Related Experiment Video
Updated: Feb 25, 2026
Detecting Somatic Genetic Alterations in Tumor Specimens by Exon Capture and Massively Parallel Sequencing
Published on: October 18, 2013
Analysis of somatic mutations across the kinome reveals loss-of-function mutations in multiple cancer types
Runjun D Kumar1,2, Ron Bose3
1Division of Oncology, Department of Medicine, Washington University School of Medicine, 660S Euclid Ave, St. Louis, MO, 63110, USA.
Abstract:
In this study we use somatic cancer mutations to identify important functional residues within sets of related genes. We focus on protein kinases, a superfamily of phosphotransferases that share homologous sequences and structural motifs and have many connections to cancer. We develop several statistical tests for identifying Significantly Mutated Positions (SMPs), which are positions in an alignment with mutations that show signs of selection. We apply our methods to 21,917 mutations that map to the alignment of human kinases and identify 23 SMPs. SMPs occur throughout the alignment, with many in the important A-loop region, and others spread between the N and C lobes of the kinase domain. Since mutations are pooled across the superfamily, these positions may be important to many protein kinases. We select eleven mutations from these positions for functional validation. All eleven mutations cause a reduction or loss of function in the affected kinase. The tested mutations are from four genes, including two tumor suppressors (TGFBR1 and CHEK2) and two oncogenes (KDR and ERBB2). They also represent multiple cancer types, and include both recurrent and non-recurrent events. Many of these mutations warrant further investigation as potential cancer drivers.
Insights
This study identifies key functional residues in protein kinases using cancer mutation data. Eleven validated mutations from these sites significantly impair kinase function, highlighting potential cancer drivers.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- Protein kinases are crucial in cell signaling and frequently implicated in cancer.
- Somatic mutations in cancer provide insights into gene function and disease mechanisms.
Purpose of the Study:
- To identify functionally important residues in protein kinases using somatic mutation data.
- To develop and apply statistical methods for detecting significantly mutated positions (SMPs).
Main Methods:
- Development of statistical tests to identify SMPs indicative of selection pressure.
- Analysis of 21,917 somatic mutations across aligned human kinase sequences.
- Functional validation of eleven selected mutations from identified SMPs.
Main Results:
- Identification of 23 SMPs within the human kinase superfamily, located in key regions like the A-loop and kinase lobes.
- Experimental validation confirmed that all eleven tested mutations lead to reduced or lost kinase function.
- Mutations were found in tumor suppressors (e.g., TGFBR1, CHEK2) and oncogenes (e.g., KDR, ERBB2) across various cancer types.
Conclusions:
- The identified SMPs represent critical functional residues potentially important across multiple protein kinases.
- These findings suggest several mutations may act as significant drivers of cancer.
- Further investigation of these mutations is warranted for understanding cancer development and therapeutic targeting.
Related Concept Videos
02:21Cancers Originate from Somatic Mutations in a Single Cell
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:33Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...