Alterations of ATM and CADM1 in chromosomal 11q22.3–23.2 region are associated with the development of invasive cervical carcinoma

• Published in: Human genetics 2011-12, Vol.130 (6), p.735-748
• Main Authors: Mazumder Indra, Dipanjana, Mitra, Sraboni, Roy, Anup, Mondal, Ranajit Kumar, Basu, Partha Sarathi, Roychoudhury, Susanta, Chakravarty, Runu, Panda, Chinmay Kumar
• Format: Article
• Language: English
• Subjects: Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer; Carcinoma; Cell Adhesion Molecule-1; Cell Adhesion Molecules - biosynthesis; Cell Adhesion Molecules - genetics; Cell Cycle Proteins - biosynthesis; Cell Cycle Proteins - genetics; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cervical cancer; Cervical carcinoma; Cervical Intraepithelial Neoplasia - genetics; Cervical Intraepithelial Neoplasia - pathology; Cervical Intraepithelial Neoplasia - virology; Cervix; Checkpoint Kinase 1; Chromosome Aberrations; Chromosomes, Human, Pair 11; Classical genetics, quantitative genetics, hybrids; Colon; Data processing; Development and progression; Disease Progression; DNA Damage; DNA Methylation; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; epigenetics; Epigenomics - methods; Female; Female genital diseases; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; Gene Function; Genes; Genetics of eukaryotes. Biological and molecular evolution; Gynecology. Andrology. Obstetrics; HeLa Cells; Human; Human Genetics; Humans; Immunoglobulins - biosynthesis; Immunoglobulins - genetics; Invasiveness; Medical sciences; Metabolic Diseases; Molecular and cellular biology; Molecular Medicine; mRNA; Mutation; Neoplasia; Neoplasm Staging; Original Investigation; Ovaries; Papillomavirus Infections - complications; Papillomavirus Infections - genetics; Papillomavirus Infections - metabolism; Papillomavirus Infections - pathology; Patients; Promoter Regions, Genetic; Protein Kinases - genetics; Protein Phosphatase 2 - biosynthesis; Protein Phosphatase 2 - genetics; Protein-Serine-Threonine Kinases - biosynthesis; Protein-Serine-Threonine Kinases - genetics; Proteins; Signal Transduction; Survival; Tumor Suppressor Proteins - biosynthesis; Tumor Suppressor Proteins - genetics; Tumors; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - virology
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-011-1015-8

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.