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Page 6 of 25                         Battaglin et al. J Cancer Metastasis Treat 2018;4:12  I  http://dx.doi.org/10.20517/2394-4722.2018.04

               and recombination, as well as repairing some forms of DNA damage. The loss of MMR proteins activity
               leads to an accumulation of DNA replication errors, a phenomenon known as MSI, characterized by high
               frequency of frameshift mutations in microsatellite DNA which translates into a high somatic mutational
               burden in MMR-deficient (MMR-D) cells (mutator phenotype) .
                                                                    [64]
               The prevalence of MSI in CRC depends on the stage of the disease. Approximately 20% of CRCs in stage I-II,
               12% in stage III and 4%-5% in stage IV, are deficient in one or more DNA MMR proteins, with one-quarter
               of these resulting from Lynch syndrome (LS), an autosomal dominant condition characterized by germline
                                                                                               [65]
               mutations in genes coding for MMR proteins (i.e. MLH1, MSH2, MSH6, PMS2 or EPCAM) . The vast
               majority (circa 80%-90%) of sporadic MSI cases are due to hypermethylation of the MLH1 gene promoter [66,67] ,
               associated with a high CpG island methylation phenotype (CIMP+) and about 30% harbor a BRAF V600E
               mutation [6,68] . The remaining cases of sporadic MSI can be explained mainly by the presence of multiple somatic
                                                                                                        [69]
               mutations in the MMR genes without an identifiable germline MMR mutation (“double somatic” MSI cases) ,
               found to be associated with a higher frequency of somatic mutations in PIK3CA . According to the recent CMS
                                                                               [70]
               classification MSI is associated with CMS1 [6,71] . MSI detection is currently based on two different approaches:
               immunohistochemical staining (IHC) for MLH1, MSH2, MSH6, and PMS2 on tumor samples to identify the loss
               of protein expression which characterizes MMR deficiency as a surrogate for MSI ; DNA MSI testing through a
                                                                                 [72]
               polymerase chain reaction (PCR)-based approach evaluating specific panels of microsatellite markers . If either
                                                                                                 [73]
               MSI or MMR deficiency is detected, further evaluation is recommended to rule out LS, rather than sporadic
               MSI. Of note, recently new computational approaches based on the evaluation of next generation sequencing
               (NGS) data have been proposed as a tool for MSI assessment [74-77] , as well as the evaluation of mutational burden
               on circulating cell-free tumor-DNA testing as a surrogate marker of mismatch repair deficiency or microsatellite
                                         [78]
               instability in patients with CRC .
               MSI-H CRCs are characterized by distinct clinical and pathological features such as right-sided colon
               location,  early-stage  at  diagnosis,  prominent  lymphocytic  infiltrate,  poor  differentiation  and  mucinous
                       [79]
               histology . When diagnosed in the metastatic setting, MSI-H mCRCs arise more frequently in women
               and in elderly; presenting often with synchronous metastases involving peritoneum, lymph nodes and
               lung rather than liver. Notably, distinct patterns characterize inherited and sporadic MSI-H mCRCs .
                                                                                                       [80]
               In addition to LS screening, in patients with early-stage (especially stage II) CRCs, MMR status provides
               important prognostic and predictive information, with MMR deficiency being associated with both a good
               prognosis and apparently a lack of efficacy from fluorouracil treatment, although data regarding whether or
               not MSI status predicts response to adjuvant chemotherapy in this setting has been controversial [81-85] . The
               most solid data derive from the analyses of the ACCENT database investigating the impact of MSI in stage
               II and III CRCs treated with surgery vs. surgery followed by 5-FU-based adjuvant therapy across 17 different
               trials. Stage II and III patients with MSI tumors showed better outcome with surgery alone compared to
               those with microsatellite stable (MSS) tumors. Conversely, stage III patients showed a significant survival
               benefit from the addition of 5-FU adjuvant therapy after surgery both in case of MSS and MSI tumors .
                                                                                                       [84]
               To date, adjuvant chemotherapy is not recommended for patients with low risk stage II MSI-H tumors
               due to their excellent prognosis, while stage III patients should receive adjuvant treatment irrespective of
               MSI status. Of note, MSI etiology (germline vs. sporadic) seems to affect the predicted benefit from 5-FU,
               as Sinicrope et al.  showed, in a retrospective evaluation of stage II and III CRC patients who received
                               [86]
               either adjuvant 5-FU or placebo, that individuals with MSI-H CRCs due to germline mutations (i.e. LS) had
               an improved disease free survival (DFS) with 5-FU compared to those with sporadic MSI-H tumors. The
               role of MSI as a predictive marker with modern combination regimens, such as FOLFOX and FOLFIRI,
               has less evidence [87-89] , and although an MSI-H status was retrospectively shown to predict improved DFS
               with adjuvant irinotecan and 5-FU (IFL regimen) in the CALGB (Alliance) 89803 trial, these results were
               inconsistently demonstrated in other exploratory analyses [90,91] . In the metastatic setting, recent data suggest
               a greater activity of irinotecan in MSI-H mCRC and better outcomes in favor of bevacizumab treatment
               compared to anti-EGFRs . Indeed, vascular endothelial growth factor (VEGF) is known to play a crucial
                                    [92]
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