"It's got a little bit to do with destiny, fate, and what's written in the stars."
Part of Dean wants the handprint to be nothing more than a scar. A freakish, physical manifestation of forty years in Hell. The second, much smaller part — full of fragile, tentative hope — is one he forces himself to bury until he knows for sure.
After months of dead ends, solid information turns up in the form of Sam, who coughs and mutters something about reliable sources before dropping the world's biggest bombshell of "Some soul mate marks can indicate non humans... like angels."
God must be screwing with him now.
Dean elects to handle the news by getting devastatingly drunk.