1. ¹Department of Pediatrics, University Hospital, Messina, Italy
2. ²Department of Oncology and Neurosciences, University G d'Annunzio, Chieti, Italy
3. ³Center of Excellence on Aging (CeSI), G d'Annunzio Foundation, Chieti, Italy
4. ⁴Department of Experimental Medicine and Pathology, University La Sapienza, Rome, Italy
5. ⁵Pathology Division, Istituti Ospedalieri, Cremona, Italy
6. ⁶Department of Clinical and Experimental Medicine, Gastroenterology Unit, University Federico II, Naples, Italy
7. ⁷Department of Human Pathology, University Hospital, Messina, Italy

Correspondence: Professor RA Caruso, MD, Dipartimento di Patologia Umana, Policlinico Universitario, I-98125 Messina, Italy. E-mail: rosariocaruso@tin.it

Received 5 March 2007; Revised 16 October 2007; Accepted 21 October 2007; Published online 18 April 2008.

Abstract

Somatic mutations of mitochondrial DNA (mtDNA) are associated with various types of human cancer. To elucidate their role in gastric carcinogenesis, we analyzed mutations in the displacement loop region of mtDNA in 24 paraffin-embedded gastric intraepithelial neoplasias (formerly dysplasia) from a high gastric cancer risk area in northern Italy. Helicobacter pylori infection was assessed by histological examination (Giemsa staining). Gastritis was classified according to the guidelines of the Updated Sydney System. The mtDNA displacement loop region was amplified and sequenced from gastric intraepithelial neoplasia samples and adjacent non-neoplastic gastric mucosa. The gastric intraepithelial neoplasias were divided into two groups by their association with H. pylori gastritis. Group A with lesions arising on a background of H. pylori-positive gastritis contained 7 patients, and group B with lesions associated with H. pylori-negative gastritis contained 17 patients. Group A had a larger proportion of high-grade lesions than group B and showed a foveolar phenotype (type II dysplasia). Group B had a larger proportion of cases with mtDNA displacement loop region mutations than group A (P=0.004, Fisher's exact test) and exhibited an intestinal phenotype. No evidence of heteroplasmic variants in the mtDNA displacement loop, suggestive of mutations, was detected in gastric biopsies from 25 H. pylori-negative subjects and 60 cancer-unaffected H. pylori-positive patients. These results provide further evidence for the morphologic and mtDNA biomolecular differences of gastric intraepithelial neoplasias, and suggest the existence of two distinct pathways to gastric cancer—corpus-dominant H. pylori gastritis and the atrophy–metaplasia pathway.