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The train, crammed with people due to road traffic disruption between the two cities, left the tracks just before reaching the central city of Eseka, Transport minister Edgar Alain Mebe Ngo’o said earlier.
Crtv gave the tolls of 53 dead and more than 300 injured, adding that some of the injured were in a very serious condition.
“Cause of the accident is not yet clear,” the broadcaster added.
The minister said the derailment had “caused significant human and material damage but I can’t at this time give you any figures”.
A ministerial delegation was being sent to the accident site.
According to Crtv the train left for Yaounde shortly after 11:00 am (1000 GMT) packed with passengers.
The route was particularly busy after a bridge on the road linking Yaounde and Douala collapsed in heavy rain overnight Thursday to Friday, paralysing traffic and sending extra waves of travellers on to trains.
“Intervention and security teams have been mobilised,” the rail company Camrail said.