In this study, the impact of KRAS gene on recurrence differed in CLM after RFA according to the primary tumor location. In left-sided CRC, the recurrence in the KRAS wild-type and KRAS mutation patients was significantly different. However, there was a similar outcome in right-sided CRC patients. This may be explained by the varying embryological origins of the right-sided colon (originated from the midgut) and the left-sided colon (originated from the hindgut) [32]. These could develop on two different molecular carcinogenic pathways and as distal metastases [33, 34]. A Meta-analysis made up of 66 studies revealed that primary right-sided CRC was associated with a significantly worse outcome, which was considered a stratification factor in future studies [35].
KRAS gene is a small G protein. Its mutations can activate the RAS/MAPK signaling pathway that permits the cell to evade apoptosis, promotes growth and proliferation [36, 37], Approximately 40% of CRCs harbor KRAS mutations [38]. Large phase II trials [12, 13] comprised of 2721 and 4268 patients reported that KRAS mutations were associated with an increased risk of recurrence and death of CRC patients. Meanwhile, some studies suggest otherwise [39, 40]. Similarly, the conclusion whether KRAS gene affects the prognosis of CLM patients who undergo RFA is also inconsistent [41, 42], Therefore, further discussion is necessary.
This study showed that KRAS mutations were more prevalent in right-sided CRC than in left‐sided CRC before RFA, which is consistent with findings of a prior study [23]. Thus, the primary tumor site may interact with KRAS gene, which reflects a more aggressive tumor biology. Although the association between primary location and gene expression is not well reported, some investigators proposed possible reasons. The KRAS-mutation’s aggressive behavior is associated with methylation [43]. Concurrent methylation of more CpG islands was more common in right-sided CRC than in left-sided CRC [44]. Therefore, right-sided CRC with KRAS mutation may have an aggressive biological behavior. We used the primary site for hierarchical analysis to show the relationship between KRAS and recurrence better.
Recurrence after RFA could influence treatment and survival for CLM [20]. Thus, a better understanding of recurrence was necessary. As we know, the liver is a common target for CRC metastases because cancer cells are arrested there primarily and cellular interactions within the mutation is a significant predictor of intrahepatic recurrence after RFA in CLM patients. However, in our prior study [18], we concluded that the intrahepatic recurrence between the two groups was not significantly different, which is consistent with the outcome of right-sided CRC patients with CLM. The possible reason was that the prior study paid mainly attention to LTP and made no further analysis of intrahepatic recurrence after RFA by stratification. Thus, frequent follow-up to detect early recurrence might be reasonable for CLM patients with different KRAS statuses according to the primary tumor site.
Extrahepatic recurrence among patients with CLM did not differ between tumors with a KRAS mutation and that with KRAS wild-type, regardless of the primary site. This was different from findings of another study in which CLM patients with KRAS mutation had more peritoneal metastases after RFA of CLM [19]. There are fewer studies on recurrence after RFA. However, there are also controversial conclusions on the relationship between KRAS gene and extrahepatic recurrence after surgical resection of CLM. Some studies showed that the cumulative incidence of extrahepatic recurrence, such as bone, brain, or lung metastases, was significantly higher for patients with KRAS mutation than for those with KRAS wild-type [5, 14, 17, 45]. Meanwhile, another study reported that KRAS mutation was not linked to recurrence specifically after surgery [46]. Therefore, the association between extrahepatic recurrence and KRAS gene in CLM patients who underwent RFA requires evaluation in further studies.
This study had several limitations. First, the study was retrospective and subject to inherent bias. Second, we considered the primary location and KRAS gene, which may occur in collinearity, the tumors were stratified according to the primary site, but the proportion of patients with right-sided CRC was small (16.5%), A possible reason for this is that the incidence of right colon cancer is lower than that of left colon cancer, right-sided CRC may have an aggressive biological behavior and have no chance of RFA. In addition, it is consistent with the recent study on the incidence of right colon cancer(18.1%)[47]. Prospective and large sample studies are needed to verify the conclusion. Next, other gene mutations, such as BRAF and NRAS, were not considered. However, these mutations do not commonly occur and may not affect the generalizability of our study.