1. ¹Cancer Genetics Group, Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Porto, Portugal
2. ²Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, USA
3. ³Medical Faculty, University of Porto, Porto, Portugal
4. ⁴Department of Genetics, FFFCMPA, Porto Alegre, Brazil
5. ⁵Hereditary Cancer Program, British Columbia Cancer Agency, Vancouver, Canada

Correspondence: Professor C Oliveira, Cancer Genetics Laboratory, IPATIMUP, Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal. E-mail: carlaol@ipatimup.pt; Professor MF Wilkinson, Department of Biochemistry and Molecular Biology, Unit 1000, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX77030, USA. E-mail: mwilkins@mdanderson.org

Received 27 September 2007; Revised 3 January 2008; Accepted 21 February 2008; Published online 21 April 2008.

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.