PMID- 34067951
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230920
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 13
IP  - 10
DP  - 2021 May 13
TI  - Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch 
      Repair Deficiency Syndrome.
LID - 10.3390/cancers13102345 [doi]
LID - 2345
AB  - Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are 
      hereditary disorders characterised by a highly increased risk of cancer 
      development. This is due to germline aberrations in the mismatch repair (MMR) 
      genes, which results in a high mutational load in tumours of these patients, 
      including insertions and deletions in genes bearing microsatellites. This 
      generates microsatellite instability and cause reading frameshifts in coding 
      regions that could lead to the generation of neoantigens and opens up avenues for 
      neoantigen targeting immune therapies prophylactically and therapeutically. 
      However, major obstacles need to be overcome, such as the heterogeneity in tumour 
      formation within and between LS and CMMRD patients, which results in considerable 
      variability in the genes targeted by mutations, hence challenging the choice of 
      suitable neoantigens. The machine-learning methods such as NetMHC and MHCflurry 
      that predict neoantigen- human leukocyte antigen (HLA) binding affinity provide 
      little information on other aspects of neoantigen presentation. Immune escape 
      mechanisms that allow MMR-deficient cells to evade surveillance combined with the 
      resistance to immune checkpoint therapy make the neoantigen targeting regimen 
      challenging. Studies to delineate shared neoantigen profiles across patient 
      cohorts, precise HLA binding algorithms, additional therapies to counter immune 
      evasion and evaluation of biomarkers that predict the response of these patients 
      to immune checkpoint therapy are warranted.
FAU - Abidi, Asima
AU  - Abidi A
AD  - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, 
      Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
FAU - Gorris, Mark A J
AU  - Gorris MAJ
AUID- ORCID: 0000-0003-3621-226X
AD  - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, 
      Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
FAU - Brennan, Evan
AU  - Brennan E
AD  - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, 
      Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
FAU - Jongmans, Marjolijn C J
AU  - Jongmans MCJ
AD  - Princess Maxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.
AD  - Department of Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The 
      Netherlands.
FAU - Weijers, Dilys D
AU  - Weijers DD
AD  - Princess Maxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.
FAU - Kuiper, Roland P
AU  - Kuiper RP
AUID- ORCID: 0000-0003-4928-3809
AD  - Princess Maxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.
AD  - Department of Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The 
      Netherlands.
FAU - de Voer, Richarda M
AU  - de Voer RM
AUID- ORCID: 0000-0002-8222-0343
AD  - Department of Human Genetics, Radboud University Medical Center, 6525 GA 
      Nijmegen, The Netherlands.
FAU - Hoogerbrugge, Nicoline
AU  - Hoogerbrugge N
AUID- ORCID: 0000-0003-2393-8141
AD  - Department of Human Genetics, Radboud University Medical Center, 6525 GA 
      Nijmegen, The Netherlands.
FAU - Schreibelt, Gerty
AU  - Schreibelt G
AUID- ORCID: 0000-0002-0156-8365
AD  - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, 
      Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
FAU - de Vries, I Jolanda M
AU  - de Vries IJM
AUID- ORCID: 0000-0002-8653-4040
AD  - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, 
      Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
AD  - Department of Medical Oncology, Radboud University Medical Center, 6525 GA 
      Nijmegen, The Netherlands.
LA  - eng
GR  - n.a./Radboudumc/
GR  - 359/KiKa Foundation/
PT  - Journal Article
PT  - Review
DEP - 20210513
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC8152233
OTO - NOTNLM
OT  - CMMRD
OT  - Lynch Syndrome
OT  - colorectal cancer
OT  - hereditary cancer
OT  - mismatch repair deficiency
OT  - neoantigen
OT  - targeted therapy
COIS- The authors declare no conflict of interest.
EDAT- 2021/06/03 06:00
MHDA- 2021/06/03 06:01
PMCR- 2021/05/13
CRDT- 2021/06/02 01:20
PHST- 2021/04/07 00:00 [received]
PHST- 2021/04/28 00:00 [revised]
PHST- 2021/04/30 00:00 [accepted]
PHST- 2021/06/02 01:20 [entrez]
PHST- 2021/06/03 06:00 [pubmed]
PHST- 2021/06/03 06:01 [medline]
PHST- 2021/05/13 00:00 [pmc-release]
AID - cancers13102345 [pii]
AID - cancers-13-02345 [pii]
AID - 10.3390/cancers13102345 [doi]
PST - epublish
SO  - Cancers (Basel). 2021 May 13;13(10):2345. doi: 10.3390/cancers13102345.