This study systematically analyzed over 70 pairs of primary human colon tumors using next-generation sequencing to identify somatic mutations, copy-number alterations, and gene fusions. The analysis identified 36,303 protein-altering somatic changes, including recurrent mutations in the Wnt pathway gene *TCF12*, chromatin-modelling genes such as *TET2* and *TET3*, and receptor tyrosine kinases like *ERBB3*. Copy-number and RNA-seq data revealed amplifications and overexpression of *IGF2* in a subset of colon tumors. Notably, multiple fusion transcripts involving R-spondin family members *RSPO2* and *RSPO3* were identified in 10% of colon tumors, which were mutually exclusive with *APC* mutations. These fusions were found to potentiate Wnt signaling, suggesting a potential role in tumorigenesis. The study provides new insights into the genetic landscape of colon cancer and identifies potential therapeutic targets.This study systematically analyzed over 70 pairs of primary human colon tumors using next-generation sequencing to identify somatic mutations, copy-number alterations, and gene fusions. The analysis identified 36,303 protein-altering somatic changes, including recurrent mutations in the Wnt pathway gene *TCF12*, chromatin-modelling genes such as *TET2* and *TET3*, and receptor tyrosine kinases like *ERBB3*. Copy-number and RNA-seq data revealed amplifications and overexpression of *IGF2* in a subset of colon tumors. Notably, multiple fusion transcripts involving R-spondin family members *RSPO2* and *RSPO3* were identified in 10% of colon tumors, which were mutually exclusive with *APC* mutations. These fusions were found to potentiate Wnt signaling, suggesting a potential role in tumorigenesis. The study provides new insights into the genetic landscape of colon cancer and identifies potential therapeutic targets.