Gastroenterol. latinoam 2016; Vol 27; Supl. 2
Alarcón A1,2, Olivares W1,2, Bernal C1, Maturana MJ1,2, Escobar C1, Guzmán L3, Corvalán AH1. 1Laboratorio de Oncología, Centro de Investigaciones Médicas, Pontificia Universidad Católica de Chile. 2Advanced Center for Chronic Disease (ACCDiS), Pontificia Universidad Católica de Chile. 3Laboratory of Biological Chemistry, Pontificia Universidad Católica de Valparaíso.
Introduction: Loss of expression or dysfunction of E-cadherin (CDH-1), a well-known cell adhesion and tumor suppressor protein, has been identified as the most common driver of diffuse-type gastric cancer (DGC), including sporadic and hereditary subtypes. However, somatic CDH1 mutational frequencies vary between 3-50% of sporadic cases depending on geographical locations. Moreover, second-hit CDH1 promoter hypermethylation (HM) has not been able to explain completely CDH1 inactivation in sporadic diffuse-type gastric cancer (SDGC). Objective: To screen and characterize major CDH1 inactivating mechanisms in SDGC in Chilean patients. Methods: We performed an integrative analysis of 20 Chilean SDGC cases by immunohistochemistry, mutational analysis and methylation-specific PCR. Results: Total loss of E-cadherin expression or aberrant pattern was observed in 35% (7/20) of cases. Mutational analysis revealed one case with a novel missense mutation on exon 16 (p.Ala824Ser) of uncertain clinical significance, which was consistent with a reduced CDH1 expression and HM. We also found 2 likely benign mutations (one synonymous: p.Asn751Asn; and one intronic: c.164-31T>G). The first showing normal expression and the second weak expression and HM. CDH-1 promoter HM was observed in 80% (16/20) of cases. Two cases showed weak expression but no mutation or HM. Discussion: Our results show that aberrant methylation of the CDH-1 promoter region is the most common mechanism of E-cadherin in Chilean SDGC and that mutational inactivation is an infrequent event. Grant Support: CONICYT-Fondap#15130011 and Fondecyt#1151411.