261 DNA and RNA alterations associated with colorectal peritoneal metastases: A systematic review DNA/RNA Alterations Outcomes and Association with PM All details about the reported alterations are displayed in Table 3. Mitogen-Activated Protein Kinase (MAPK) Pathway Outcomes BRAF and RAS are both involved in the MAPK pathway and were most commonly reported. BRAF mutations were analyzed in 17 articles 21-23, 27, 29, 33-35, 37, 39, 40, 43-46, 48, 49. In ten studies, it was found on a statistically significant level that BRAF mutant tumors were more likely to develop PM and/or that patients with PM had more often BRAF mutated primary tumors compared to PM-free CRC patients 22, 27, 33, 34, 39, 40, 45, 46, 48, 49. Most studies conducted the BRAF mutation analysis on codon 600, exon 15 (n = 12). Taniguchi et al. reported that the frequencies of BRAF mutations, in combination with RAS wild-type (WT) tumors, were significantly higher in CRC patients with PM 39. Smith et al. showed a statistically significant association when BRAF status in unresectable CRC patients with PM was compared to other metastatic sites. This result, however, did not remain significant after a post hoc Bonferroni correction 37. The authors also mention that BRAF mutations were significantly more common in patients with peritoneal-only metastases compared to patients with liver-only metastases. This, however, did not withstand a correction for multiple testing 37. Atreya et al. and Bruzzi et al. reported no statistically significant difference in metastatic sites and BRAF mutation, although PM were more commonly observed in patients whose tumors harbored a BRAF mutation 21, 43. He et al. investigated therapy-naïve synchronous mCRC patients and found no significant differences in mutation status 23. Shelygin et al. found no association between PM and BRAF status when comparing patients, with and without PM, undergoing surgery for CRC 35. Christensen et al. looked at the probability of developing PM while having a BRAF mutated tumor. The hazard ratio for developing PM and having a BRAF-mutated tumor was statistically not significant 44. One article did not report any data about BRAF mutations and its relation to PM, although they intended to investigate this 28. RAS pathway mutation analyses were reported in 14 studies. Seven studies focused on both KRAS and NRAS genes 21, 27-29, 34, 37, 44, and the other seven studies only described KRAS variants 23, 33, 35, 40, 45, 47, 51. Lan et al. reported that the proportion of PM was significantly higher in stage I–IV CRC patients whose tumors carried a RAS pathway mutation, and KRAS-mutated tumors had a trend toward a higher proportion of PM, which was not significant 28. Both Zihui Yong et al. and He et al. found a significant association between KRAS mutant tumors and PM 23, 51. He et al. also stated that therapy-naïve synchronous PM patients tend to carry a mutant KRAS codon 12 23. One article did not report any outcomes, although they aimed to do so 28. All other studies did not find a significant association or trend between KRAS/NRAS mutant tumors and the development of PM 21, 27, 33-35, 37, 40, 44, 45, 47. To conclude, most articles (n = 10/17) state that BRAF mutant tumors are more likely to have PM and/or mutations in BRAF were more common in patients with PM compared to those 11
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