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A polymorphism but no mutations in the GADD45 gene in breast cancers
H Blaszyk1, A Hartmann, S S Sommer
1Department of Oncology, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
Abstract:
The p53 gene product is part of a pathway regulating growth arrest at the G1 checkpoint of the cell cycle. Mutation of other components of this pathway, including the products of the ataxia telangiectasia (AT), GADD45, mdm2, and p21WAF1/CIP1 genes may have effects comparable to mutations in the p53 gene. The GADD45 gene is induced by ionizing radiation and several DNA-damaging xenobiotics. Induction requires the binding of wild-type p53 to an evoulutionarily highly conserved putative intronic p53 binding site in intron 3 of GADD45. We recently analyzed the entire coding region of the p53 gene in primary breast cancers of Midwestern white women and found 21 mutations among 53 tumors (39.6%). We now have shown by direct sequencing that there are no mutations in the intronic p53 binding site of the GADD45 gene in any of the 53 primary breast cancers and no mutations in the entire coding region of the GADD45 gene in a subset of 26 consecutive tumors (12 with p53 mutation and 14 without p53 mutation). The only sequence variation detected was a common polymorphism in intron 3. The absence of mutations in the GADD45 gene, including the putative p53-binding intronic site, suggests that this gene is not a frequent target of mutations in breast cancer. Although mutations of the p53 gene have been studied in a wide spectrum of human cancers, GADD45 has not been examined in any tumor or cell line to the best of our knowledge. Our results raise the possibility that mutation of the GADD45 gene alone is not functionally equivalent to loss of wild-type p53 activity.
Insights
Mutations in the p53 pathway are common in breast cancer. However, the GADD45 gene, crucial for p53 function, shows no mutations in breast tumors, suggesting it
Area of Science:
- Molecular Biology
- Cancer Genetics
- Cell Cycle Regulation
Background:
- The p53 tumor suppressor is critical for cell cycle control, responding to DNA damage.
- Mutations in p53 pathway genes, including GADD45, can impact cancer development.
- GADD45 induction by DNA damage requires functional wild-type p53 binding to its intronic site.
Purpose of the Study:
- To investigate mutations in the GADD45 gene, specifically its p53-binding site, in primary breast cancers.
- To determine if GADD45 mutations contribute to breast cancer development, similar to p53 mutations.
Main Methods:
- Direct sequencing of the entire coding region of the p53 gene in 53 breast tumors.
- Direct sequencing of the intronic p53-binding site in GADD45 for all 53 tumors.
- Direct sequencing of the entire coding region of GADD45 in a subset of 26 tumors.
Main Results:
- 21 out of 53 (39.6%) breast tumors harbored p53 gene mutations.
- No mutations were detected in the intronic p53-binding site of the GADD45 gene in any of the 53 tumors.
- No mutations were found in the coding region of GADD45 in the 26-tumor subset.
Conclusions:
- The GADD45 gene, including its critical p53-binding site, is not a frequent target of mutation in breast cancer.
- The absence of GADD45 mutations suggests that GADD45 gene alterations alone are unlikely to be functionally equivalent to p53 loss of function in breast cancer.