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HIGH THYMIDYLATE SYNTHASE EXPRESSION IN GASTRIC ADENOCARCINOMAS WITH MICROSATELLITE INSTABILITY
Gastric cancer (GC) with microsatellite instability (MSI) is recognized as a less aggressive disease and associates with resistance to 5-fluorouracil (5-FU)-based chemotherapy. Thymidylate synthase (TS) is inhibited by 5-FU, being another potential mediator of therapeutic resistance to 5-FU. However, the reasons for the clinical behavior observed in MSI GC have not been fully elucidated, and no data is available regarding the relationship between MSI and TS expression in GC.
The present study aimed to analyze the MSI status and the expression of TS in GC to determine: I) their relationship, II) characteristics and association to other biomarkers and lymphocyte inflammatory response, and III) impact on disease`s outcomes.
We retrospectively evaluated patients with gastric adenocarcinoma who underwent D2-gastrectomy with curative intent. Patients were analyzed for MSI and TS expression by immunohistochemistry. TS level was evaluated according to the intensity and percentage of cells marked by a score system (TS-score), and TS-high/low groups determined based on the median value. Additionally, we also investigated p53 expression in an attempt to explain the different clinical behavior, and the tumor-infiltrating lymphocytes (CD3, CD4, CD8), since they reflect the host antitumor immune response.
Of 284 GC studied, 60 (21.1%) were MSI. The median TS-score for all cases was 16.5. TS expression was significantly higher in MSI tumors compared to microsatellite-stable (MSS) GC (TS-score= 33.2 vs 62.5, p<0.001). Considering both status, 44 (15.5%) patients were classified as TS-high/MSI, 98 (34.5%) as TS-high/MSS, 16 (5.6%) as TS-low/MSI, and 126 (44.4%) as TS-low/MSS. TS-high/MSI tumors were predominantly Lauren's intestinal type (p<0.001) and had lower TNM stage (p=0.005). TS-high/MSI GC was also associated with higher CD8 levels (p<0.001) and normal p53 expression (p<0.001). Improved overall survival was observed in TS-high/MSI GC compared with others groups (70.4% vs TS-low/MSI= 62.5%, p=0.573; vs TS-low/MSS= 51.2%, p=0.039; vs TS-high/MSS= 49.9%, p=0.030).
MSI GC was associated with high TS expression, suggesting that TS levels may explain therapeutic resistance to 5-FU. In addition, TS-high/MSI GC showed earlier stage at presentation and better survival rates. We believe that the greater infiltration of CD8 lymphocytes, that plays a role in anti-tumour immunity, and the normal p53 observed in these cases may also elucidate why these tumors have a better prognosis.
gastric cancer, gastric neoplasms, microsatellite instability, thymidylate synthase, 5-fluorouracil, chemoterapy.
Trato gastrointestinal alto*
MARINA ALESSANDRA PEREIRA, ANDRE RONCON DIAS, MARCUS FERNANDO KODAMA PERTILLE RAMOS, LEONARDO CARDILI, RAFAEL DYER RODRIGUES DE MORAES, BRUNO ZILBERSTEIN, ULYSSES RIBEIRO JR, SERGIO CARLOS NAHAS, VENÂNCIO AVANCINI FERREIRA ALVES, EVANDRO SOBROZA DE MELLO