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Related Concept Videos

Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

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Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
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...
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Mismatch Repair01:20

Mismatch Repair

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Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
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Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

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Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
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...
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Cancer-Critical Genes I: Proto-oncogenes01:33

Cancer-Critical Genes I: Proto-oncogenes

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Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
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Abnormal Proliferation02:23

Abnormal Proliferation

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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
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The Retinoblastoma Gene01:20

The Retinoblastoma Gene

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Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
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Related Experiment Video

Updated: Jul 23, 2025

Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA1
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Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA1

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ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants

Lenka Stolarova1, Petra Kleiblova2,3, Petra Zemankova2,4

  • 1Laboratory of Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 14, 2023
PubMed
Summary
This summary is machine-generated.

Germline CHEK2 variants of uncertain significance were functionally assessed. Functionally impaired variants increase breast cancer risk, while wild-type-like variants do not, improving genetic testing utility.

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Functional Assessment of BRCA1 variants using CRISPR-Mediated Base Editors
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Area of Science:

  • Genetics
  • Oncology
  • Molecular Biology

Background:

  • Germline pathogenic variants in CHEK2 increase breast cancer risk, but variants of uncertain significance (VUS) complicate genetic testing.
  • Clarifying the clinical utility of CHEK2 VUS is crucial for accurate risk assessment and personalized screening.

Approach:

  • Functional characterization of 460 CHEK2 missense VUS using complementation assays in human cells.
  • Categorization of VUS into functionally impaired, intermediate, or wild-type (WT)-like based on concordant assay results.
  • Association analysis of categorized VUS with breast cancer risk in a large case-control cohort (73,048 cases, 88,658 controls).

Key Points:

  • 340/430 analyzed VUS (79.1%) showed concordant functional assay results.
  • Functionally impaired VUS (N=102) were associated with a significantly elevated breast cancer risk (OR=2.83).
  • Functionally WT-like VUS (N=226) showed no clinically relevant increase in breast cancer risk (OR=1.19).

Conclusions:

  • The functional consequences of most CHEK2 missense VUS in breast cancer patients were determined.
  • Functionally impaired CHEK2 VUS confer a moderate breast cancer risk, similar to truncating variants.
  • Functionally WT-like/intermediate CHEK2 VUS do not increase breast cancer risk in heterozygous carriers, aiding clinical interpretation.