High Mutability of the Tumor Suppressor Genes RASSF1 and RBSP3 (CTDSPL) in Cancer
| Autor: | Eleonora A. Braga, George Klein, Blinov Vm, Ingemar Ernberg, Tatiana Eshchenko, Lev L. Kisselev, Eugene R. Zabarovsky, Julia Kobliakova, Veronica I. Zabarovska, Vladimir I. Kashuba, Michael I. Lerman, Tatiana V. Pavlova, Jingfeng Li, Yi Xin Zeng, Alexey S. Kutsenko, V. N. Senchenko, Fuli Wang, Olga Vorontsova, Elvira V. Grigorieva, Alexei Protopopov, Klas Haraldson, Surya Pavan Yenamandra, Igor Kuzmin |
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| Rok vydání: | 2009 |
| Předmět: |
Somatic cell
lcsh:Medicine Mice SCID medicine.disease_cause Polymerase Chain Reaction Mice Neoplasms Mutation frequency Oncology/Hematological Malignancies lcsh:Science Genetics and Genomics/Genetics of Disease Oncology/Renal Cancer Genetics and Genomics/Medical Genetics Expressed Sequence Tags Genetics Mutation Genome Multidisciplinary Escherichia coli Proteins Founder Effect Kidney Neoplasms Oncology/Breast Cancer Computational Biology/Sequence Motif Analysis Oncology/Gynecological Cancers Research Article DNA Bacterial DNA Complementary APOBEC-1 Deaminase Somatic hypermutation Biology Cell Line Cell Line Tumor Cytidine Deaminase medicine Animals Humans Genetics and Genomics/Cancer Genetics Carcinoma Renal Cell Gene Oncology/Lung Cancer Cell Proliferation Tumor Suppressor Proteins Point mutation lcsh:R Computational Biology Cancer medicine.disease Clone Cells Hematopoiesis Cancer cell lcsh:Q |
| Zdroj: | PLoS ONE, Vol 4, Iss 5, p e5231 (2009) PLoS ONE |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0005231 |
| Popis: | Background Many different genetic alterations are observed in cancer cells. Individual cancer genes display point mutations such as base changes, insertions and deletions that initiate and promote cancer growth and spread. Somatic hypermutation is a powerful mechanism for generation of different mutations. It was shown previously that somatic hypermutability of proto-oncogenes can induce development of lymphomas. Methodology/Principal Findings We found an exceptionally high incidence of single-base mutations in the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) both located in 3p21.3 regions, LUCA and AP20 respectively. These regions contain clusters of tumor suppressor genes involved in multiple cancer types such as lung, kidney, breast, cervical, head and neck, nasopharyngeal, prostate and other carcinomas. Altogether in 144 sequenced RASSF1A clones (exons 1–2), 129 mutations were detected (mutation frequency, MF = 0.23 per 100 bp) and in 98 clones of exons 3–5 we found 146 mutations (MF = 0.29). In 85 sequenced RBSP3 clones, 89 mutations were found (MF = 0.10). The mutations were not cytidine-specific, as would be expected from alterations generated by AID/APOBEC family enzymes, and appeared de novo during cell proliferation. They diminished the ability of corresponding transgenes to suppress cell and tumor growth implying a loss of function. These high levels of somatic mutations were found both in cancer biopsies and cancer cell lines. Conclusions/Significance This is the first report of high frequencies of somatic mutations in RASSF1 and RBSP3 in different cancers suggesting it may underlay the mutator phenotype of cancer. Somatic hypermutations in tumor suppressor genes involved in major human malignancies offer a novel insight in cancer development, progression and spread. |
| Databáze: | OpenAIRE |
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