RESUMEN
OBJECTIVES: Current prospective studies investigating the frequency of hereditary criteria in a Caucasian population for adenocarcinoma of the esophagogastric junction (AEG) and stomach (GC) are missing. Genetic testing criteria (screening criteria) for hereditary diffuse gastric cancer (HDGC) were updated in 2020, but do not address patients with intestinal histology (familial intestinal gastric cancer FIGC). Thus, we prospectively screened patients residing in Berlin newly diagnosed with AEG or GC for hereditary criteria to gain insights into the frequency of HDGC. METHODS: Prospective documentation of familial/clinical parameters in patients residing in Berlin with AEG or GC over three years was conducted. Besides HDGC criteria from 2015 and revised 2020, we also documented patients fulfilling these criteria but with intestinal type gastric cancer (FIGC). Statistical analysis was performed using X2-test. RESULTS: One hundred fifty-three patients were finally included (92 GC; male: 50 (n.s.); 61 AEG; male: 47; p = 0.007). Hereditary criteria for HDGC were detected in 9/92 (9.8%) (2015 criteria) and in 14/92 (15.2%) (2020 criteria) of GC patients (AEG: 2015 criteria 3/61 (4.9%) versus 4/61 according to 2020 criteria (6.5%)). Patients fulfilling hereditary criteria but with intestinal histology (FIGC) increased from 8.7% (2015) to 14.1%, respectively (2020) (AEG: 3.2% (2015) versus 6.6% (2020)). Hereditary criteria including intestinal histology were found in 29.3% (GC) and 13.1% (AEG) (p = 0.03) according to the 2020 criteria. CONCLUSIONS: HDGC criteria were found in 15.2% of GC patients according to the 2020 criteria. Percentage increased to 29.3% including patients with intestinal histology among the GC group, and was 13.1% in cases with AEG. These data indicate that family history seems to be of utmost importance in GC to further detect potential hereditary genetic risks. This equally applies for patients with intestinal subtype GC.
RESUMEN
The death ligand TRAIL synergizes with DNA-damaging therapies such as chemotherapeutic drugs or ionizing irradiation. Here, we show that the synergism of TRAIL and 5-fluorouracil (5-FU) and cross-sensitization between TRAIL and 5-FU for induction of apoptosis, entirely depend on Bax proficiency in human DU145 and HCT116 carcinoma cells. DU145 prostate carcinoma cells that have lost Bax protein expression due to mutation fail to release cytochrome c and to activate caspase-3 and -9 when exposed to TRAIL and 5-FU. In contrast, TRAIL sensitized for 5-FU-induced apoptosis and vice versa upon reconstitution of Bax expression. Isobolographic analyses of ED50 doses for 5-FU at increasing TRAIL concentrations showed a clear synergism of TRAIL and 5-FU in Bax-expressing cells. In contrast, the effect was merely additive in DU145 cells lacking Bax. Notably, both DU145 and HCT116 Bax-deficient cells still express Bak. This indicates that Bak is not sufficient to mediate cross-sensitization and synergism between 5-FU and TRAIL. Stable overexpression of Bak in DU145 sensitized for epirubicin-induced apoptosis but failed to confer synergy between TRAIL and 5-FU. Moreover, we show by the use of EGFP-tagged Bax and Bak that TRAIL and 5-FU synergistically trigger oligomerization and clustering of Bax but not Bak. These data clearly establish distinct roles for Bax and Bak in linking the TRAIL death receptor pathway to the mitochondrial apoptosis signaling cascade and delineate a higher degree of specificity in signaling for cell death by multidomain Bcl-2 homologs.
