Distinct Clinicopathological Patterns of Mismatch Repair Status in Colorectal Cancer Stratified by KRAS Mutations

In sporadic colorectal cancer (CRC), the BRAF^V600E mutation is associated with deficient mismatch repair (MMR) status and inversely associated with to KRAS mutations. In contrast to deficient MMR (dMMR) CRC, data on the presence of KRAS oncogenic mutations in proficient MMR (pMMR) CRC and their relationship with tumor progression are scarce. We therefore examined the MMR status in combination with KRAS mutations in 913 Chinese patients and correlated the findings obtained with clinical and pathological features. The MMR status was determined based on detection of MLH1, MSH2, MSH6 and PMS2 expression. KRAS mutation and dMMR status were detected in 36.9% and 7.5% of cases, respectively. Four subtypes were determined by MMR and KRAS mutation status: KRAS (+)/pMMR (34.0%), KRAS (+)/dMMR (2.9%), KRAS (-)/pMMR (58.5%) and KRAS (-)/dMMR (4.6%). A higher percentage of pMMR tumors with KRAS mutation were most likely to be female (49.0%), proximal located (45.5%), a mucinous histology (38.4%), and to have increased lymph node metastasis (60.3%), compared with pMMR tumors without BRAF^V600E and KRAS mutations (36.0%, 29.3%, 29.4% and 50.7%, respectively; all P < 0.01). To the contrary, compared with those with KRAS(-)/dMMR tumors, patients with KRAS(+)/dMMR tumors demonstrated no statistically significant differences in gender, tumor location, pT depth of invasion, lymph node metastasis, pTNM stage, and histologic grade. This study revealed that specific epidemiologic and clinicopathologic characteristics are associated with MMR status stratified by KRAS mutation. Knowledge of MMR and KRAS mutation status may enhance molecular pathologic staging of CRC patients and metastatic progression in CRC can be estimated based on the combination of these biomarkers.