Confirmation that somatic mutations of beta‐2 microglobulin correlate with a lack of recurrence in a subset of stage II mismatch repair deficient colorectal cancers from the QUASAR trial

Abstract

Aims Beta2‐microglobulin (B2M) forms part of the HLA class I complex and plays a role in metastatic biology. B2M mutations occur frequently in mismatch repair‐deficient colorectal cancer (dMMR CRC), with limited data suggesting they may protect against recurrence. Our experimental study tested this hypothesis by investigating B2M mutation status and B2M protein expression and recurrence in patients in the stage II QUASAR clinical trial. Methods and results Sanger sequencing was performed for the three coding exons of B2M on 121 dMMR and a subsample of 108 pMMR tumours; 52 with recurrence and 56 without. B2M protein expression was assessed by immunohistochemistry. Mutation status and protein expression were correlated with recurrence and compared to proficient mismatch repair (pMMR) CRCs. Deleterious B2M mutations were detected in 39 of 121 (32%) dMMR tumours. Five contained missense B2M‐variants of unknown significance, so were excluded from further analyses. With median follow‐up of 7.4 years, none of the 39 B2M‐mutant tumours recurred, compared with 14 of 77 (18%) B2M‐wild‐type tumours (P = 0.005); six at local and eight at distant sites. Sensitivity and specificity of IHC in detecting B2M mutations was 87 and 71%, respectively. Significantly (P < 0.0001) fewer (three of 104, 2.9%) of the 108 pMMR CRCs demonstrated deleterious B2M mutations. One pMMR tumour, containing a frameshift mutation, later recurred. Conclusion B2M mutations were detected in nearly one‐third of dMMR cancers, none of which recurred. B2M mutation status has potential clinical utility as a prognostic biomarker in stage II dMMR CRC. The mechanism of protection against recurrence and whether this protection extends to stage III disease remains unclear.

Beta-2-microglobulin Mutations Are Linked to a Distinct Metastatic Pattern and a Favorable Outcome in Microsatellite-Unstable Stage IV Gastrointestinal Cancers

“…B2M mutations have been reported to be associated with prolonged survival for non-metastatic MSI cancer patients ( 8 , 10 , 15 , 16 ). To the best of our knowledge, no systematic data exist about the survival of B2M -mutant stage IV MSI cancer patients.…”

“…What may be the mechanisms responsible for a favorable clinical course of B2M -mutant cancers in the absence of ICB? Previous studies have demonstrated that B2M loss limits the metastatic potential in MSI colorectal cancer ( 8 , 15 , 16 ) and other tumor types, such as uveal melanoma ( 18 ). Although the details are not yet fully understood, one hypothesis suggests that the lack of HLA class I antigens as ligands to the NK cell-inhibitory receptors renders B2M -mutant cells susceptible to NK cell-mediated elimination ( 18 , 19 ).…”

Deregulation of HLA-I in cancer and its central importance for immunotherapy

“…25 Non-silent mutations in β2M have been reported in a broad range of patients 26 and LOH at chromosome 15q21, assessed using two microsatellite markers, was found in 44% of bladder carcinomas (n=69), 35% of colon carcinomas (n=95), 16% of melanomas (n=70) but only 7% of renal cancers (n=45). [27][28][29] Interestingly the rate of mutations was appreciably higher in microsatellite unstable disease (particularly colorectal, gastric and uterine cancers) and was associated with an increased overall burden of mutations for both microsatellite stable and unstable disease, commensurate with the role of the HLA system in presenting acquired mutations for immunosurveillance. Moreover, loss of B2M mediated acquired resistance to immune checkpoint inhibitors (ICIs) has been reported in clinical investigations.…”

Prognostic and Predictive Values of Mismatch Repair Deficiency in Non-Metastatic Colorectal Cancer

“…In this regard, Kloor et al evaluated B2M mutation status in 104 dMMR/MSI CRC patients and found B2M mutation was only detected in localized disease [ 95 ]. Barrow et al investigated B2M mutation and protein expression in 229 stage II colon cancer patients (121 dMMR/MSI cases) in the QUASAR study [ 96 ]. The investigators detected B2M mutations in 32% (39/121 cases) of dMMR/MSI tumors and none of these patients had tumor recurrence while 18% of B2M wild-type tumors developed disease recurrence.…”