Spontaneous and mutagen-induced loss of DNA mismatch repair in Msh2-heterozygous mammalian cells

Borgdorff, Viola; Hees-Stuivenberg, Sandrine van; Meijers, Caro M.; Wind, Niels de

doi:10.1016/j.mrfmmm.2005.01.021

Cited by 16 publications

(17 citation statements)

References 26 publications

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“…Because tumor development generally occurs late in life, the effects on reproductive fitness are small to moderate. Homozygous knockouts of MMR genes can elevate mutation rates by as much as 100-fold, whereas the effects in heterozygotes are much more modest, again implying partial dominance (' 10% penetrance) (Borgdorff et al 2005;Hegan et al 2006;Burr et al 2007). On the other hand, consistent with the observations on heterologous systems noted above, the degree of dominance for missense mutations with moderate effects on repair efficiency can be much more pronounced (Parsons et al 1995;Drotschmann et al 1999), with some data suggesting that heterozygous mammalian carriers of missense mutations at MMR loci have mutation rates elevated by factors of 5-10 (Coolbaugh- Murphy et al 2004;Alazzouzi et al 2005).…”

Section: Expected Frequency Of Detrimental Alleles For Replication/rementioning

confidence: 99%

The Cellular, Developmental and Population-Genetic Determinants of Mutation-Rate Evolution

2008

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Although the matter has been subject to considerable theoretical study, there are numerous open questions regarding the mechanisms driving the mutation rate in various phylogenetic lineages. Most notably, empirical evidence indicates that mutation rates are elevated in multicellular species relative to unicellular eukaryotes and prokaryotes, even on a per-cell division basis, despite the need for the avoidance of somatic damage and the accumulation of germline mutations. Here it is suggested that multicellularity discourages selection against weak mutator alleles for reasons associated with both the cellular and the population-genetic environments, thereby magnifying the vulnerability to somatic mutations (cancer) and increasing the risk of extinction from the accumulation of germline mutations. Moreover, contrary to common belief, a cost of fidelity need not be invoked to explain the lower bound to observed mutation rates, which instead may simply be set by the inability of selection to advance very weakly advantageous antimutator alleles in finite populations.

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Section: Expected Frequency Of Detrimental Alleles For Replication/rementioning

confidence: 99%

The Cellular, Developmental and Population-Genetic Determinants of Mutation-Rate Evolution

2008

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“…To isolate clones that have become MMR-deficient because of a mutagenic event at the monoallelic MMR gene, we subsequently exposed cells to the nucleotide analog 6-thioguanine (6TG; Fig. 1B), to which MMR-deficient cells are tolerant (14,16). Then, unwanted clones that had acquired 6TG tolerance because of mutational inactivation of the X-linked yypoxanthine phosphorybosyl transferase (Hprt) gene, rather than loss of MMR, were killed by culture in a hypoxanthine-aminopterin-thymidinesupplement-containing medium (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1D) or by loss of heterozygosity (Msh2 −/− in Fig. 1D) (14). The latter clones were discarded after screening with an Msh2 allele-specific PCR.…”

Section: Resultsmentioning

confidence: 99%

“…Surviving clones were picked and expanded in 96-well plates. Next, clones that had lost the wild-type Msh2 allele by loss of heterozygosity, rather than by mutational inactivation, were discarded after their identification by allele-specific PCR (14). In the remaining clones, the status of the Msh2 mRNA was analyzed by reverse transcriptase-PCR analysis.…”

Section: Msh2mentioning

confidence: 99%

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Genetic screens to identify pathogenic gene variants in the common cancer predisposition Lynch syndrome

Drost

Lützen

Hees

et al. 2013

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

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In many individuals suspected of the common cancer predisposition Lynch syndrome, variants of unclear significance (VUS), rather than an obviously pathogenic mutations, are identified in one of the DNA mismatch repair (MMR) genes. The uncertainty of whether such VUS inactivate MMR, and therefore are pathogenic, precludes targeted healthcare for both carriers and their relatives. To facilitate the identification of pathogenic VUS, we have developed an in cellulo genetic screen-based procedure for the large-scale mutagenization, identification, and cataloging of residues of MMR genes critical for MMR gene function. When a residue identified as mutated in an individual suspected of Lynch syndrome is listed as critical in such a reverse diagnosis catalog, there is a high probability that the corresponding human VUS is pathogenic. To investigate the applicability of this approach, we have generated and validated a prototypic reverse diagnosis catalog for the MMR gene MutS Homolog 2 (Msh2) by mutagenizing, identifying, and cataloging 26 deleterious mutations in 23 amino acids. Extensive in vivo and in vitro analysis of mutants listed in the catalog revealed both recessive and dominant-negative phenotypes. Nearly half of these critical residues match with VUS previously identified in individuals suspected of Lynch syndrome. This aids in the assignment of pathogenicity to these human VUS and validates the approach described here as a diagnostic tool. In a wider perspective, this work provides a model for the translation of personalized genomics into targeted healthcare.

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“…The accumulation of somatic mutations in tumors is rarely detectable during early stages of development, and difficult to detect at later stages because of the high mutational load [5]. From a population genetics standpoint, homozygous mutations in both alleles of mismatch-repair genes result in a 100-fold increase in mutation rates [6], [7], [8], [9], but have zero fitness and won't survive [10]. On the other hand, heterozygosity confers a 5–10 fold increase in mutations [11], [12], which in the presence of activated DNA repair pathways will result in a tolerable selective advantage.…”

Section: Introductionmentioning

confidence: 99%

Progression inference for somatic mutations in cancer

Peterson

Kovyrshina

2017

Heliyon

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Computational methods were employed to determine progression inference of genomic alterations in commonly occurring cancers. Using cross-sectional TCGA data, we computed evolutionary trajectories involving selectivity relationships among pairs of gene-specific genomic alterations such as somatic mutations, deletions, amplifications, downregulation, and upregulation among the top 20 driver genes associated with each cancer. Results indicate that the majority of hierarchies involved TP53, PIK3CA, ERBB2, APC, KRAS, EGFR, IDH1, VHL, etc. Research into the order and accumulation of genomic alterations among cancer driver genes will ever-increase as the costs of nextgen sequencing subside, and personalized/precision medicine incorporates whole-genome scans into the diagnosis and treatment of cancer.

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Spontaneous and mutagen-induced loss of DNA mismatch repair in Msh2-heterozygous mammalian cells

Cited by 16 publications

References 26 publications

The Cellular, Developmental and Population-Genetic Determinants of Mutation-Rate Evolution

The Cellular, Developmental and Population-Genetic Determinants of Mutation-Rate Evolution

Genetic screens to identify pathogenic gene variants in the common cancer predisposition Lynch syndrome

Progression inference for somatic mutations in cancer

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