Roque had spent time with English Premier League side, Liverpool, before signing for Betis in 2009, reported Xinhua.
He announced his retirement in March 2011 as the result of a malignant tumour in his pelvis.
His club Betis published a communique expressing its “tremendous sadness” for Roque’s death and those sentiments were echoed throughout Spain.
Spain coach Vicente del Bosque, who is currently with the national side in the European Championships, sent a message of condolence.
“We are all upset as it is something that you never expect to happen, even though we knew it was serious, even more so in a young sportsman such as Roque. We want to send an embrace to all of the boy’s family and friends and also to his club and its supporters,” added Del Bosque, while members of the Spain squad used their “Twitter” accounts to send their sympathy.
“It is very sad, I want to send my sympathies to the family of Miki Roque,” published Andres Iniesta, while Sergio Ramos wrote, “Life is unfair, I really can’t find the words,” over the death of the young defender.