Abstract
To understand the importance of chr11q22.3-23.2 region in the development of cervical cancer, we have studied the genetic and epigenetic alterations of the candidate genes ATM, PPP2R1B, SDHD and CADM1 in cervical intraepithelial neoplasia (CIN) and cervical carcinoma (CACX) samples. Our study revealed low expression and high alterations (methylation/deletion) (55-59%) of ATM and CADM1 genes along with poor patient outcome. The alterations of ATM and CADM1 are associated with the progression of tumor from CIN to Stage I/II, thus implying their role in early invasiveness. The two genes, PPP2R1B and SDHD, lying in between ATM and CADM1, have low frequency of alterations, and majority of the alterations are in CACX samples, indicating that their alterations might be associated with disease progression. Expressions (mRNA/protein) of the genes showed concordance with their molecular alterations. Significant co-alteration of ATM and CADM1 points to their synergic action for the development of CACX. Mutation is, however, a rare phenomenon for inactivation of ATM. Association between the alteration of ATM and CHEK1 and poor survival of the patients having co-alterations of ATM and CHEK1 points to the DNA damage response pathway disruption in development of CACX. Thus, our data suggest that inactivation of ATM-CHEK1-associated DNA damage response pathway and CADM1-associated signaling network might have an important role in the development of CACX.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Ataxia Telangiectasia Mutated Proteins
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Cell Adhesion Molecule-1
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Cell Adhesion Molecules / biosynthesis
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Cell Adhesion Molecules / genetics*
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / genetics*
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Cell Line, Tumor
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Checkpoint Kinase 1
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Chromosome Aberrations*
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Chromosomes, Human, Pair 11*
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DNA Damage
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DNA Methylation
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics*
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Disease Progression
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Epigenomics / methods
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Female
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Gene Expression Regulation, Neoplastic
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HeLa Cells
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Humans
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Immunoglobulins / biosynthesis
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Immunoglobulins / genetics*
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Mutation
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Neoplasm Staging
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Papillomavirus Infections / complications
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Papillomavirus Infections / genetics
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Papillomavirus Infections / metabolism
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Papillomavirus Infections / pathology
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Promoter Regions, Genetic
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Protein Kinases / genetics
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Protein Phosphatase 2 / biosynthesis
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Protein Phosphatase 2 / genetics
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics*
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Signal Transduction
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Tumor Suppressor Proteins / biosynthesis
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Tumor Suppressor Proteins / genetics*
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Uterine Cervical Dysplasia / genetics*
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Uterine Cervical Dysplasia / pathology
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Uterine Cervical Dysplasia / virology
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Uterine Cervical Neoplasms / genetics*
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Uterine Cervical Neoplasms / metabolism
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Uterine Cervical Neoplasms / pathology*
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Uterine Cervical Neoplasms / virology
Substances
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CADM1 protein, human
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Cell Adhesion Molecule-1
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Cell Adhesion Molecules
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Cell Cycle Proteins
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DNA-Binding Proteins
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Immunoglobulins
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PPP2R1B protein, human
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Tumor Suppressor Proteins
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Protein Kinases
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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CHEK1 protein, human
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Checkpoint Kinase 1
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Protein Serine-Threonine Kinases
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Protein Phosphatase 2