In this study, we performed exome analysis of 3 sCRC tumor samples with LoF mutation screening strategy, together with systems-level analysis, we uncovered well-studied tumor suppressor APC, TCF7L2, and ELF3 in CRC, as well as novel top rank gene BMP5 that can affect CRC initiation, progression and prognosis. Here, TCF7L2 is linked to colorectal carcinoma.