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MGMT promoter hypermethylation and K-RAS, PTEN and TP53 mutations in tamoxifen-exposed and non-exposed endometrial cancer cases

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MGMT promoter hypermethylation and K-RAS, PTEN and TP53 mutations in tamoxifen-exposed and non-exposed endometrial cancer cases. / Nagy , E.; Gajjar, Ketan; Patel, Imran I. et al.

In: British Journal of Cancer, Vol. 110, No. 12, 10.06.2014, p. 2874-2880.

Research output: Contribution to Journal/MagazineJournal articlepeer-review

Harvard

Nagy , E, Gajjar, K, Patel, II, Taylor, S, Martin-Hirsch, PL, Stringfellow, HF, Martin, FL & Phillips, DH 2014, 'MGMT promoter hypermethylation and K-RAS, PTEN and TP53 mutations in tamoxifen-exposed and non-exposed endometrial cancer cases', British Journal of Cancer, vol. 110, no. 12, pp. 2874-2880. https://doi.org/10.1038/bjc.2014.263

APA

Nagy , E., Gajjar, K., Patel, I. I., Taylor, S., Martin-Hirsch, P. L., Stringfellow, H. F., Martin, F. L., & Phillips, D. H. (2014). MGMT promoter hypermethylation and K-RAS, PTEN and TP53 mutations in tamoxifen-exposed and non-exposed endometrial cancer cases. British Journal of Cancer, 110(12), 2874-2880. https://doi.org/10.1038/bjc.2014.263

Vancouver

Nagy E, Gajjar K, Patel II, Taylor S, Martin-Hirsch PL, Stringfellow HF et al. MGMT promoter hypermethylation and K-RAS, PTEN and TP53 mutations in tamoxifen-exposed and non-exposed endometrial cancer cases. British Journal of Cancer. 2014 Jun 10;110(12):2874-2880. Epub 2014 May 22. doi: 10.1038/bjc.2014.263

Author

Nagy , E. ; Gajjar, Ketan ; Patel, Imran I. et al. / MGMT promoter hypermethylation and K-RAS, PTEN and TP53 mutations in tamoxifen-exposed and non-exposed endometrial cancer cases. In: British Journal of Cancer. 2014 ; Vol. 110, No. 12. pp. 2874-2880.

Bibtex

@article{02416043719d4a389ef22143bbac6730,
title = "MGMT promoter hypermethylation and K-RAS, PTEN and TP53 mutations in tamoxifen-exposed and non-exposed endometrial cancer cases",
abstract = "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.",
keywords = "tamoxifen, epigenetics, hypermethylation, endometrial cancer, TP53, K-RAS, PTEN",
author = "E. Nagy and Ketan Gajjar and Patel, {Imran I.} and S. Taylor and Martin-Hirsch, {Pierre Leonard} and Stringfellow, {Helen F.} and Martin, {Francis Luke} and Phillips, {David H.}",
year = "2014",
month = jun,
day = "10",
doi = "10.1038/bjc.2014.263",
language = "English",
volume = "110",
pages = "2874--2880",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "12",

}

RIS

TY - JOUR

T1 - MGMT promoter hypermethylation and K-RAS, PTEN and TP53 mutations in tamoxifen-exposed and non-exposed endometrial cancer cases

AU - Nagy , E.

AU - Gajjar, Ketan

AU - Patel, Imran I.

AU - Taylor, S.

AU - Martin-Hirsch, Pierre Leonard

AU - Stringfellow, Helen F.

AU - Martin, Francis Luke

AU - Phillips, David H.

PY - 2014/6/10

Y1 - 2014/6/10

N2 - 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.

AB - 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.

KW - tamoxifen

KW - epigenetics

KW - hypermethylation

KW - endometrial cancer

KW - TP53

KW - K-RAS

KW - PTEN

U2 - 10.1038/bjc.2014.263

DO - 10.1038/bjc.2014.263

M3 - Journal article

VL - 110

SP - 2874

EP - 2880

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 12

ER -