-author correspondent Michael Gillette, MD, Ph.D., a pulmonary and critical care physician at Massachusetts General Hospital and senior group leader in proteomics at Broad.
“The science is powerful and exciting, but ultimately it’s what we can offer the patient that makes it important,” concluded Gillette.
Reference
[1] Madugundu AK, Na CH, Nirujogi RS, Renuse S, Kim KP, Burns KH, Wilks C, Langmead B, Ellis SE, Collado-Torres L, Halushka MK, Kim MS, Pandey A. Integrated transcriptomic and proteomic analysis of the human navel primary Endothelial cells of the vein. Proteomics. 2019 August; 19 (15): e1800315. doi: 10.1002 / pmic.201800315. Epub 2019 Jun 26. PMID: 30983154; PMCID: PMC6812510.
[2] Ang MY, Low TY, Lee PY, Wan Mohamad Nazarie WF, Guryev V, Jamal R. Proteogenomics: From Next Generation Sequencing (NGS) and Mass Spectrometry-Based Proteomics to Precision Medicine. Clin Chim Acta. 2019 November; 498: 38-46. doi: 10.1016 / j.cca.2019.08.010. Epub 2019 Aug 14. PMID: 31421119.
[3] Krug K, Jaehnig EJ, Satpathy S, Ellis MJ, Gillette MA. Proteogenomic landscape of breast cancer tumorigenesis and targeted therapy. Cell. Published: November 18, 2020DOI: https: //doi.org/10.1016/j.cell.2020.10.036 [Article]
Featured Image: Baylor College of Medicine, Lester and Sue Smith Breast Center. Photo Courtesy: © 2020 Baylor College of Medicine. used with permission.
Source link
