The aim of the present study was to explore the genetic heterogeneity of adenomas and early carcinomas by analyzing the mutation spectrum of well-known genes involved in colorectal carcinogenesis (APC, BRAF, EGFR, NRAS, KRAS, PIK3CA, POLE, POLD1, SMAD4, PTEN, and TP53) in a large, well-defined series of adenomas and in situ carcinomas with follow up using a next generation sequencing approach. The gene discussed is SMAD4; the disease is in situ carcinoma.