Microsatellite instability and Beta2-Microglobulin mutations as prognostic markers in colon cancer: results of the FOGT-4 trial

Abstract

Background:High-level microsatellite instability (MSI-H) has been reported as a prognostic marker in colon cancer. We here analysed the prognostic significance of MSI and mutations of the Beta2-Microglobulin (B2M) gene, which occur in about 30% of MSI-H colon cancer, in the cohort of the prospective FOGT-4 (Forschungsruppe Onkologie Gastrointestinale Tumoren, FOGT) trial.Methods:Microsatellite instability status was determined using standard protocols (NCI/ICG-HNPCC panel and CAT25) in 223 colon cancer lesions. Beta2-Microglobulin mutation status was evaluated by exon-wise sequencing in all MSI-H lesions.Results:Patients with MSI-H (n=34) colon cancer presented with a significantly lower risk of relapse after 12 months of follow-up compared with MSS (n=189) colon cancer patients (5 year time to relapse: MSI-H 0.82 vs MSS 0.66, P=0.03). No significant difference in overall survival was detected. Beta2-Microglobulin mutations were identified in 10 (29.4%) out of 34 MSI-H colon cancers and were associated with a complete absence of disease relapse or tumour-related death events (P=0.09).Conclusion:The risk of late disease relapse was significantly lower in patients with MSI-H compared with MSS colon cancer. Moreover, B2M mutations may contribute to the favourable outcome of MSI-H colon cancer patients and should therefore be evaluated as a potential prognostic marker in future clinical trials.

Immunoprofiles of colorectal cancer from Lynch syndrome

“…Studies on non-selected colon cancers have associated low expression levels with lymph node metastases, T stage, and poor survival, 24,25 while studies on MMR-deficient colorectal cancers have correlated B2M loss with favorable survival. 13,26,27 Our results support previous studies showing that B2M loss is significantly associated with improved prognosis in Lynch syndrome tumors and that B2M loss added prognostic value to the CD8 levels. The improved prognosis observed in B2M negative tumors has been associated with complete absence of metastases.…”

“…The improved prognosis observed in B2M negative tumors has been associated with complete absence of metastases. 13,26,27 With three Lynch syndrome metastatic colorectal cancers showing loss of B2M, we did not find such an association, though low levels of CD3 and CD8 positive cells was observed in all three cases.…”

“…The involvement of natural killer cells may offer an explanation to the favorable prognosis in B2M negative tumors though validation of the molecular profiles and the prognostic implications are needed. 26,27 In less immunogenic baseline environments tumors may develop through a B2M proficient pathway, during which neoepitopes will recruit and activate cytotoxic T cells (Figure 3). Tumor progression will in this situation likely depend on further adaptation and immune-evasion through up-regulation of PD-L1, which is localized at the invasive margin of the tumors in contrast to complete loss of B2M.…”

Low density of FOXP3-positive T cells in normal colonic mucosa is related to the presence of beta2-microglobulin mutations in Lynch syndrome-associated colorectal cancer

“…Interestingly, MSI-H colorectal cancers with B2M mutations are associated with an excellent prognosis and the absence of disease relapses or distant organ metastases. 17,35,36 Consequently, Treg cell depletion may improve survival not only by facilitating tumor cell killing, but also by shaping the tumor in a way that favors the formation of a less aggressive, locally restricted phenotype.…”

Expression status of wild-type HSP110 correlates with HSP110 T17 deletion size and patient prognosis in microsatellite-unstable colorectal cancer

“…16 Although the BRAF V600E mutation has been thought to be related to a poor prognosis in colorectal cancer, 1,17 its prognostic effect was significant only in MSS colorectal cancer, not in MSI-H colorectal cancer. 18,19 In addition, the Beta2-microglobulin mutation, myosin 1A expression level, SMAD4 expression level and LINE-1 methylation level have been suggested to be associated with prognosis in patients with MSI-H colorectal cancer, [20][21][22][23][24] but more investigations are needed to establish molecular prognostic markers specific to MSI-H colorectal cancer. Recently, Dorard et al 25 published data indicating the mutant expression of heat shock protein 110 kDa (HSP110, also known as HSP105) as a prognostic and predictive marker in MSI-H colorectal cancer.…”