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Heterogeneity Mapping of Protein Expression in Tumors using Quantitative Immunofluorescence
Published on: October 25, 2011
Oncogenic MAP2K1 mutations in human epithelial tumors
Young Lim Choi1, Manabu Soda, Toshihide Ueno
1Division of Functional Genomics, Jichi Medical University, Tochigi 329-0498, Japan.
Abstract:
The scirrhous subtype of gastric cancer is a highly infiltrative tumor with a poor outcome. To identify a transforming gene in this intractable disorder, we constructed a retroviral complementary DNA (cDNA) expression library from a cell line (OCUM-1) of scirrhous gastric cancer. A focus formation assay with the library and mouse 3T3 fibroblasts led to the discovery of a transforming cDNA, encoding for MAP2K1 with a glutamine-to-proline substitution at amino acid position 56. Interestingly, treatment with a MAP2K1-specific inhibitor clearly induced cell death of OCUM-1 but not of other two cells lines of scirrhous gastric cancer that do not carry MAP2K1 mutations, revealing the essential role of MAP2K1(Q56P) in the transformation mechanism of OCUM-1 cells. By using a next-generation sequencer, we further conducted deep sequencing of the MAP2K1 cDNA among 171 human cancer specimens or cell lines, resulting in the identification of one known (D67N) and four novel (R47Q, R49L, I204T and P306H) mutations within MAP2K1. The latter four changes were further shown to confer transforming potential to MAP2K1. In our experiments, a total of six (3.5%) activating mutations in MAP2K1 were thus identified among 172 of specimens or cell lines for human epithelial tumors. Given the addiction of cancer cells to the elevated MAP2K1 activity for proliferation, human cancers with such MAP2K1 mutations are suitable targets for the treatment with MAP2K1 inhibitors.
Insights
Researchers identified activating mutations in MAP2K1, a gene crucial for cell growth, within scirrhous gastric cancer. These MAP2K1 mutations make cancer cells dependent on the gene, suggesting MAP2K1 inhibitors as a potential treatment for these tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Scirrhous gastric cancer is an aggressive tumor subtype with a poor prognosis.
- Identifying the genetic drivers of this cancer is critical for developing effective therapies.
Purpose of the Study:
- To identify novel transforming genes in scirrhous gastric cancer.
- To investigate the role of identified mutations in cancer development and therapeutic targeting.
Main Methods:
- Construction of a complementary DNA (cDNA) expression library from scirrhous gastric cancer cells (OCUM-1).
- Focus formation assay using mouse 3T3 fibroblasts to identify transforming genes.
- Next-generation sequencing (deep sequencing) of MAP2K1 cDNA in human cancer specimens and cell lines.
- Treatment of cancer cells with a MAP2K1-specific inhibitor.
Main Results:
- Discovery of a transforming cDNA encoding MAP2K1 with a specific mutation (Q56P) in OCUM-1 cells.
- MAP2K1(Q56P) was essential for OCUM-1 cell transformation, as inhibiting MAP2K1 induced cell death.
- Deep sequencing identified six activating MAP2K1 mutations (including four novel ones) in 3.5% of 172 human epithelial tumor specimens/cell lines.
- The novel mutations (R47Q, R49L, I204T, P306H) conferred transforming potential to MAP2K1.
Conclusions:
- Activating mutations in MAP2K1 are present in a subset of human epithelial tumors, including scirrhous gastric cancer.
- Cancer cells with these MAP2K1 mutations exhibit addiction to elevated MAP2K1 activity for proliferation.
- MAP2K1 inhibitors represent a promising targeted therapy for human cancers harboring these specific MAP2K1 mutations.
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