Intratumoral heterogeneity of KRAS mutations in patients with colorectal cancer and metastatic livers in southwest China

Introduction: KRAS mutations are the most common somatic alterations in colorectal cancer (CRC) patients. Epidermal growth factor receptor (EGFR) antibody therapies are effective in 50% of the CRC patients with wild-type KRAS. To confirm the possible causes of the therapeutic failure, we examined KRAS mutations and analyzed their intratumoral heterogeneity in different areas of the primary tumors and the metastatic liver lesions. Methods: The sequences of exon 2 of KRAS were evaluated by direct sequencing of samples from 26 CRC patients, including 2 patients with colorectal liver metastasis. Tumor tissues were macrodissected from five different areas in primary CRC tumors and two different areas of metastatic liver lesions. Results: KRAS mutations were detected in 26.9% of the primary tumors. By comparing the different areas of primary tumors and liver metastasis, the intratumoral heterogeneity of KRAS mutations was observed in 11.5% of the primary tumors, but not in patients with liver metastasis. This study is the first to report the intratumoral heterogeneity of KRAS mutations in CRC patients from Southwest China, although our relatively small sample size might not provide sufficient statistical power. Conclusions: The failure of EGFR antibody therapies in CRC patients with wild-type KRAS might be attributed to the false-negative sequencing results caused by intratumoral heterogeneity. Considering the high rates of heterogeneity among primary tumors, the different parts of tumors should be tested to correctly predict the KRAS mutations.