264 Chapter 11 DISCUSSION This systematic review provides an overview of the results of studies which analyzed genomic DNA and RNA expression alterations correlated to PM with the goal of identifying alterations that could potentially serve as a predictive biomarker in patients with CRC. Of the 17 studies investigating BRAF mutations, ten studies reported a significant association with PM. Mutations in ARID1A, ASXL1, Kif18A, NEK2, MACC1, PAX5, PKHD1, REG1A, RET, Tip60 and UBR5 were also reported to be associated with PM 20, 29-32, 38, 41, 50, although these results were only described in maximum of one study. A recent analysis with a cancer panel of 770 genes from Jacob et al. did not show a significant down- or upregulation of distinct gene sets between CRC patients with PM and without distant metastases. Their sample size was, however, small (n = 18) 26. BRAF Mutations BRAF gene mutations occur in 5–15% of the mCRC cases; over 95% of these mutations consist of a substitution of valine to glutamic acid at codon 600 (V600E) 13, 16, 53. BRAF is a serine/threonine protein kinase that plays an important role in the MAPK pathway. This pathway drives cell proliferation, differentiation, migration, survival, and angiogenesis, and therefore, changes in this pathway are associated with tumorigenesis 54. BRAF mutations can be considered as an independent negative prognostic factor in early-stage microsatellite stable tumors and as a negative predictive factor for therapeutic approaches 54. Due to its chemoresistance and resistance to BRAF inhibitor therapy, BRAF-mutated tumors are difficult to treat 54, 55. Therefore, trials are currently going on with dual or triple drug therapy to enhance blockade of the MAPK pathway. Nowadays, CRC patients without metastases are not screened for BRAF mutations, and further molecular examination is only conducted in metastatic disease 56. As only 55% of the studies reported a significant association between BRAF mutations and PM, we cannot conclude yet that BRAF mutations are specific enough to identify patients with colorectal PM. Other Mutations First, RAS pathway mutations are the most commonly investigated mutations in mCRC. Different codons of both KRAS and NRAS genes were included, thereby creating a broader overview of this pathway. KRAS is the most commonly activated oncogene in CRC, with mutations occurring in exon 2 codon 12 and 13, exon 3 codon 59 and 61, and exon 4 codon 117 and 146 16, 57. Approximately 30–50% of the CRC patients carry a somatic KRAS mutation 16. KRAS mutations have been associated with lung metastases but not with PM 16. NRAS is mutually exclusive with BRAF and KRAS and occurs in approximately 3% of CRC patients 16. There has been no previously described association with PM, which is in line with the findings of this review. Second, PIK3CA (exon 9 and 20) gene mutations occur in 10–18% of CRC patients 53. They commonly co-occur with KRAS or BRAF mutations. Approximately 70% of PIK3CA mutant patients have concurrent mutations 16, 58, although they have never been
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