High Mutability of the Tumor Suppressor Genes RASSF1 and RBSP3 (CTDSPL) in Cancer

Abstract

BackgroundMany 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 FindingsWe 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/SignificanceThis 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.

Damage-induced localized hypermutability

“…Multiple mutations that appear to be simultaneous or coordinated in time (chronocoordinate) have been detected in normal mouse and human tissues 15,16 and in tumors. [17][18][19] While the fraction of mutations that appear to be chronocoordinate is small, they may play bigger roles in some types of cancers, especially those associated with a high density of DNA damage (see below).…”

Understanding thrombocytopenia: physiological role of microRNA in survival of neonatal megakaryocytes

“…Based on the known role of CTDSPL, a target of miR-99a, we believe that the lower levels of CTDSPL in CB could be partially responsible for the high proliferative rate of neonatal MK progenitors. CTDSPL is identified as phosphatase-like tumor suppressor gene that dephosphorylates the RB1 serine on Ser-807 and Ser-811 [13,14]. We therefore evaluated protein expression levels of CTDSPL downstream regulators such as pRB, Cyclin D1, D2, D3 and E2F1 in mature CB-and PB-derived MKs.…”

“…a miR-99a levels in CB cells at different stages (day 0,7,11,14) of MK differentiation in culture, expressed as relative to miR-99a levels in PB cells at the same stage of differentiation. Bars represent mean ± SD of three independent experiments (*p \ 0.05).…”

Lentivirus-mediated silencing of USO1 inhibits cell proliferation and migration of human colon cancer cells

“…USO1 (vesicle transport factor), also known as P115/ TAP, is a member of tether protein family, including a central coiled-coil domain, N-terminal globular domain and C-terminal acidic region in its structure [4,5]. USO1 has a crucial role not only in vesicle trafficking, especially in endoplasmic reticulum-Golgi transport [6,7] promoting the homotype vesicles fusion by recruitment of Rab1a [8], but also enhances other proteins to target Golgi membrane by interacting with soluble NSF attachment protein receptors (SNARE) [7].…”