265 DNA and RNA alterations associated with colorectal peritoneal metastases: A systematic review described to be associated with PM. The results of our study demonstrate this as well. Third, TP53 gene mutations are one of the most frequently described mutations as they occur in 35%–75% of the colorectal PM patients 13. Previous research shows the contradictory result of TP53 mutations and their prognostic value in CRC patients 53. In this review, some authors showed a significant association, while others did not reach the significance. MSI Status Of the included studies, only 10 articles reported on MSI status, all without extensive analysis. This is unfortunate, as MSI status is the only prognostic molecular marker used in deciding adjuvant therapy options 56. MSI originates from the inactivation of mismatch repair genes by either MLH1 hypermethylation or mutation. This results in the accumulation of somatic mutations and subsequent genomic instability, which is associated with nonhereditary CRC 53. It is well reported that MSI is a good prognostic factor for some treatments in early-stage CRC 59. We believe it is important to always report MSI status in biomarker research to incorporate all relevant characteristics. Clinical Relevancy Clinically, the known risk factors for metachronous colorectal PM are an advanced tumor stage, right-sided tumor, infiltrative or ulcero-infiltrative tumors, history of perforation, and obstruction 3, 8, 60. A randomized trial (COLOPEC-1) investigating the therapeutic effectiveness of adjuvant HIPEC to prevent PM development in high-risk CRC patients showed that this treatment strategy did not improve PM-free survival 11. In contrast, a Spanish study by ArjonaSánchez et al. concluded that adjuvant HIPEC therapy might be useful in patients with T4 tumors 61. Identifying genetic alterations in high-risk metachronous PM patients may have additional benefit on improving survival by additional targeted therapies such as adjuvant HIPEC. In synchronous PM patients, the alterations provide added value to determine prognosis or to predict response to therapy. For example, RAS pathway activating mutations are negative predictive markers for the efficacy of anti-epidermal growth factor receptor (EGFR) therapies 62, while MSI tumors with BRAF and PIK3CA mutations show survival benefit 39. For CRS and HIPEC scheduled patients, a BRAF mutation is a marker for poor prognosis, whereas KRAS tumors do not influence the outcomes 63. The choice of cytostatic in HIPEC can be based on mutation status, or specific therapy can be developed in the case of targetable mutations. Unfortunately, most of the studies did not clearly specify whether the authors were using tumors from synchronous or metachronous PM patients. It was therefore hard to distinguish and separate these two scenarios in the results. Future studies should clearly specify the time of metastases onset, the aim of the genetic analysis, and clinical implications. 11
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