O6-methylguanine methyltransferase in colorectal cancers: detection or mutations, loss of expression, and weak association with G:C>A:T transitions

Halford, S.; Rowan, A.; Sawyer, E.; Talbot, I.; Tomlinson, I.
June 2005
Gut;Jun2005, Vol. 54 Issue 6, p797
Academic Journal
Background and aims: O6-methylguanine methyltransferase (MGMT) repairs inappropriately methylated guanine in DNA. MGMT mutations have not previously been reported in Cancers, but in colorectal tumours MGMT promoter methylation is common and has been associated with increased G:C>A:T transitions, a high frequency of K-ras mutations, and low level microsatellite instability (MSI low). However, some have suggested that MGMT changes are background or secondary events, with little importance for tumorigenesis. Methods: We have analysed fresh frozen colorectal cancers and colorectal cancer cell lines for MGM T changes: mutations, allelic loss, and protein expression. Results: Six of 113 cancers harboured somatic missense MGMT mutations, at least three of which probably caused reduced MGMT function and were accompanied by silencing or loss of the wild-type allele. Cancers with pathogenic MGMT mutations tended to harbour G:C>.A:T somatic mutations at other loci. Overall, MGMT expression was reduced or lost in more than half of the cancers. We found no association between MGMT expression and the somatic mutation spectrum at APC, beta-catenin, K-ras, or p53, but decreased MGMT expression was weakly associated with the presence of a G:C>A:T change at any one of these loci. Reduced MGMT expression was not however associated with an increased frequency of K-ras mutations or with MSI low. Conclusion: In summary, we found that mutation of MGMT contributes to decreased protein function. Our findings provide good evidence to show that MGMT changes, including methylation, are selected rather than background events, at least in some cases. Decreased MGMT expression or function probably has a weak or moderate effect on the mutation spectrum in colorectal cancers.


Related Articles

  • Mutational analysis of BRAF and K-ras in gastric cancers: absence of BRAF mutations in gastric cancers. Il-Jin Kim; Jae-Hyun Park; Hio Chung Kang; Yong Shin; Hye-Won Park; Hye-Rin Park; Ja-Lok Ku; Seok-Byung Lim; Jae-Gahb Park // Human Genetics;Dec2003, Vol. 114 Issue 1, p118 

    Recently, BRAF mutations were found in a variety of human cancers. Interestingly, the most common of BRAF mutation (V599E) has not been identified in tumors with K-ras mutations. Whereas the majority of human cancer types has been screened for BRAF mutations, no detailed studies on gastric...

  • Breast Tumor Cells with PI3K Mutation or HER2 Amplification Are Selectively Addicted to Akt Signaling. Qing-Bai She; Chandarlapaty, Sarat; Qing Ye; Lobo, Jose; Haskell, Kathleen M.; Leander, Karen R.; DeFeo-Jones, Deborah; Huber, Hans E.; Rosen, Neal // PLoS ONE;2008, Vol. 3 Issue 8, p1 

    Background: Dysregulated PI3K/Akt signaling occurs commonly in breast cancers and is due to HER2 amplification, PI3K mutation or PTEN inactivation. The objective of this study was to determine the role of Akt activation in breast cancer as a function of mechanism of activation and whether...

  • Upregulation of PTEN in Glioma Cells by Cord Blood Mesenchymal Stem Cells Inhibits Migration via Downregulation of the PI3K/Akt Pathway. Dasari, Venkata Ramesh; Kaur, Kiranpreet; Velpula, Kiran Kumar; Gujrati, Meena; Fassett, Daniel; Klopfenstein, Jeffrey D.; Dinh, Dzung H.; Rao, Jasti S. // PLoS ONE;2010, Vol. 5 Issue 4, p1 

    Background: PTEN (phosphatase and tensin homologue deleted on chromosome ten) is a tumor suppressor gene implicated in a wide variety of human cancers, including glioblastoma. PTEN is a major negative regulator of the PI3K/Akt signaling pathway. Most human gliomas show high levels of activated...

  • Characterization of a Novel Breast Carcinoma Xenograft and Cell Line Derived from a BRCA1 Germ-Line Mutation Carrier. Johannsson, Oskar T.; Staff, Synnöve; Vallon-Christersson, Johan; Kytöla, Soili; Gudjonsson, Thorarinn; Rennstam, Karin; Hedenfalk, Ingrid A.; Adeyinka, Adewale; Kjellén, Elisabeth; Wennerberg, Johan; Baldetorp, Bo; Petersen, Ole W.; Olsson, Håkan; Oredsson, Stina; Isola, Jorma; Borg, Åke // Laboratory Investigation (00236837);Mar2003, Vol. 83 Issue 3, p387 

    A human tumor xenograft (L56Br-X1) was established from a breast cancer axillary lymph node metastasis of a 53-year-old woman with a BRCA1 germ-line nonsense mutation (1806C>T; Q563X), and a cell line (L56Br-C1) was subsequently derived from the xenograft. The xenograft carries only the mutant...

  • Frequent MAGE Mutations in Human Melanoma. Caballero, Otavia L.; Qi Zhao; Rimoldi, Donata; Stevenson, Brian J.; Suzanne Svobodová; Devalle, Sylvie; Röhrig, Ute F.; Pagotto, Anna; Michielin, Olivier; Speiser, Daniel; Wolchok, Jedd D.; Liu, Cailian; Pejovic, Tanja; Odunsi, Kunle; Brasseur, Francis; Van den Eynde, Benoit J.; Old, Lloyd J.; Xin Lu; Cebon, Jonathan; Strausberg, Robert L. // PLoS ONE;2010, Vol. 5 Issue 9, p1 

    Background: Cancer/testis (CT) genes are expressed only in the germ line and certain tumors and are most frequently located on the X-chromosome (the CT-X genes). Amongst the best studied CT-X genes are those encoding several MAGE protein families. The function of MAGE proteins is not well...

  • Association between Acquired Uniparental Disomy and Homozygous Mutations and HER2/ER/PR Status in Breast Cancer. Tuna, Musaffe; Smid, Marcel; Dakai Zhu; Martens, John W. M.; Amos, Christopher I. // PLoS ONE;2010, Vol. 5 Issue 11, p1 

    Background: Genetic alterations in cellular signaling networks are a hallmark of cancer, however, effective methods to discover them are lacking. A novel form of abnormality called acquired uniparental disomy (aUPD) was recently found to pinpoint the region of mutated genes in various cancers,...

  • Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. Søndergaard, Jonas N.; Nazarian, Ramin; Qi Wang; Deliang Guo; Hsueh, Teli; Mok, Stephen; Sazegar, Hooman; MacConaill, Laura E.; Barretina, Jordi G.; Kehoe, Sarah M.; Attar, Narsis; von Euw, Erika; Zuckerman, Jonathan E.; Chmielowski, Bartosz; Comin-Anduix, Begoña; Koya, Richard C.; Mischel, Paul S.; Lo3, Roger S.; Ribas, Antoni // Journal of Translational Medicine;2010, Vol. 8, p39 

    Blocking oncogenic signaling induced by the BRAFV600E mutation is a promising approach for melanoma treatment. We tested the anti-tumor effects of a specific inhibitor of Raf protein kinases, PLX4032/RG7204, in melanoma cell lines. PLX4032 decreased signaling through the MAPK pathway only in...

  • Three new chondrosarcoma cell lines: one grade III conventional central chondrosarcoma and two dedifferentiated chondrosarcomas of bone. van Oosterwijk, Jolieke G.; de Jong, Danielle; van Ruler, Maayke A.J.H.; Hogendoorn, Pancras C.W.; Dijkstra, P.D. Sander; van Rijswijk, Carla S.P.; Machado, Isidro; Llombart-Bosch, Antonio; Szuhai, Karoly; Bov�e, Judith V.M.G. // BMC Cancer;2012, Vol. 12 Issue 1, p375 

    Background: Chondrosarcoma is the second most common primary sarcoma of bone. High-grade conventional chondrosarcoma and dedifferentiated chondrosarcoma have a poor outcome. In pre-clinical research aiming at the identification of novel treatment targets, the need for representative cell lines...

  • Role of nuclear and cytoplasmic localization in the tumour-suppressor activity of the von Hippel-Lindau protein. Lewis, Martin D; Roberts, Ben J // Oncogene;6/26/2003, Vol. 22 Issue 26, p3992 

    Mutations in the von Hippel-Lindau (VHL) tumour-suppressor gene result in several forms of cancer. In the present study, we investigated the role of VHL subcellular localization in its antitumour properties. We generated renal cell carcinoma (RCC) lines stably expressing either exclusively...


Read the Article


Sign out of this library

Other Topics