Browsing by Author "Alarcón Alarcón, María Alejandra"

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    Identification of c.1531C>T Pathogenic Variant in the CDH1 Gene as a Novel Germline Mutation of Hereditary Diffuse Gastric Cancer
    (2019) Norero Muñoz, Enrique Eduardo; Alarcón Alarcón, María Alejandra; Hakkaart, Cristopher; de Mayo, Tomás; Mellado Sagredo, Cecilia Ximena; Garrido Salvo, Marcelo Adán; Aguayo Bonniard, Gloria Alejandra; Lagos, Marcela; Torres, Javiera; Calvo, Alfonso; Guilford, Parry; Corvalan, Alejandro H
    Germline pathogenic variants in the CDH1 gene are a well-established cause of hereditary diffuse gastric cancer (HDGC) syndrome. The aim of this study was to characterize CDH1 mutations associated with HDGC from Chile, a country with one of the highest incidence and mortality rates in the world for gastric cancer (GC). Here, we prospectively include probands with family history/early onset of diffuse-type of GC. The whole coding sequence of the CDH1 gene was sequenced from genomic DNA in all patients, and a multidisciplinary team managed each family member with a pathogenic sequence variant. Thirty-six cases were included (median age 44 years/male 50%). Twenty-seven (75%) patients had diffuse-type GC at <= 50 years of age and 19 (53%) had first or second-degree family members with a history of HDGC. Two cases (5.5%) carried a non-synonymous germline sequence variant in the CDH1 gene: (a) The c.88C>A missense variant was found in a family with three diffuse-type GC cases; and (b) c.1531C>T a nonsense pathogenic variant was identified in a 22-year-old proband with no previous family history of HDGC. Of note, six family members carry the same nonsense pathogenic variant. Prophylactic gastrectomy in the proband's sister revealed stage I signet-ring cell carcinoma. The finding of 1531C>T pathogenic variant in the CDH1 in proband with no previous family history of HDGC warrants further study to uncover familial clustering of disease in CDH1 negative patients. This finding may be particularly relevant in high incidence countries, such as the case in this report.
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    Role of Reprimo-like as a a tumor suppressor and candidate biomarker in gastric cancer
    (2020) Alarcón Alarcón, María Alejandra; Corvalán R., Alejandro; Pontificia Universidad Católica de Chile. Facultad de Medicina
    Reprimo-like (RPRML) is an uncharacterized member of the Reprimo gene family. Herein, we evaluated the role of RPRML and whether its regulation by DNA methylation is a potential non-invasive biomarker of gastric cancer. RPRML expression was evaluated by immunohistochemistry in 90 patients with gastric cancer and associated with clinicopathologic characteristics and outcome. The role of RPRML in cancer biology was investigated in vitro, through RPRML ectopic overexpression. Functional experiments included colony formation, soft agar, MTS, and Ki67 immunofluorescence assays. DNA methylation-mediated silencing was evaluated by the 5-azacytidine assay and direct bisulfite sequencing. Non-invasive detection of circulating methylated RPRML DNA was assessed in 25 gastric cancer cases and 64 controls by the MethyLight assay. Downregulation of RPRML protein expression was associated with poor overall survival in advanced gastric cancer. RPRML overexpression significantly inhibited clonogenic capacity, anchorage-independent growth, and proliferation, in vitro. Circulating methylated RPRML DNA discriminated patients with gastric cancer from controls with an area under the curve of 0.729. The in vitro overexpression results and the poor patient survival associated with lower RPRML levels suggest that RPRML plays a tumor-suppressive role in the stomach. Circulating methylated RPRML DNA may serve as a biomarker for the non-invasive detection of gastric cancer.
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    The Reprimo Gene Family: A Novel Gene Lineage in Gastric Cancer with Tumor Suppressive Properties
    (2018) Amigo Donoso, Julio; Wichmann Pérez, Ignacio Alberto; Jorquera Cifuentes, Roddy Alberto.; García Bloj, Benjamín.; Alarcón Alarcón, María Alejandra; Owen, Gareth Ivor; Corvalán R., Alejandro; Opazo, Juan C.
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    The reprimo-like gene is an epigenetic-mediated tumor suppressor and a candidate biomarker for the non-invasive detection of gastric cancer
    (2020) Alarcón Alarcón, María Alejandra; Olivares, W.; Córdova Delgado, M.; Wichmann Pérez, Ignacio Alberto; Amigo, Julio; Norero Muñoz, Enrique; Riquelme Pérez, Arnoldo; Garrido S., Marcelo; Owen, Gareth Ivor; Corvalán R., Alejandro; Muñoz-Medel, M.; Mayo, T. de; Carrasco-Aviño, G.; Landeros, N.; Villarroel Espíndola, F.