Genetic and epigenetic analysis of the beta-2-microglobulin gene in microsatellite instable colorectal cancer

Kasubova, Ivana; Kalman, Michal; Grendár, Marian; Mikolajcik, Peter; Laca, Ľ; Čaprnda, Martin; Rodrigo, Luís; Ciccocioppo, Rachele; Kružliak, Peter; Lasabová, Zora

doi:10.1007/s10238-019-00601-7

Cited by 22 publications

(12 citation statements)

References 51 publications

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“…Unlike with melanoma and lung cancer, B2M and JAK1/2 loss-of-function mutations do not necessarily confer resistance to anti-PD-1 therapy in MSI-H CRC. Snahnicanova et al 12 found no significant difference in TILs and peritumoral lymphoid reaction between patients with B2M mutation and patients without. It was also shown that the infiltration of CD3 + and CD8 + T cells was not significantly correlated with the presence of B2M mutations.…”

Section: Discussionmentioning

confidence: 95%

“… 11 Therefore, the absence of MHC class I caused by B2M loss-of-function mutation theoretically may lead to resistance to PD-1 blockade, which has been supported by some preclinical models. 12 , 13 …”

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confidence: 99%

“…11 Therefore, the absence of MHC class I caused by B2M lossof-function mutation theoretically may lead to resistance to PD-1 blockade, which has been supported by some preclinical models. 12,13 Similarly, JAK1/2 loss-of-function mutations can lead to resistance to anti-PD-1 therapy. 10,14 Inactivation of JAK1 and JAK2 impairs the downstream signaling of interferon (IFN) γ receptors and thus lessens the ability of IFN-γ to exert antitumor effects.…”

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confidence: 99%

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B2M and JAK1/2–mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy

Zhang

Xiao

et al. 2022

Journal of Immunotherapy

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β2-microglobulin (B2M) and Janus kinases 1 and 2 (JAK1/2) mutations have been suggested as genetic mechanisms of immune evasion for anti-programmed cell death protein 1 (PD-1) therapy. Whether B2M and JAK1/2 lose-of-function mutation can cause primary resistance to anti-PD-1 therapy in colorectal carcinoma (CRC) patients remains controversial. Here, we sought to compare the efficacy of anti-PD-1 therapy in DNA mismatch repair deficient/microsatellite instability-high CRC patients with or without B2M or JAK1/2 mutations. Thirty-Five CRC patients who received anti-PD-1 therapy were enrolled in this study. All tumor samples underwent nextgeneration sequencing. The clinical and molecular data from 110 CRC patients sequenced with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay and accessed through cBioportal were also analyzed in this study. Of the 35 CRC patients from our center, 10 (28.6%) had a B2M lossof-function mutation, and 8 (22.9%) had a JAK1/2 loss-offunction mutation. Compared with B2M wild-type CRCs, B2M-mutated CRCs did not show a higher frequency of resistance to anti-PD-1 therapy (P = 0.71). There was even better response to anti-PD-1 therapy in patients with JAK1/2 mutation than in those without (P = 0.015). Of the 110 CRC patients in the MSK-IMPACT datasets, 13 (11.8%) had a B2M mutation, and 15 (13.6%) had a JAK1/2 mutation. After analyzing the response to anti-PD-1 therapy in these 110 patients, we found similar results (P = 0.438 and 0.071, respectively). Moreover, patients with B2M or JAK1/2 mutation had a lower tumor mutational burden score compared with those without. B2M and JAK1/2 loss-of-function mutations occur frequently in microsatellite instability-high CRC. Our study demonstrated that patients with CRC harboring B2M or JAK1/2 mutations should not be excluded from anti-PD-1 therapy.

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confidence: 95%

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B2M and JAK1/2–mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy

Zhang

Xiao

et al. 2022

Journal of Immunotherapy

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“…Published data regarding β2M expression are limited, and the frequency of β2M downregulation in MSI‐H CRC was reported as 80% in one study 28 . The prevalence of β2M mutations in MSI‐H CRC was reported to be 7.5% to 33.9%, while that of MSS tumors was considerably low (<1%) 14,20,30‐36 . Considering that approximately 70% of β2M‐mutated MSI‐H CRC showed complete loss of expression in IHC according to the study done by Middha et al, 30 the frequency of HLA A/B/C and β2M downregulation detected in the current study is presumed to be higher in both MSI‐H (70.2% and 42.9%) and MSS (38.8% and 12.2%) cases than in previous studies.…”

Section: Discussionmentioning

confidence: 98%

“…Recently, downregulation of HLA class I molecules, including β2M, has been suggested as one of possible mechanisms of immune evasion in these immunogenic tumors 4,13,14 . The presence of β2M mutation has been reported in both immunotherapy‐naïve 32‐36,39 and immunotherapy‐resistant MSI‐H CRCs, 4 suggesting that it can cause both intrinsic and acquired resistance. Our results are in line with these previous studies, suggesting immune evasion through altered HLA class I molecules might take place in a considerable proportion of MSI‐H CRCs even before immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Expression of human leukocyte antigen class I and β2‐microglobulin in colorectal cancer and its prognostic impact

Park

Nam

et al. 2020

Cancer Science

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Enhancing cancer immunotherapy and antiangiogenic therapy by regulating gut microbes: Opportunities and challenges

Xu,

Tian,

et al. 2024

MedComm – Oncology

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As the largest microecosystem in the human body, gut microbes (GMs) and their metabolites play an important role in regulating human health. In recent years, immune checkpoint therapy (ICT) combined with antiangiogenic agents is an emerging combination therapy for cancer. There is growing evidence that GMs can affect the effectiveness of drugs to treat cancer. GMs not only regulate angiogenesis in the tumor microenvironment, but also influence the efficacy of immune checkpoint inhibitors. Many studies show that Bifidobacterium can upregulate the anticancer function of immune checkpoint blockers. In addition, GMs have been found to be involved in the formation of blood vessels and other developmental processes. Clinically, GMs are believed to play a key role in patients receiving antiangiogenic therapy and ICT. In this perspective, we provide an overview of the composition and function of the gut microbiome, and discuss the role of the GMs against the conditioning of angiogenic therapy and ICT. We also summarize new approaches and clinical translational trials using GMs for cancer therapy, and present opportunities and challenges for targeting GMs for cancer therapy in the future.

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Genetic and epigenetic analysis of the beta-2-microglobulin gene in microsatellite instable colorectal cancer

Cited by 22 publications

References 51 publications

B2M and JAK1/2–mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy

B2M and JAK1/2–mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy

Expression of human leukocyte antigen class I and β2‐microglobulin in colorectal cancer and its prognostic impact

Enhancing cancer immunotherapy and antiangiogenic therapy by regulating gut microbes: Opportunities and challenges

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