Intestinal adenomas can develop with a stable karyotype and stable microsatellites

Haigis, Kevin M.; Caya, James G.; Reichelderfer, Mark; Dove, William F.

doi:10.1073/pnas.132275099

Cited by 85 publications

(74 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All mice were backcrossed to B6 for at least 11 (Atm), 10 (Blm) or 5 (Lig4) generations. Mouse husbandry and dissection were performed as previously described (Haigis et al, 2002). All mice were dissected between 3 and 5 months of age except for irradiated mice, which became moribund at 2 months.…”

Section: Apcmentioning

confidence: 99%

Atm is a negative regulator of intestinal neoplasia

et al. 2007

View full text Add to dashboard Cite

The ataxia telangiectasia-mutated (ATM) gene has been implicated as an early barrier to the growth and progression of incipient solid tumors. Here, we show that germ-line nullizygosity for the mouse Atm gene significantly increases the proliferative index, net growth rate and multiplicity of intestinal adenomas in two distinct models of familial colon cancer: Apc Min/ þ and Apc 1638N/ þ . These effects of Atm deficiency are quantitatively different from deficiency for either of the genomic stability genes Bloom's syndrome helicase or DNA ligase 4, and the effect of Atm loss on tumor multiplicity is largely independent of the effect of ionizing radiation. Furthermore, the loss of heterozygosity rates at the adenomatous polyposis coli (Apc) locus are unaffected by Atm loss. Taken together, these data implicate the Atm gene product as a barrier to dysplastic growth in the early stages of intestinal tumor progression, independent of its effects on genomic stability.

show abstract

Section: Apcmentioning

confidence: 99%

Atm is a negative regulator of intestinal neoplasia

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Genetic instability is one of the most active research areas of cancer biology (12,13,(21)(22)(23)(24)(25)(26). Loeb and colleagues (14,27) were the first to suggest that somatic evolution of cancer might be driven by cells with increased mutation rates, so-called mutator phenotypes.…”

Section: [2]mentioning

confidence: 99%

Evolutionary dynamics of tumor suppressor gene inactivation

Nowak

Michor

Komarova

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Tumor suppressor genes (TSGs) are important gatekeepers that protect against somatic evolution of cancer. Losing both alleles of a TSG in a single cell represents a step toward cancer. We study how the kinetics of TSG inactivation depends on the population size of cells and the mutation rates for the first and second hit. We calculate the probability as function of time that at least one cell has been generated with two inactivated alleles of a TSG. We find three different kinetic laws: in small, intermediate, and large populations, it takes, respectively, two, one, and zero rate-limiting steps to inactivate a TSG. We also study the effect of chromosomal and other genetic instabilities. Small lesions without genetic instability can take a very long time to inactivate the next TSG, whereas the same lesions with genetic instability pose a much greater risk for cancer progression.I n 1971, Knudson (1) performed a statistical analysis of the incidence of retinoblastoma in young children. This analysis and subsequent work eventually led to the model invoking two hits of the retinoblastoma gene as rate-limiting steps in tumorigenesis (2-6). In the inherited form, the first mutation is already present in the germ line, whereas the second mutation emerges during somatic cell divisions. These observations led to the concept of a tumor suppressor gene (TSG). In the meantime, a large number of TSGs have been discovered that are involved in various human cancers (7-10). Here, we will calculate the dynamics of inactivating TSGs in populations of dividing cells with or without genetic instability (11-15).A normal cell has two alleles of a TSG. Inactivating the first allele is considered to be a neutral (or almost neutral) mutation. Inactivating the second allele provides the cell with an increased net reproductive rate. Point mutations, small insertions, deletions, structural changes of the chromosome, or chromosomal loss can constitute the first hit, whereas all of these events plus mitotic recombination can occur as the second hit. Usually large deletions or chromosome loss do not account both for the first and second step in one cell, because large homozygous deletions are often lethal for a cell. Denote by u 1 and u 2 the mutation rates for the first and second hit (including all possible mechanisms). It is natural to assume that u 1 is less than u 2 , because there are more possibilities for the second hit.We will now ask the most basic question regarding the somatic evolutionary dynamics of TSGs: how long does it take for a population of N cells to generate a single cell with two inactivated alleles of a TSG?For small populations, N Ͻ 1͞ ͌ u 2 , the first hit takes over the population before the second hit occurs (Fig. 1). There is an intuitive explanation for this threshold: a cell with one hit is a neutral mutant that takes on average N generations to reach fixation, whereas the waiting time for the second hit is 1͞(Nu 2 ). From N Ͻ 1͞(Nu 2 ) we obtain N Ͻ 1͞ ͌ u 2 . In this case, the probability that a single cell wi...

show abstract

“…As a model for early Apc-associated tumorigenesis, we examined the Min/ϩ mouse, an animal that develops numerous intestinal adenomas as a result of germline mutation of Apc (3). Adenomas arising in Min/ϩ mice (Apc Min/Ϫ ) uniformly sustain loss of heterozygosity of the remaining Apc ϩ allele and are consequently devoid of Apc function (4,5). Previous work demonstrated the inhibition of adenoma formation in these mice by administration of various chemopreventive compounds, including nonsteroidal anti-inflammatory drugs (NSAIDs) (6 -8), plant phenolics (9, 10), phytoestrogens, 2 and exogenous estrogens (11).…”

mentioning

confidence: 99%