MYC Deregulation in Gastric Cancer and Its Clinicopathological Implications

Abstract

Our study investigated the relationship between MYC alterations and clinicopathological features in gastric cancers. We evaluated the effect of MYC mRNA expression and its protein immunoreactivity, as well as copy number variation, promoter DNA methylation, and point mutations, in 125 gastric adenocarcinoma and 67 paried non-neoplastic tissues. We observed that 77% of the tumors presented MYC immunoreactivity which was significantly associated with increased mRNA expression (p<0.05). These observations were associated with deeper tumor extension and the presence of metastasis (p<0.05). MYC protein expression was also more frequently observed in intestinal-type than in diffuse-type tumors (p<0.001). Additionally, MYC mRNA and protein expression were significantly associated with its copy number (p<0.05). The gain of MYC copies was associated with late-onset, intestinal-type, advanced tumor stage, and the presence of distant metastasis (p<0.05). A hypomethylated MYC promoter was detected in 86.4% of tumor samples. MYC hypomethylation was associated with diffuse-type, advanced tumor stage, deeper tumor extension, and the presence of lymph node metastasis (p<0.05). Moreover, eighteen tumor samples presented at least one known mutation. The presence of MYC mutations was associated with diffuse-type tumor (p<0.001). Our results showed that MYC deregulation was mainly associated with poor prognostic features and also reinforced the presence of different pathways involved in intestinal-type and diffuse-type gastric carcinogenesis. Thus, our findings suggest that MYC may be a useful marker for clinical stratification and prognosis.

Effect of Helicobacter pylori on NFKB1, p38α and TNF-α mRNA expression levels in human gastric mucosa

“…Numerous studies of gene expression in human gastric mucosa use GAPDH as the reference gene (58,59), despite the knowledge that GAPDH is upregulated in stomach cancer (24). The present study demonstrated that GAPDH was highly variable between groups, and was therefore not recommended as a reference gene.…”

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

“…In another study, MYC amplification significantly correlated with MYC mRNA levels and MYC immunoreactivity, suggesting that MYC CNV indeed contributes to its overexpression in GC. 95 In mucinous gastric carcinoma, c-MYC amplification was correlated with greater invasion depth and advanced tumor stage, while these differences were not found in non-mucinous gastric carcinomas, suggesting that c-MYC amplification in mucinous gastric carcinoma may be a genetic alteration contributing to the frequent presentation of advanced stage of MGC. 96 The POU5F1B gene (POU domain class 5 transcription factor 1B, the OCT4 pseudogene), which is located on human chromosome 8q24 near MYC, 97 is frequently amplified in GC.…”

Factores genéticos y epigenéticos del cáncer gástrico

“…MYC es un protooncogén que se activa por mutaciones, reordenamientos genéticos, inserciones y/o duplicaciones, todos estos cambios se encuentran con frecuencia en CG (de Souza et al 2013, Leal et al 2011, Calcagno et al 2009. En cánceres como endometrio, páncreas y pulmón se encuentran mutaciones en MYC, las más frecuentes son de cambio de sentido (80,3%), seguidas de mutaciones silenciosas (19,7%).…”

“…En cánceres como endometrio, páncreas y pulmón se encuentran mutaciones en MYC, las más frecuentes son de cambio de sentido (80,3%), seguidas de mutaciones silenciosas (19,7%). En CG-TI no se reportan mutaciones para este gen (Sanger Institute 2011), las mutaciones se asocian, principalmente, con CG-TD (9%) y con metástasis (tabla 1) (de Souza et al 2013). Por otro lado, MYC se encuentra sobreexpresado con mayor frecuencia en CG-TI que en CG-TD, 45% frente al 10%, respectivamente (Calcagno et al 2009, Leal et al 2011), y con poca frecuencia (11%) en metaplasia intestinal (Calcagno et al 2010).…”

“…La sobreexpresión de MYC se asocia con tumores más agresivos, principalmente en CG-TI (Panani 2008) y con mal pronóstico (de Souza et al 2013, Nobili et al 2011, Panani y Roussos 2005. Finalmente, la infección por de H. pylori cagA+ aumenta la sobreexpresión de MYC en mucosa gástrica (Lima et al 2008).…”