I'm glad that I saw this thread before I hooked up my Mega, it saved me a ruined board. I'm running off of a 80's vintage backplane, with a typical 5v supply. The supply runs hot, about 5.25 volts. Thanks to seeing these posts I disconnect the Mega2560 from the external supply while programing, then disconect the USB when installed. Works so far. The one time I left the USB conneced when attached to external supply, the Mega USB IC got hot fast.
I also use a modified USB cable with the 5v line cut for when I need to get data while running.
Since the problem is known and can break boards, how about a sticky, or a warning.
Get the word out.
Thanks
Bob Prescott