We defined two mutually-exclusive paralogous oncogenic drivers, Zmiz1 and Zmiz2 among the most recurrent drivers and our report is the first to identify Zmiz2 as a significant candidate cancer gene in any SB study and the first to discover mutual exclusivity among activated Zmiz1, Zmiz2, and Mamld1 in early keratinocyte transformation and cuSCC progression. Here, ZMIZ1 is linked to cancer.