High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer.
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 mut...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2009-05-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2684631?pdf=render |
| _version_ | 1819060642072494080 |
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| author | Vladimir I Kashuba Tatiana V Pavlova Elvira V Grigorieva Alexey Kutsenko Surya Pavan Yenamandra Jingfeng Li Fuli Wang Alexei I Protopopov Veronika I Zabarovska Vera Senchenko Klas Haraldson Tatiana Eshchenko Julia Kobliakova Olga Vorontsova Igor Kuzmin Eleonora Braga Vladimir M Blinov Lev L Kisselev Yi-Xin Zeng Ingemar Ernberg Michael I Lerman George Klein Eugene R Zabarovsky |
| author_facet | Vladimir I Kashuba Tatiana V Pavlova Elvira V Grigorieva Alexey Kutsenko Surya Pavan Yenamandra Jingfeng Li Fuli Wang Alexei I Protopopov Veronika I Zabarovska Vera Senchenko Klas Haraldson Tatiana Eshchenko Julia Kobliakova Olga Vorontsova Igor Kuzmin Eleonora Braga Vladimir M Blinov Lev L Kisselev Yi-Xin Zeng Ingemar Ernberg Michael I Lerman George Klein Eugene R Zabarovsky |
| author_sort | Vladimir I Kashuba |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T14:30:14Z |
| format | Article |
| id | doaj.art-6ded5c2809ec482d9488ed168810d39c |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T14:30:14Z |
| publishDate | 2009-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-6ded5c2809ec482d9488ed168810d39c2022-12-21T19:00:31ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-05-0145e523110.1371/journal.pone.0005231High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer.Vladimir I KashubaTatiana V PavlovaElvira V GrigorievaAlexey KutsenkoSurya Pavan YenamandraJingfeng LiFuli WangAlexei I ProtopopovVeronika I ZabarovskaVera SenchenkoKlas HaraldsonTatiana EshchenkoJulia KobliakovaOlga VorontsovaIgor KuzminEleonora BragaVladimir M BlinovLev L KisselevYi-Xin ZengIngemar ErnbergMichael I LermanGeorge KleinEugene R ZabarovskyBACKGROUND: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.http://europepmc.org/articles/PMC2684631?pdf=render |
| spellingShingle | Vladimir I Kashuba Tatiana V Pavlova Elvira V Grigorieva Alexey Kutsenko Surya Pavan Yenamandra Jingfeng Li Fuli Wang Alexei I Protopopov Veronika I Zabarovska Vera Senchenko Klas Haraldson Tatiana Eshchenko Julia Kobliakova Olga Vorontsova Igor Kuzmin Eleonora Braga Vladimir M Blinov Lev L Kisselev Yi-Xin Zeng Ingemar Ernberg Michael I Lerman George Klein Eugene R Zabarovsky High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer. PLoS ONE |
| title | High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer. |
| title_full | High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer. |
| title_fullStr | High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer. |
| title_full_unstemmed | High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer. |
| title_short | High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer. |
| title_sort | high mutability of the tumor suppressor genes rassf1 and rbsp3 ctdspl in cancer |
| url | http://europepmc.org/articles/PMC2684631?pdf=render |
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