Induction of gene mutations and chromosomal aberrations by simian virus 40 in cultured mammalian cells

Marshak, Marina I.; Varshaver, Nina B.; Shapiro, N.I.

doi:10.1016/0027-5107(75)90009-3

Cited by 39 publications

(8 citation statements)

References 23 publications

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“…The non-random nature of viral integration and the potential for integration events to cause toxicity and cancer have long been realized [17,18]. However, a formal VIS hot-spot definition was not described until the turn of the century when Suzuki et al (2002) developed a definition for retroviral integration in cancer cells to discover potential cancer-related genes [19].…”

Section: Introductionmentioning

confidence: 99%

Methodology and software to detect viral integration site hot-spots

et al. 2011

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BackgroundModern gene therapy methods have limited control over where a therapeutic viral vector inserts into the host genome. Vector integration can activate local gene expression, which can cause cancer if the vector inserts near an oncogene. Viral integration hot-spots or 'common insertion sites' (CIS) are scrutinized to evaluate and predict patient safety. CIS are typically defined by a minimum density of insertions (such as 2-4 within a 30-100 kb region), which unfortunately depends on the total number of observed VIS. This is problematic for comparing hot-spot distributions across data sets and patients, where the VIS numbers may vary.ResultsWe develop two new methods for defining hot-spots that are relatively independent of data set size. Both methods operate on distributions of VIS across consecutive 1 Mb 'bins' of the genome. The first method 'z-threshold' tallies the number of VIS per bin, converts these counts to z-scores, and applies a threshold to define high density bins. The second method 'BCP' applies a Bayesian change-point model to the z-scores to define hot-spots. The novel hot-spot methods are compared with a conventional CIS method using simulated data sets and data sets from five published human studies, including the X-linked ALD (adrenoleukodystrophy), CGD (chronic granulomatous disease) and SCID-X1 (X-linked severe combined immunodeficiency) trials. The BCP analysis of the human X-linked ALD data for two patients separately (774 and 1627 VIS) and combined (2401 VIS) resulted in 5-6 hot-spots covering 0.17-0.251% of the genome and containing 5.56-7.74% of the total VIS. In comparison, the CIS analysis resulted in 12-110 hot-spots covering 0.018-0.246% of the genome and containing 5.81-22.7% of the VIS, corresponding to a greater number of hot-spots as the data set size increased. Our hot-spot methods enable one to evaluate the extent of VIS clustering, and formally compare data sets in terms of hot-spot overlap. Finally, we show that the BCP hot-spots from the repopulating samples coincide with greater gene and CpG island density than the median genome density.ConclusionsThe z-threshold and BCP methods are useful for comparing hot-spot patterns across data sets of disparate sizes. The methodology and software provided here should enable one to study hot-spot conservation across a variety of VIS data sets and evaluate vector safety for gene therapy trials.

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Section: Introductionmentioning

confidence: 99%

Methodology and software to detect viral integration site hot-spots

et al. 2011

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“…Of especial interest is the fact that the transformation character under study (ser-+ser+) is induced by the oncogenic virus SV40. In our previous studies of viral mutagenesis (Marshak et al, 1975;Varshaver et al, 1977) we have hypothesized that the viruses might cause malignant transformation by inducing mutations in the relevant genes. The data presented in this study seem to support that possibility.…”

Section: Discussionmentioning

confidence: 99%

“…The data presented in this study seem to support that possibility. A comparison of the values of induction of ser+ variants and HPRT++HPRT-mu-tations after infection with SV40 shows them to be roughly equal (Marshak et al, 1973(Marshak et al, , 1975. Another important fact is that the induction of ser+ variants was detected after 3-4 days expression time, which is typical of gene mutations (Marshak et al, 1975;Varshaver et al, 1977;Bellett and Younghusband, 1979;Landolph and Heidelberger, 1979).…”

Section: Discussionmentioning

confidence: 99%

The mutational origin of serum independence in Chinese hamster cells in vitro

Varshaver

Marshak

Shapiro

1983

Intl Journal of Cancer

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The genetic mechanisms determining the ability of transformed cells to grow in a medium with a low serum content (ser+) were studied in a clone of Chinese hamster cells with normal serum requirements. The fluctuation test has shown that serum independence occurs as a random spontaneous event. Its rate of occurrence is about 10(-5). The concomitant study of a gene mutation (resistance to 6-mercaptopurine--6MP) revealed similar characteristics with respect to the distribution of the number of mutants in replicative cultures. N-methyl-N1-nitro-N-nitrosoguanidine (MNNG) and SV40 significantly increased the frequency of ser+ colonies. Induction was detected after an expression time of 3-4 days, which is typical of gene mutations. In 16 out of 18 ser+ clones of independent origin the ser+ character remained stable. The results suggest that the ser+ character originates in most cases from a mutation event.

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“…The extent to which any potential mutagenic activity of SV40 is related to its transforming activity is unknown. A number of studies have shown that SV40 infection of nonpermissive and semipermissive cell lines results in chromosomal changes, such as polyploidization (7,8) and chromosomal breaks and rearrangements (8,12,29), and in somatic mutations at different loci (12,24,25,27,28). The observation that some cells transformed by SV40 have altered karyotypes (9, 29) led to the suggestion that polyploidization may be involved in the process of malignant transformation (9).…”

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confidence: 99%

Relationship of Simian Virus 40 Tumor Antigens to Virus-Induced Mutagenesis

Zannis‐Hadjopoulos

Martin

1983

Molecular and Cellular Biology

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We analyzed the mutation frequency to 8-azaguanine (8AZ) resistance in rat FR3T3 cells acutely infected with simian virus 40 wild type and tsA and early deletion mutants and in a series of temperature-sensitive (N) and temperature-insensitive (A) transformants derived from Chinese hamster lung (CHL) cells. Upon acute infection, the frequency of mutation to 8AZ resistance was raised at most by two- to eightfold over the spontaneous frequency, and it was independent of the presence of a functional 90,000-molecular-weight T antigen or 20,000-molecular-weight t antigen or both. Similarly, in the stable transformants of CHL cells, no correlation was found between functional T antigens and mutation to 8AZ resistance. It therefore seems unlikely that simian virus 40-induced transformation results from any mutagenic activity of this virus.

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Induction of gene mutations and chromosomal aberrations by simian virus 40 in cultured mammalian cells

Cited by 39 publications

References 23 publications

Methodology and software to detect viral integration site hot-spots

Methodology and software to detect viral integration site hot-spots

The mutational origin of serum independence in Chinese hamster cells in vitro

Relationship of Simian Virus 40 Tumor Antigens to Virus-Induced Mutagenesis

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