Specific combinations of DNA repair gene variants and increased risk for non-small cell lung cancer

Popanda, Odilia; Schattenberg, Torsten; Phong, Chi Tai; Butkiewicz, Dorota; Risch, Angela; Edler, Lutz; Kayser, Klaus; Dienemann, Hendrik; Schulz, Volker; Drings, P.; Bartsch, Helmut; Schmezer, Peter

doi:10.1093/carcin/bgh264

Cited by 186 publications

(132 citation statements)

References 30 publications

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“…For the offspring of genotype cmlh1-29/kMLH1 kPMS1͞kPMS1, loss of heterozygosity at one locus (kMLH1) would confer a MMR defect; i.e., cancer risk for these individuals is the same as in typical HNPCC families. Interactions among polymorphic loci have been identified in other cancers but have not yet been studied extensively for HNPCC (31). Our observations provide an additional incentive to investigate whether such a mechanism underlies some cases of familial colorectal cancer.…”

Section: Discussionmentioning

confidence: 76%

Negative epistasis between natural variants of the Saccharomyces cerevisiae MLH1 and PMS1 genes results in a defect in mismatch repair

Heck

Argueso²,

Gemici³

et al. 2006

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

113

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In budding yeast, the MLH1-PMS1 heterodimer is the major MutL homolog complex that acts to repair mismatches arising during DNA replication. Using a highly sensitive mutator assay, we observed that Saccharomyces cerevisiae strains bearing the S288c-strain-derived MLH1 gene and the SK1-strain-derived PMS1 gene displayed elevated mutation rates that conferred a long-term fitness cost. Dissection of this negative epistatic interaction using S288c-SK1 chimeras revealed that a single amino acid polymorphism in each gene accounts for this mismatch repair defect. Were these strains to cross in natural populations, segregation of alleles would generate a mutator phenotype that, although potentially transiently adaptive, would ultimately be selected against because of the accumulation of deleterious mutations. Such fitness ''incompatibilities'' could potentially contribute to reproductive isolation among geographically dispersed yeast. This same segregational mutator phenotype suggests a mechanism to explain some cases of a human cancer susceptibility syndrome known as hereditary nonpolyposis colorectal cancer, as well as some sporadic cancers.colorectal cancer ͉ incompatibility T he highly conserved mismatch repair (MMR) system contributes to genome stability by repairing errors that occur during DNA replication (1). In Escherichia coli, MMR is initiated by the binding of MutS protein to DNA mismatches. MutL interacts with the MutS-mismatch complex and activates downstream repair factors. Multiple MutS homologs (MSH) and MutL homologs (MLH) have evolved in eukaryotes that form heterodimers with specialized functions in DNA repair and recombination (2, 3). In Saccharomyces cerevisiae, MSH2-MSH3 and MSH2-MSH6 function in mismatch recognition, and MLH1-PMS1 is the primary MLH heterodimer in postreplicative MMR. Mutations in MSH and MLH genes that act in MMR elevate mutation rate, as measured in reversion and forward mutation assays, and reduce spore viability of diploid cells due to the accumulation of recessive lethal mutations (4-6). In addition, MMR proteins act to prevent recombination between divergent DNA sequences. This activity has been shown to prevent chromosomal rearrangements (7,8) and to enforce reproductive barriers between species (9, 10).Previously we created 60 alleles of the S. cerevisiae MLH1 gene from the S288c strain (cMLH1) in which clusters of charged residues were simultaneously changed to Ala (11). These alleles were tested for defects in MMR in the S288c (12) and SK1 (13) strains. More than one-third of the mutation set conferred a more severe MMR defect in SK1 strains than in S288c strains. Two mutations, cmlh1-29 and cmlh1-56, conferred wild-type-like phenotypes in S288c but null-like phenotypes in SK1. Introduction of the S288c PMS1 gene into the SK1 strain suppressed the mutator phenotype of these mutants, suggesting that the MMR phenotype was due to incompatibility, or negative epistasis, between MLH components (11).The influences of epistatic interactions on a wide variety of traits and proc...

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Section: Discussionmentioning

confidence: 76%

Negative epistasis between natural variants of the Saccharomyces cerevisiae MLH1 and PMS1 genes results in a defect in mismatch repair

Heck

Argueso²,

Gemici³

et al. 2006

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

113

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“…The Glu/Glu genotype has been associated with increased risk of lung cancer in a recent case-control study in Japan 20 and, conversely, with a statistically nonsignificant decreased risk of nonsmall cell lung cancer in a case-control study in Germany. 21 Finally, APE1 genotype was not associated with lung cancer risk among male smokers in Finland. 22 An interaction between APE1 genotype and smoking was seen in the Japanese study such that the genotypic effect was apparent primarily among ''light'' smokers (those with 40 packyears of consumption or less), as compared with never smokers and ''heavy'' smokers.…”

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confidence: 89%

“…The German study found no statistically significant interactions with any of the examined DNA repair genotypes, including APE1, but did not report odds ratios (ORs). 21 Given the inconclusive evidence, the interaction between APE1 genotype and smoking status in the Japanese study, the dearth of studies on APE1 genotype and cancer risk, and effect modification of the association between other genes and risk of lung and bladder cancer by smoking, 23,24 more evidence regarding the association between APE1 genotype and cancer risk is warranted. Therefore, we examined the associations between the APE1 genotype, cigarette smoking and bladder cancer risk, in a case-control study in the United States.…”

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confidence: 99%

APE1 genotype and risk of bladder cancer: Evidence for effect modification by smoking

Terry

Umbach

Taylor

2006

Intl Journal of Cancer

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Apurinic/apyrimidinic (AP) sites are common mutagenic and cytotoxic DNA lesions that arise from the loss of normal bases. APE1, the major AP endonuclease of human cells, plays a central role in the repair of AP sites through both its endonuclease and phosphodiesterase activities. A common APE1 polymorphism, a TfiG transversion (Asp 148 Glu), was previously shown to be associated with risk of lung cancer, an association that was modified by cigarette smoking. To explore the association between APE1 genotype, smoking and bladder cancer risk, we examined data from an existing case-control study of bladder cancer patients (n 5 239) and control individuals (n 5 215) recruited from urology clinics at 2 hospitals in North Carolina. Genotype at the polymorphic site was determined using allele-specific primer extension reactions, followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. We found no overall association between APE1 genotype and bladder cancer risk. In stratified analyses, however, a positive association with risk was observed with an increasing number of Glu alleles among never smokers, but not among smokers (p-value for interaction 5 0.005). We can speculate that small allelic differences that are apparent in never smokers are obscured by the large amount of DNA damage found in smokers. Given the lack of established biological mechanisms, and suboptimal numbers of subjects in some exposure categories, our findings should be interpreted cautiously. Published 2006 Wiley-Liss, Inc.Key words: bladder neoplasms; apurinic endonuclease; polymorphism; smoking; case-control studies Several etiological factors have been associated with the development of bladder cancer, cigarette smoking being among the most important. 1 The precise mechanisms by which smoking causes bladder cancer have yet to be fully clarified. Tobacco smoke is known to contain many potential human carcinogens, including aromatic amines and N-nitrosamines, 1,2 compounds that have been linked to DNA adduct formation 2 and bladder cancer development. 1,3 Cigarette smoke also generates large quantities of free radicals, 4 which are highly reactive species that induce base modifications and strand breaks. 5 Thus, smoking may induce bladder cancer through different types of DNA damage.Apurinic/apyrimidinic (AP) sites are common mutagenic and cytotoxic DNA lesions that arise from the loss of normal bases, either through spontaneous processes, or excision of damaged bases by DNA glycosylases during the DNA repair process. 6,7 AP sites are repaired by a series of reactions involving the multiple repair proteins of the base excision repair (BER) pathway. 6,8 AP Endonuclease 1 (APE1), the major AP endonuclease of human cells, plays a central role in BER by hydrolyzing the phosphodiester backbone immediately 5 0 to the AP site. 9,10 This incision generates a normal 3 0 -hydroxyl group and an abasic deoxyribose-5-phosphate, which is processed by enzymes in the subsequent steps of the BER pathway. 11 APE1 also acts as a 3 0 -p...

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“…This effect was further increased in persons with a deletion polymorphism in the gene coding for the detoxification enzyme glutathione-S-transferase M1 (GSTM1). The RAD51 G135C polymorphism has also been associated with increased risk of breast cancer in BRCA2 mutation carriers, 19 and epidemiological studies noted positive associations between XRCC3 Thr241Met and melanomas, 20 bladder cancer, 21 breast cancer, 22 lung cancer 23 and gliomas. 24 The functional importance of deletion of the GSTM1 is well described.…”

Section: Introductionmentioning

confidence: 99%

DNA repair polymorphisms and outcome of chemotherapy for acute myelogenous leukemia: a report from the Children's Oncology Group

et al. 2007

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Polymorphisms of DNA repair genes RAD51 and XRCC3 increase susceptibility to acute myeloid leukemia (AML) in adults, an effect enhanced by deletion of the glutathione-Stransferase M1 (GSTM1) gene. In this study, we genotyped 452 children with de novo AML treated on CCG protocols 2941 and 2961 and compared genotype frequencies with those of normal blood donors, and analyzed the impact of genotype on outcome of therapy. XRCC3 Thr241Met, RAD51 G135C and GSTM1 genotypes did not increase susceptibility to AML when assessed singly. In contrast, when XRCC3 and RAD51 genotypes were examined together a significant increase in susceptibility to AML was seen in children with variant alleles. Analysis of outcome of therapy showed that patients heterozygous for the XRCC3 Thr241Met allele had improved postinduction disease-free survival compared to children homozygous for the major or minor allele, each of whom had similar outcomes. Improved survival was due to reduced relapse in the heterozygous children, and this effect was most marked in children randomized to therapy likely to generate DNA doublestrand breaks (etoposide, daunomycin), compared with antimetabolite (fludarabine, cytarabine) based therapy. In contrast, RAD51 G135C and the GSTM1 deletion polymorphism did not influence outcome of AML therapy in our study population.

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Specific combinations of DNA repair gene variants and increased risk for non-small cell lung cancer

Cited by 186 publications

References 30 publications

Negative epistasis between natural variants of the Saccharomyces cerevisiae MLH1 and PMS1 genes results in a defect in mismatch repair

Negative epistasis between natural variants of the Saccharomyces cerevisiae MLH1 and PMS1 genes results in a defect in mismatch repair

APE1 genotype and risk of bladder cancer: Evidence for effect modification by smoking

DNA repair polymorphisms and outcome of chemotherapy for acute myelogenous leukemia: a report from the Children's Oncology Group

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