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Association between human cancer and two polymorphisms occurring together in the p21Waf1/Cip1 cyclin-dependent kinase
E A Facher1, M J Becich, A Deka
1Department of Human Genetics, University of Pittsburgh, PA 15261, USA.
Background:
The cyclin-dependent kinase inhibitor gene p21Waf1/Cip1 plays a role in signaling cellular growth arrest. In response to DNA damage, p21 is induced by the p53 gene, thereby playing a direct role in mediating p53-induced G1 arrest. Alterations in this gene may adversely affect regulation of cellular proliferation and increase susceptibility for cancer. Two polymorphisms have previously been characterized in the p21 gene: a C-->A transversion at codon 31 (ser-->arg) and a C-->T transition 20 nucleotides downstream from the 3' end of exon 3.
Methods:
The codon 31 polymorphism in exon 2 of the p21 gene was identified by restriction digestion (Alw26I) of products amplified by polymerase chain reaction (PCR). The polymorphism downstream from exon 3 of the p21 gene was identified by single strand conformation polymorphism (SSCP) analysis of PCR amplified products and was confirmed by PstI enzyme restriction digestion. DNA variant alleles were confirmed by direct DNA sequencing. The entire coding region and the promoter region (p53 binding domain) of the p21 gene were screened for mutations by SSCP analysis or DNA sequencing.
Results:
The two polymorphisms were found in 18 of 96 tumor samples lacking p53 alterations (18.8%). Nine of 54 prostate adenocarcinoma samples (16.7%) contained both p21 variants, whereas 9 of 42 squamous cell carcinomas of the head and neck (21.4%) displayed both polymorphisms. Of the 110 controls examined, 10 (9.1%) had both alterations. Both p21 polymorphisms occurred together in all samples examined and there was no indication of mutation in the coding region of the p21 gene or in the p53 binding domain of the promoter region.
Conclusions:
These data suggest that p21 gene variants may play a role in increased susceptibility for the development of some types of cancer. In the current study, the authors demonstrated that the occurrence of these two polymorphisms is increased in prostate adenocarcinoma and squamous cell carcinoma of the head and neck. The polymorphic sites may be directly responsible for this apparent increased susceptibility or they may be linked to regulatory region alterations.
Insights
Two p21 gene variants are linked to increased cancer susceptibility. These polymorphisms were more frequent in prostate and head and neck cancers, suggesting a role in cancer development.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- The p21Waf1/Cip1 gene is crucial for cell cycle arrest, particularly in response to DNA damage via the p53 pathway.
- Alterations in p21 gene function can disrupt cellular proliferation control, potentially increasing cancer risk.
- Two known polymorphisms exist in the p21 gene: one at codon 31 (serine to arginine) and another downstream of exon 3.
Purpose of the Study:
- To investigate the association between p21 gene polymorphisms and cancer susceptibility.
- To determine the frequency of these p21 variants in specific cancer types and compare them to controls.
Main Methods:
- Polymerase chain reaction (PCR) amplification followed by restriction digestion (Alw26I) for the codon 31 polymorphism.
- Single-strand conformation polymorphism (SSCP) analysis and PstI digestion for the downstream polymorphism.
- Direct DNA sequencing to confirm variant alleles and screen the coding and promoter regions for mutations.
Main Results:
- Both p21 polymorphisms were found together in 18.8% of tumor samples without p53 alterations.
- The combined polymorphisms were observed in 16.7% of prostate adenocarcinomas and 21.4% of head and neck squamous cell carcinomas.
- A lower frequency of both polymorphisms (9.1%) was found in control subjects, with no coding region or p53 binding domain mutations detected.
Conclusions:
- p21 gene variants may contribute to an increased susceptibility to certain cancers.
- The study observed a higher prevalence of these two p21 polymorphisms in prostate and head and neck cancers.
- These polymorphic sites might directly influence cancer risk or be linked to other regulatory alterations.