Beta2‐microglobulin mutations in microsatellite unstable colorectal tumors

Abstract

Defects of DNA mismatch repair (MMR) cause the high level microsatellite instability (MSI-H) phenotype. MSI-H cancers may develop either sporadically or in the context of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome that is caused by germline mutations of MMR genes. In colorectal cancer (CRC), MSI-H is characterized by a dense lymphocytic infiltration, reflecting a high immunogenicity of these cancers. As a consequence of immunoselection, MSI-H CRCs frequently display a loss of human leukocyte antigen (HLA) class I antigen presentation caused by mutations of the b2-microglobulin (b2m) gene. To examine the implications of b2m mutations during MSI-H colorectal tumor development, we analyzed the prevalence of b2m mutations in MSI-H colorectal adenomas (n 5 38) and carcinomas (n 5 104) of different stages. Mutations were observed in 6/38 (15.8%) MSI-H adenomas and 29/104 (27.9%) MSI-H CRCs. A higher frequency of b2m mutations was observed in MSI-H CRC patients with germline mutations of MMR genes MLH1 or MSH2 (36.4%) compared with patients without germline mutations (15.4%). The high frequency of b2m mutations in HNPCC-associated MSI-H CRCs is in line with the hypothesis that immunoselection may be particularly pronounced in HNPCC patients with inherited predisposition to develop MSI-H cancers. b2m mutations were positively related to stage in tumors without distant metastases (UICC I-III), suggesting that loss of b2m expression may promote local progression of colorectal MSI-H tumors. However, no b2m mutations were observed in metastasized CRCs (UICC stage IV, p 5 0.04). These results suggest that functional b2m may be necessary for distant metastasis formation in CRC patients. ' 2007 Wiley-Liss, Inc.

Immunoprofiles of colorectal cancer from Lynch syndrome

“…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.…”

“…Loss of B2M was, however, observed in 28% and may result in loss of MHC class I presentation and confer decreased sensitivity to therapies directed at cytotoxic T cells, such as anti-PD-1 therapies. 11,13,15,17 …”

“…8,20–22 Loss of B2M in 28% of the Lynch syndrome tumors was within previous reported range of 21–30% and are likely caused by frameshift mutations in microsatellite regions of the B2M gene (Figure 1). 13,15 The tumorigenic event of B2M loss is likely occurring in the middle of the adenoma-carcinoma sequence since B2M loss has not been found in metastasizing tumors or MMR deficient adenomas. 13,23 The prognostic value of B2M has been investigated in several studies with contradicting results.…”

“…13,15 The tumorigenic event of B2M loss is likely occurring in the middle of the adenoma-carcinoma sequence since B2M loss has not been found in metastasizing tumors or MMR deficient adenomas. 13,23 The prognostic value of B2M has been investigated in several studies with contradicting results. 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.…”

“…2,5 This anti-tumorigenic effect may be counter-balanced by immune-evasive mechanisms, such as loss of the MHC class I subunit, beta-2-microglobulin (B2M) and up-regulation of the T-cell inhibitor programmed death 1 ligand 1 (PD-L1). 13,14 B2M loss has been associated with loss of MHC class I receptors suggesting that this subset may not elicit neoepitope-induced T cell responses. 4,15 In contrast, high levels of PD-L1 have been associated with T cell exhaustion that can be reversed by inhibition of the programmed death 1 (PD-1)/PD-L1 binding.…”