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Altered WAF1 genes do not play a role in abnormal cell cycle regulation in breast cancers lacking p53 mutations
K E McKenzie1, A Siva, S Maier
1Breast Cancer Program, Johns Hopkins Oncology Center, Baltimore, Maryland 21045, USA.
Abstract:
Seventy-five to 80% of breast cancers are negative for p53 gene mutations. We have investigated the possibility that altered WAF1 genes provide an alternative mode of cell cycle disruption in these tumors. DNA from a total of 85 primary breast tumors and cell lines from both the United States and Australia were examined for WAF1 and p53 mutations. With the exception of one primary tumor containing the polymorphic codon 31 (AGC-->AGA), no missense mutations in the WAF1 gene were found in 33 primary tumors or in the 19 cell lines from the United States. By contrast, 2 of 33 tumors from Australia contained tumor-specific missense mutations in the WAF1 gene, while an additional six cases contained the AGC-->AGA polymorphic 31st codon in the WAF1 gene. The p53 mutation frequency in the Australian cohort (18%) was found to be similar to that reported by us (Glebov et al., Cancer Res., 54: 3703-3709, 1994; Runnebaum et al., Proc. Natl. Acad. Sci. USA, 88: 10657-10661, 1991) in the tumors of United States patients (13%) with sporadic breast cancer. Thus, mutations in the WAF1 gene are rare in tumors with or without p53 mutations, suggesting that except in a minor population of breast cancer patients of Caucasian origin, cell cycle dysregulation by mutated p53 or WAF1 genes may not contribute to breast tumor initiation or progression.
Insights
Most breast cancers lack p53 gene mutations. This study found WAF1 gene mutations are rare in breast tumors, suggesting they rarely cause cell cycle disruption, except in a small Caucasian population.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Most breast cancers (75-80%) do not exhibit p53 gene mutations.
- Investigating alternative mechanisms of cell cycle disruption is crucial for understanding breast cancer development.
Purpose of the Study:
- To investigate WAF1 gene mutations as an alternative cause of cell cycle disruption in breast cancers lacking p53 mutations.
- To compare WAF1 and p53 mutation frequencies in breast tumors from the United States and Australia.
Main Methods:
- DNA analysis of 85 primary breast tumors and cell lines from the US and Australia.
- Screening for WAF1 and p53 gene mutations, including specific polymorphic sites.
Main Results:
- No significant WAF1 missense mutations were detected in US breast tumors or cell lines.
- Two Australian tumors showed WAF1 missense mutations; six had a common WAF1 polymorphism.
- p53 mutation rates were similar in both US (13%) and Australian (18%) cohorts.
Conclusions:
- WAF1 gene mutations are infrequent in breast tumors, irrespective of p53 mutation status.
- Altered WAF1 or p53 genes are unlikely to be major drivers of breast cancer initiation or progression, except in a minor Caucasian subgroup.