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Somatic POLE exonuclease domain mutations elicit enhanced intratumoral immune responses in stage II colorectal cancer

Previous studies found patients with POLE exonuclease domain mutations (EDMs) in targeted exons were related to significant better outcomes in stage II-III colorectal cancer (CRC). The detailed mutational profile of the entire POLE exonuclease domain, tumor mutation burden (TMB) and immune cell infi...

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Autores principales: Mo, Shaobo, Ma, Xiaoji, Li, Yaqi, Zhang, Long, Hou, Ting, Han-Zhang, Han, Qian, Juanjuan, Cai, Sanjun, Huang, Dan, Peng, Junjie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454238/
https://www.ncbi.nlm.nih.gov/pubmed/32859741
http://dx.doi.org/10.1136/jitc-2020-000881
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author Mo, Shaobo
Ma, Xiaoji
Li, Yaqi
Zhang, Long
Hou, Ting
Han-Zhang, Han
Qian, Juanjuan
Cai, Sanjun
Huang, Dan
Peng, Junjie
author_facet Mo, Shaobo
Ma, Xiaoji
Li, Yaqi
Zhang, Long
Hou, Ting
Han-Zhang, Han
Qian, Juanjuan
Cai, Sanjun
Huang, Dan
Peng, Junjie
author_sort Mo, Shaobo
collection PubMed
description Previous studies found patients with POLE exonuclease domain mutations (EDMs) in targeted exons were related to significant better outcomes in stage II-III colorectal cancer (CRC). The detailed mutational profile of the entire POLE exonuclease domain, tumor mutation burden (TMB) and immune cell infiltration in POLE EDMs tumors, and the prognostic value of such mutations in stage II CRCs were largely unknown to us. This study was to clarify the characteristics, immune response and prognostic value of somatic POLE EDMs in stage II CRC. A total of 295 patients with stage II CRC were sequenced by next-generation sequencing with a targeted genetic panel. Simultaneous detection of the immune cells was conducted using a five-color immunohistochemical multiplex technique. The detailed molecular characteristics, tumor-infiltrating lymphocyte (TIL) and prognostic effect of POLE EDMs in stage II CRC were analyzed. For stage II CRCs, the POLE EDMs were detected in 3.1% of patients. Patients with POLE EDMs were more prone to be microsatellite instability-high (MSI-H) (33.3% vs 11.2%, p=0.043), younger at diagnosis (median 46 years vs 62 years, p<0.001) and more common at right-sided location (66.7% vs 23.1%; p=0.003). All patients with POLE EMDs were assessed as extremely high TMB, with a mean TMB of 200.8. Compared with other stage II CRCs, POLE EDMs displayed an enhanced intratumoral cytotoxic T cell response, evidenced by increased numbers of CD8+TILs and CD8A expression. Patients with stage II CRCs could be classified into three risk subsets, with significant different 5 years disease-free survival rates of 100% for POLE EDMs, 82.0% for MSI-H and 63.0% for MSS, p=0.013. In conclusion, characterized by a robust intratumoral T cell response, ultramutated POLE EDMs could be detected in a small subset of stage II CRCs with extremely high TMB. Patients with POLE EDMs had excellent outcomes in stage II CRCs, regardless of MSI status. Sequencing of all the exonuclease domain of POLE gene is recommended in clinical practice.
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spelling pubmed-74542382020-09-09 Somatic POLE exonuclease domain mutations elicit enhanced intratumoral immune responses in stage II colorectal cancer Mo, Shaobo Ma, Xiaoji Li, Yaqi Zhang, Long Hou, Ting Han-Zhang, Han Qian, Juanjuan Cai, Sanjun Huang, Dan Peng, Junjie J Immunother Cancer Immunotherapy Biomarkers Previous studies found patients with POLE exonuclease domain mutations (EDMs) in targeted exons were related to significant better outcomes in stage II-III colorectal cancer (CRC). The detailed mutational profile of the entire POLE exonuclease domain, tumor mutation burden (TMB) and immune cell infiltration in POLE EDMs tumors, and the prognostic value of such mutations in stage II CRCs were largely unknown to us. This study was to clarify the characteristics, immune response and prognostic value of somatic POLE EDMs in stage II CRC. A total of 295 patients with stage II CRC were sequenced by next-generation sequencing with a targeted genetic panel. Simultaneous detection of the immune cells was conducted using a five-color immunohistochemical multiplex technique. The detailed molecular characteristics, tumor-infiltrating lymphocyte (TIL) and prognostic effect of POLE EDMs in stage II CRC were analyzed. For stage II CRCs, the POLE EDMs were detected in 3.1% of patients. Patients with POLE EDMs were more prone to be microsatellite instability-high (MSI-H) (33.3% vs 11.2%, p=0.043), younger at diagnosis (median 46 years vs 62 years, p<0.001) and more common at right-sided location (66.7% vs 23.1%; p=0.003). All patients with POLE EMDs were assessed as extremely high TMB, with a mean TMB of 200.8. Compared with other stage II CRCs, POLE EDMs displayed an enhanced intratumoral cytotoxic T cell response, evidenced by increased numbers of CD8+TILs and CD8A expression. Patients with stage II CRCs could be classified into three risk subsets, with significant different 5 years disease-free survival rates of 100% for POLE EDMs, 82.0% for MSI-H and 63.0% for MSS, p=0.013. In conclusion, characterized by a robust intratumoral T cell response, ultramutated POLE EDMs could be detected in a small subset of stage II CRCs with extremely high TMB. Patients with POLE EDMs had excellent outcomes in stage II CRCs, regardless of MSI status. Sequencing of all the exonuclease domain of POLE gene is recommended in clinical practice. BMJ Publishing Group 2020-08-27 /pmc/articles/PMC7454238/ /pubmed/32859741 http://dx.doi.org/10.1136/jitc-2020-000881 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.
spellingShingle Immunotherapy Biomarkers
Mo, Shaobo
Ma, Xiaoji
Li, Yaqi
Zhang, Long
Hou, Ting
Han-Zhang, Han
Qian, Juanjuan
Cai, Sanjun
Huang, Dan
Peng, Junjie
Somatic POLE exonuclease domain mutations elicit enhanced intratumoral immune responses in stage II colorectal cancer
title Somatic POLE exonuclease domain mutations elicit enhanced intratumoral immune responses in stage II colorectal cancer
title_full Somatic POLE exonuclease domain mutations elicit enhanced intratumoral immune responses in stage II colorectal cancer
title_fullStr Somatic POLE exonuclease domain mutations elicit enhanced intratumoral immune responses in stage II colorectal cancer
title_full_unstemmed Somatic POLE exonuclease domain mutations elicit enhanced intratumoral immune responses in stage II colorectal cancer
title_short Somatic POLE exonuclease domain mutations elicit enhanced intratumoral immune responses in stage II colorectal cancer
title_sort somatic pole exonuclease domain mutations elicit enhanced intratumoral immune responses in stage ii colorectal cancer
topic Immunotherapy Biomarkers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454238/
https://www.ncbi.nlm.nih.gov/pubmed/32859741
http://dx.doi.org/10.1136/jitc-2020-000881
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