ABSTRACT
Gastric cancer is a leading cause of cancer mortality and health disparities in Latinos. We evaluated gastric intratumoral heterogeneity using multiregional sequencing of >700 cancer genes in 115 tumor biopsies from 32 patients, 29 who were Latinos. Analyses focused on comparisons with The Cancer Genome Atlas (TCGA) and on mutation clonality, druggability, and signatures. We found that only approximately 30% of all mutations were clonal and that only 61% of the known TCGA gastric cancer drivers harbored clonal mutations. Multiple clonal mutations were found in new candidate gastric cancer drivers such as EYS, FAT4, PCDHA1, RAD50, EXO1, RECQL4, and FSIP2. The genomically stable (GS) molecular subtype, which has the worse prognosis, was identified in 48% of our Latino patients, a fraction that was >2.3-fold higher than in TCGA Asian and White patients. Only a third of all tumors harbored clonal pathogenic mutations in druggable genes, with most (93%) GS tumors lacking actionable clonal mutations. Mutation signature analyses revealed that, in microsatellite-stable (MSS) tumors, DNA repair mutations were common for both tumor initiation and progression, while tobacco, POLE, and inflammation signatures likely initiate carcinogenesis. MSS tumor progression was likely driven by aging- and aflatoxin-associated mutations, as these latter changes were usually nonclonal. In microsatellite-unstable tumors, nonclonal tobacco-associated mutations were common. Our study, therefore, contributed to advancing gastric cancer molecular diagnostics and suggests clonal status is important to understanding gastric tumorigenesis. Our findings of a higher frequency of a poor prognosis associated molecular subtype in Latinos and a possible new aflatoxin gastric cancer etiology also advance cancer disparities research. Significance: Our study contributes to advancing our knowledge of gastric carcinogenesis, diagnostics, and cancer health disparities.
Subject(s)
Genetic Heterogeneity , Hispanic or Latino , Stomach Neoplasms , Humans , Carcinogenesis , Eye Proteins/genetics , Hispanic or Latino/genetics , Mutation , Stomach Neoplasms/genetics , Asian , White , PrognosisABSTRACT
Based on epidemiological associations and experimentation, relationships between viruses and cancer have been established. For more than 14 million new cases of cancer per year, it is estimated that 15% are related to viral agents. Epithelial, hematolymphoid and mesenchymal malignancies related to different viruses have been document such as Epstein Barr, Kaposi's sarcoma, hepatitis B and C, human lymphotropic type 1, Merkel's carcinoma and human papilloma. New virus with oncogenic potential such as cytomegalovirus, JC polyoma virus and BK have been described. The interaction of the viruses with the host induces oncogene activation, inhibition of tumor suppressor genes and activation of miRNAs, as determining factors in the development of cancer. The pathology is initiated with the infection that induces the deregulation of cell signaling. The Epstein Barr virus is the oncogenic prototype, with 1% of the human cancers related to it.
Con base en asociaciones epidemiológicas y experimentación, se ha logrado establecer relaciones entre los virus y el cáncer. Para los más de 14 millones de casos nuevos de cáncer por año, se estima que el 15% se relacionan con agentes virales. Se han documentado malignidades epiteliales, hematolinfoides y mesenquimales, relacionadas con diferentes virus: Epstein Barr, sarcoma de Kaposi, hepatitis B y C, linfotrófico humano tipo 1, carcinoma de Merkel y papiloma humano; se plantean nuevos virus con potencial oncogénico como citomegalovirus, poliomavirus JC y BK. La interacción de los virus con el hospedero muestra activación de oncogenes, inhibición de supresores tumorales y activación de miRNAs, como factores determinantes en el desarrollo de cáncer. La patología se inicia con la infección que induce la desregulación de la señalización celular. El virus de Epstein Barr es el prototipo oncogénico, el 1% de los tipos de cáncer humanos se relacionan con él.
Subject(s)
Humans , Virology , Carcinogenesis , Neoplasms , Homeopathic Pathogenesy , Hematologic NeoplasmsABSTRACT
El gen cagA de Helicobacter pylori codifica para la proteína CagA considerada uno de los factores de virulencia cuya presencia se asocia a un mayor riesgo de padecer enfermedades gástricas severas. El presente estudio planteó como objetivo el diseño de una estrategia molecular y bioinformática útil en la determinación de la presencia de secuencias repetitivas que pueden contener uno o más motivos de fosforilación (EPIYA). Se amplificó y secuenció la región variable de cagA en muestras H. pylori CagA positivas. Se realizó una búsqueda y selección de herramientas bioinformáticas que permitieran establecer las características de los motivos EPIYA. La presencia de motivos tipo EPIYA-A y EPIYA-B, seguido por una a dos repeticiones de EPIYA-C, similares a los reportados para países de Occidente, fueron encontrados. De las aplicaciones bioinformáticas evaluadas, solo un conjunto de herramientas demostró ser útil en la caracterización de las unidades de repetición en la proteína CagA.
Helicobacter pylori CagA protein, the cagA gen product, has been considered as a virulence factor associated with a considerable increase risk for develops severe gastric illness. The purpose of this research was to design a molecular and bioinformatics strategy that allowed the establishment of phosphorylation status of the tyrosine residue of the CagA protein. The amplification and sequencing of the variable fragment region of cagA in the positive CagA samples were used to do the bioinformatics analysis in order to establish the characteristics of the EPIYA motifs. The presence of the EPIYA-A and EPIYA-B motifs, followed by one or two EPIYA-C repetitions, similar to those reported previously for occidental countries were set up. From the different bioinformatics applications that were employed only one group of tools proved to be useful to characterize the repeated units presents in the CagA protein.
