Abstract
In sporadic colorectal cancer (CRC), the BRAFV600E 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 BRAFV600E 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.
Highlights
Colorectal cancer (CRC) is a heterogenous disease evolving from diverse genetic pathways and an accurate assessment of cancer based on tumor features would permit personalized cancer treatment [1,2,3]
Deficient mismatch repair (MMR) is observed in 10% to 20% of patients with sporadic CRC, of which the majority of DNA mismatch repair (dMMR) tumors are due to hypermethylation of MLH1 gene promoter, with MSH2 and MSH6 accounting for a smaller percentage [5]
A total of the 913 cases were evaluated by immunohistochemistry (IHC) for the presence or absence of MLH1, MSH2, MSH6 and PMS2 protein expression
Summary
Colorectal cancer (CRC) is a heterogenous disease evolving from diverse genetic pathways and an accurate assessment of cancer based on tumor features would permit personalized cancer treatment [1,2,3]. A germline mutation in one of the MMR genes, including MLH1, MSH2, MSH6 or PMS2, is the cause of dMMR in patients with Lynch syndrome, which is an inherited disorder that increases the risk of developing CRC [10,11]. Sporadic dMMR tumors, but not Lynch syndrome, frequently carry the activating somatic V600E mutation in the exon 15 of the BRAF oncogene [12,13,14]. Both sporadic and Lynch syndrome-associated tumors with dMMR status have distinct clinicopathologic features, such as preferential location in the proximal colon, prominent lymphocytic infiltrate, mucinous or signet ring differentiation, and association with a favorable prognosis. These results indicate that dMMR tumors have a decreased likelihood to metastasize and suggest a more favorable outcome [9,15]
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