Abstract
Germline mutations in the gene encoding the tumour suppressor E-cadherin (CDH1) are the underlying genetic defect responsible for hereditary diffuse gastric cancer (HDGC). A remarkably high percentage (∼80%) of CDH1 mutations in HDGC patients and carriers generate premature termination codons (PTCs). Here, we examined whether CDH1 transcripts harbouring PTCs are downregulated by nonsense-mediated decay (NMD), an RNA surveillance pathway that degrades PTC-bearing transcripts. Using an allele-specific expression (ASE) assay to differentiate between mutated and wild-type CDH1 alleles, we found that PTC-bearing CDH1 mRNAs are strongly downregulated in normal gastric tissue from several CDH1 mutation carriers. We show that NMD is responsible for this robust downregulation, as CDH1 transcripts harbouring PTCs in the KATO-III gastric tumour cell line were upregulated in response to protein synthesis inhibitors or depletion of the NMD factors UPF1 and eIF4AIII. Analysis of HDGC patients harbouring CDH1 alleles with PTCs at a wide variety of different positions indicates an association of their predicted ability to induce NMD and an earlier age of onset of gastric cancer. This suggests that NMD may be detrimental for HDGC patients and therefore NMD is a potentially useful therapeutic target for CDH1 mutation carriers.
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References
Carrel L, Willard HF . (2005). X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434: 400–404.
Carter MS, Doskow J, Morris P, Li S, Nhim RP, Sandstedt S et al. (1995). A regulatory mechanism that detects premature nonsense codons in T-cell receptor transcripts in vivo is reversed by protein synthesis inhibitors in vitro. J Biol Chem 270: 28995–29003.
Chang YF, Imam JS, Wilkinson MF . (2007). The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem 76: 51–74.
Dussaulx-Garin L, Blayau M, Pagenault M, Le Berre-Heresbach N, Raoul JL, Campion JP et al. (2001). A new mutation of E-cadherin gene in familial gastric linitis plastica cancer with extra-digestive dissemination. Eur J Gastroenterol Hepatol 13: 711–715.
El-Bchiri J, Buhard O, Penard-Lacronique V, Thomas G, Hamelin R, Duval A . (2005). Differential nonsense mediated decay of mutated mRNAs in mismatch repair deficient colorectal cancers. Hum Mol Genet 14: 2435–2442.
Frebourg T, Oliveira C, Hochain P, Karam R, Manouvrier S, Graziadio C et al. (2006). Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer. J Med Genet 43: 138–142.
Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P et al. (1998). E-cadherin germline mutations in familial gastric cancer. Nature 392: 402–405.
Holbrook JA, Neu-Yilik G, Hentze MW, Kulozik AE . (2004). Nonsense-mediated decay approaches the clinic. Nat Genet 36: 801–808.
Kaurah P, MacMillan A, Boyd N, Senz J, De Luca A, Chun N et al. (2007). Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 297: 2360–2372.
Knudson Jr AG . (1971). Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68: 820–823.
Oda T, Kanai Y, Oyama T, Yoshiura K, Shimoyama Y, Birchmeier W et al. (1994). E-cadherin gene mutations in human gastric carcinoma cell lines. Proc Natl Acad Sci USA 91: 1858–1862.
Oliveira C, de Bruin J, Nabais S, Ligtenberg M, Moutinho C, Nagengast FM et al. (2004). Intragenic deletion of CDH1 as the inactivating mechanism of the wild-type allele in an HDGC tumour. Oncogene 23: 2236–2240.
Oliveira C, Seruca R, Carneiro F . (2006). Genetics, pathology, and clinics of familial gastric cancer. Int J Surg Pathol 14: 21–33.
Sasaki CY, Lin H, Morin PJ, Longo DL . (2000). Truncation of the extracellular region abrogrates cell contact but retains the growth-suppressive activity of E-cadherin. Cancer Res 60: 7057–7065.
Suriano G, Oliveira MJ, Huntsman D, Mateus AR, Ferreira P, Casares F et al. (2003). E-cadherin germline missense mutations and cell phenotype: evidence for the independence of cell invasion on the motile capabilities of the cells. Hum Mol Genet 12: 3007–3016.
Wilkinson MF . (2005). A new function for nonsense-mediated mRNA-decay factors. Trends Genet 21: 143–148.
Acknowledgements
We thank the family members who collaborated in this study. We thank Dr Marjolijn Ligtenberg from Department of Human Genetics, University Medical Centre Nijmegen, NL and Dr Han van Krieken from Radboud University Nijmegen Medical Center, NL, for providing patients’ material. We also thank G.A.B.B.A. Program at University of Porto, FLAD, CAPES and GRICES. This work was supported by grants from FCT (POCTI/SAU-OBS/58111/2004 and SFRH/BD/15241/2004) and NIH (5-RO1GM058595-08).
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Karam, R., Carvalho, J., Bruno, I. et al. The NMD mRNA surveillance pathway downregulates aberrant E-cadherin transcripts in gastric cancer cells and in CDH1 mutation carriers. Oncogene 27, 4255–4260 (2008). https://doi.org/10.1038/onc.2008.62
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DOI: https://doi.org/10.1038/onc.2008.62
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