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B2M and JAK1/2–mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy
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 ca...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986629/ https://www.ncbi.nlm.nih.gov/pubmed/35343934 http://dx.doi.org/10.1097/CJI.0000000000000417 |
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author | Zhang, Chenzhi Li, Dandan Xiao, Binyi Zhou, Chi Jiang, Wu Tang, Jinghua Li, Yuan Zhang, Rongxin Han, Kai Hou, Zhenlin Zhang, Linjie Sui, Qiaoqi Liao, Leen Pan, Zhizhong Zhang, Xiaoshi Ding, Peirong |
author_facet | Zhang, Chenzhi Li, Dandan Xiao, Binyi Zhou, Chi Jiang, Wu Tang, Jinghua Li, Yuan Zhang, Rongxin Han, Kai Hou, Zhenlin Zhang, Linjie Sui, Qiaoqi Liao, Leen Pan, Zhizhong Zhang, Xiaoshi Ding, Peirong |
author_sort | Zhang, Chenzhi |
collection | PubMed |
description | 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 next-generation 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 loss-of-function mutation, and 8 (22.9%) had a JAK1/2 loss-of-function 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. |
format | Online Article Text |
id | pubmed-8986629 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-89866292022-04-13 B2M and JAK1/2–mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy Zhang, Chenzhi Li, Dandan Xiao, Binyi Zhou, Chi Jiang, Wu Tang, Jinghua Li, Yuan Zhang, Rongxin Han, Kai Hou, Zhenlin Zhang, Linjie Sui, Qiaoqi Liao, Leen Pan, Zhizhong Zhang, Xiaoshi Ding, Peirong J Immunother Basic Studies 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 next-generation 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 loss-of-function mutation, and 8 (22.9%) had a JAK1/2 loss-of-function 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. Lippincott Williams & Wilkins 2022-05 2022-03-29 /pmc/articles/PMC8986629/ /pubmed/35343934 http://dx.doi.org/10.1097/CJI.0000000000000417 Text en Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) |
spellingShingle | Basic Studies Zhang, Chenzhi Li, Dandan Xiao, Binyi Zhou, Chi Jiang, Wu Tang, Jinghua Li, Yuan Zhang, Rongxin Han, Kai Hou, Zhenlin Zhang, Linjie Sui, Qiaoqi Liao, Leen Pan, Zhizhong Zhang, Xiaoshi Ding, Peirong B2M and JAK1/2–mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy |
title |
B2M and JAK1/2–mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy |
title_full |
B2M and JAK1/2–mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy |
title_fullStr |
B2M and JAK1/2–mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy |
title_full_unstemmed |
B2M and JAK1/2–mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy |
title_short |
B2M and JAK1/2–mutated MSI-H Colorectal Carcinomas Can Benefit From Anti-PD-1 Therapy |
title_sort | b2m and jak1/2–mutated msi-h colorectal carcinomas can benefit from anti-pd-1 therapy |
topic | Basic Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986629/ https://www.ncbi.nlm.nih.gov/pubmed/35343934 http://dx.doi.org/10.1097/CJI.0000000000000417 |
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