Even the Amsterdam criteria are not entirely specific and likely identify a second inherited condition known as “Syndrome X”.12 The choice to exclude synchronous cancers may have altered the study findings as these tumors are not exclusively hereditary. In fact, synchronous colorectal tumors often have the sporadic MSI cancer features of CIMP and BRAF mutation.13 Also of note is the molecular heterogeneity even within the sporadic MSI cancer group. A significant proportion of MSI cancers arising in older patients will not mutate BRAF or exhibit CIMP. It is possible that these cancers arise due to somatic MLH1 mutation and may not originate in a serrated precursor lesion. In studies
where the goal is to better understand MSI cancers of the “serrated pathway”, MK-2206 concentration it may be prudent to select cancers based on BRAF mutation and/or CIMP in addition to MSI status. Whilst the prognostic advantage of MSI has been well documented, chemotherapeutic use of the commonly administered Crizotinib in vitro 5-fluorouracil does not appear to benefit these patients and may actually adversely impact prognosis.14 In theory, this is because 5-fluorouracil is incorporated into the cell’s DNA and a functional mismatch repair system is required to direct these damaged cells towards apoptosis. Recent evidence
suggests that these patients may benefit from the topoisomerase inhibitor irinotecan.15 This therapy introduces DNA double strand breaks, which are lethal if not repaired. Irinotecan may therefore offer an advantage to all patients with an MSI cancer, regardless of natural history or other molecular characteristics. This has not been directly investigated, however, and future trials may benefit from the addition of BRAF mutation testing in the study protocol. The molecular characterization of colorectal cancer
has greatly improved patient management. MSI is an excellent example of this in both the hereditary and sporadic settings. Causative germline mutations in mismatch repair genes are now routinely identified for Lynch syndrome families. This not only ensures mutation carriers are adequately surveilled, but also identifies unaffected individuals and prevents G protein-coupled receptor kinase unnecessary colonoscopy. MSI was also critical for identifying serrated pathway cancers and tracing their origin to serrated polyps, which has greatly impacted colonoscopic practice and surveillance recommendations. Future research efforts must now be directed towards better understanding the natural history of serrated pathway lesions and optimal therapeutic intervention for advanced cancers. To achieve this it is vital to fully exploit our molecular knowledge to identify homogeneous patient cohorts. “
“Genetic alterations in specific driver genes lead to disruption of cellular pathways and are critical events in the instigation and progression of hepatocellular carcinoma (HCC).