MGMT promoter hypermethylation and K-RAS, PTEN and TP53 mutations in tamoxifen-exposed and non-exposed endometrial cancer cases.
BACKGROUND
Tamoxifen has anti-oestrogenic and anti-tumour activity in the breast, but is oestrogenic and carcinogenic in the endometrium. It can induce experimental tumours by both hormonal and DNA-damaging mechanisms, but its carcinogenic mode of action in human endometrium remains unclear.


METHODS
We investigated whether an epigenetic mechanism, involving promoter hypermethylation of the gene for the DNA repair enzyme MGMT (O6-methylguanine DNA methyltransferase), was associated with K-RAS, TP53 and PTEN mutations in endometrial tumours from women treated with tamoxifen (TAM, n=30) or unexposed to the drug (EC, n=38).


RESULTS
There were significant (P<0.05) differences in tumour grade between the TAM and EC groups, with more favourable morphology in the latter. K-RAS mutations, predominantly G>A, occurred in small numbers in both groups. TP53 mutations were of mainly A>G, C>T and indel modifications in both groups, but more frequent in TAM cases. PTEN mutations dominated in EC tumours and were of the type that has large impact on protein function, such as indel or nonsense mutations. These observations alongside the mutational spectrum in PTEN suggest that the malignancies arise from different backgrounds, hence pointing to an effect of tamoxifen. Both groups displayed MGMT promoter hypermethylation. This coincided with mutations more frequently in the TAM (78%) than in the EC (50%) group, even though there were significantly (P<0.05) fewer mutations and methylations in TAM cases.


CONCLUSIONS
Although the difference in coincidence did not reach significance with the current sample size, the findings suggest that epigenetic processes may play a role in the way tamoxifen induces endometrial cancer.
Analytical and Environmental Sciences Division, King's College London, London SE1 9NH, UK.
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Nagy
Centre for Biophotonics, Lancaster Environment Centre, Lancaster University, Lancaster LA1 4YQ, UK.
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KB
Gajjar
Cavendish Laboratories, JJ Thomson Avenue, University of Cambridge, Cambridge CB3 0HE, UK.
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Patel
Liverpool Women's Hospital NHS Foundation Trust, Department of Gynaecology, Crown Street, Liverpool, Merseyside L8 7SS, UK.
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Taylor
1] Centre for Biophotonics, Lancaster Environment Centre, Lancaster University, Lancaster LA1 4YQ, UK [2] Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane North, Preston, Lancashire PR2 9HT, UK.
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Martin-Hirsch
Lancashire Teaching Hospitals NHS Trust, Royal Preston Hospital, Sharoe Green Lane North, Preston, Lancashire PR2 9HT, UK.
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Stringfellow
Centre for Biophotonics, Lancaster Environment Centre, Lancaster University, Lancaster LA1 4YQ, UK.
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Martin
Analytical and Environmental Sciences Division, King's College London, London SE1 9NH, UK.
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Phillips
D000368:Aged; D001483:Base Sequence; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D004717:Endometrium / Q000187:drug effects* / Q000473:pathology; D044127:Epigenesis, Genetic; D004965:Estrogen Antagonists / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011401:Promoter Regions, Genetic; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D020845:Selective Estrogen Receptor Modulators / Q000009:adverse effects* / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D013629:Tamoxifen / Q000009:adverse effects* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D004965:Estrogen Antagonists; D020845:Selective Estrogen Receptor Modulators; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras); D045643:DNA Repair Enzymes