What I’m really asking with that title is, can one game be re-worked to accomodate multiple genre concepts? I’d argue yes, and AD&D 2e kind of proved this.
All fo the different settings for 2nd Edition really showed how the game can be set up to accommodate a variety of things. It ranged from medieval fantasy to horror to sci-fi, and it was always the same game. That’s actually pretty impressive, but that shows that a mechanical system doesn’t need to be designed to specifically encompass.
That doesn’t mean problem aren’t evident. For example, a game is designed to encompass specific ideas and concepts. The mechanics are conceived to help make all of this function in a way that gives the credibility to the ideas. In and of itself, this aspect of designing a game is limiting. Overcoming this, while not impossible, is a difficult challenge.
D&D didn’t really overcome this obstacle. Instead, it published settings that could fit the fantasy mold it operated within, while simultaneously introducing radically new ideas. Ravenloft and Spelljammer really stand out in this respect. These settings made horror and sci-fi possible for a game that was, according to its creators, intended to be modeled on pulp fantasy novels. This never really stopped being the case, but the game made it possible to have vampire kingdoms alongside ray-gun wielding space aliens. It’s a bit gonzo, but the settings made it work.
In any game, this sort of thing is possible, but the ultimate issue is always that one must overcome the limitations of the mechanical system. The system was designed to operate a certain way, and that won’t every change. However, it doesn’t mean don’t have fun with it. D&D did, and it gave a multitude of brilliant settings. This could be you.