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 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.
Kashuba
Vladimir I
VI
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
Pavlova
Tatiana V
TV
Grigorieva
Elvira V
EV
Kutsenko
Alexey
A
Yenamandra
Surya Pavan
SP
Li
Jingfeng
J
Wang
Fuli
F
Protopopov
Alexei I
AI
Zabarovska
Veronika I
VI
Senchenko
Vera
V
Haraldson
Klas
K
Eshchenko
Tatiana
T
Kobliakova
Julia
J
Vorontsova
Olga
O
Kuzmin
Igor
I
Braga
Eleonora
E
Blinov
Vladimir M
VM
Kisselev
Lev L
LL
Zeng
Yi-Xin
YX
Ernberg
Ingemar
I
Lerman
Michael I
MI
Klein
George
G
Zabarovsky
Eugene R
ER
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)
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