title: High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Kashuba
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Pavlova
authors.forename: Elvira V
authors.initials: EV
authors.lastname: Grigorieva
authors.forename: Alexey
authors.initials: A
authors.lastname: Kutsenko
authors.forename: Surya Pavan
authors.initials: SP
authors.lastname: Yenamandra
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Li
authors.forename: Fuli
authors.initials: F
authors.lastname: Wang
authors.forename: Alexei I
authors.initials: AI
authors.lastname: Protopopov
authors.forename: Veronika I
authors.initials: VI
authors.lastname: Zabarovska
authors.forename: Vera
authors.initials: V
authors.lastname: Senchenko
authors.forename: Klas
authors.initials: K
authors.lastname: Haraldson
authors.forename: Tatiana
authors.initials: T
authors.lastname: Eshchenko
authors.forename: Julia
authors.initials: J
authors.lastname: Kobliakova
authors.forename: Olga
authors.initials: O
authors.lastname: Vorontsova
authors.forename: Igor
authors.initials: I
authors.lastname: Kuzmin
authors.forename: Eleonora
authors.initials: E
authors.lastname: Braga
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Blinov
authors.forename: Lev L
authors.initials: LL
authors.lastname: Kisselev
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Ingemar
authors.initials: I
authors.lastname: Ernberg
authors.forename: Michael I
authors.initials: MI
authors.lastname: Lerman
authors.forename: George
authors.initials: G
authors.lastname: Klein
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Zabarovsky
mesh_terms: D000071479:APOBEC-1 Deaminase; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002999:Clone Cells; D019295:Computational Biology; D003564:Cytidine Deaminase / Q000378:metabolism; D004269:DNA, Bacterial / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics; D020224:Expressed Sequence Tags; D018703:Founder Effect; D016678:Genome / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: C486483:CTDSPL protein, human; D004269:DNA, Bacterial; D018076:DNA, Complementary; D029968:Escherichia coli Proteins; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase