I think what you need to do, before you figure out any of the plot or mechanics (or take any advice from us regarding those things), is if (and how) you want your game to differ from other games. There are pros and cons for both, so you can go either way, but you really want to determine that for yourself. More than anything else, you should try to envision where you want your game to be and what kind of ambition and effort you have for this game: roguelike is the type of genre that produces very short and very long games, both in development time and player time. Inevitably it is these principles that help design the game, and the plot and mechanics are mere afterthought by comparison.
This aside, it sounds more like you're aiming the plot to be "not fantasy" rather than science fiction. Certainly there are topics beyond these two, even if they aren't touched upon often. What about a modern setting, along the lines of Grand Theft Auto? You could also consider a wholly-abstract setting, in which all of the characters begin as "souls" and literally will themselves and their environment into existence. There's also steampunk which fits as a sort of sci-fi/fantasy hybrid, typically placed in an industrial era and involving technomagical devices (not even with literal magic, so to speak, but technology ridiculous enough to be thought of as magical). Or how about a "real but whimsical" setting, like insect worlds or aquatic habitats? There's a lot out there when it comes to designing a "universe" for your story.
