© 2007 European Society for Medical Oncology
gastro-intestinal cancer |
Aberrant methylation within RUNX3 CpG island associated with the nuclear and mitochondrial microsatellite instability in sporadic gastric cancers. Results of a GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study
1 Section of Medical Oncology, Department of Oncology
2 Section of Surgical Oncology, Department of Surgery and Oncology
3 Section of General and Thoracic Surgery, Department of GENURTO
4 Department of Human Pathology, Università di Palermo, Italy
5 Department of Experimental Medicine and Pathology, University "La Sapienza" Rome
6 Division of Medical Oncology, National Institute of Oncology, Bari, Italy
* Correspondence to: Antonio Russo, MD Section of Medical Oncology, Department of Oncology, Università di Palermo, Via del Vespro 127, 90127 Palermo, Italy. Tel: +39-091-6552500; Fax: +39-091-6554529; E-mail: lab-oncobiologia{at}usa.net
Background: Gastric cancer (GC) development is a multistep process, during which numerous alterations accumulate in nuclear and mitochondrial DNA. A deficiency of repair machinery brings about an accumulation of errors introduced within simple repetitive microsatellite sequences during replication of DNA. Aberrant methylation is related to microsatellite instability (MSI) by the silencing of the hMLH1 gene. The aim of this study is to investigate a possible relationship between the RUNX3 promoter methylation, nuclear microsatellite instability (nMSI) and mitochondrial microsatellite instability (mtMSI), in order to clarify its biological role in GC.
Patients and methods: nMSI and mtMSI were evaluated in a consecutive series of 100 GC patients. For the analysis of the nMSI, we followed the National Cancer Institute guidelines. mtMSI was assessed by analyzing a portion of the displacement-loop region. The aberrant methylation of RUNX3 was analyzed in 40 GC patients by methylation-specific PCR.
Results: Overall, 55% of GC demonstrated methylation of the RUNX3 promoter; 82% of GC was classified as stable microsatellite instability, 5% as low-level microsatellite instability and 13% as high-level microsatellite instability (MSI-H); mtMSI was detected in 11% of GC. A significant association was found between mtMSI and tumor–node–metastasis staging, furthermore an interesting association between MSI-H status, mtMSI and RUNX3 methylation.
Conclusion: These data suggest that RUNX3 is an important target of methylation in the evolution of mtMSI and nMSI-H GC.
Key words: gastric cancer, methylation-specific PCR (MSP), mitochondrial microsatellite instability (mtMSI), nuclear microsatellite instability (nMSI), RUNX3
Both authors have contributed equally to this work.