Imperial College London
Portrait Picture

Dr James Kinross

Faculty of Medicine, Department of Surgery & Cancer

Reader in General Surgery
 
 
 
//

Contact

 

+44 (0)20 3312 1947j.kinross

 
 
//

Location

 

1029Queen Elizabeth the Queen Mother Wing (QEQM)St Mary's Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Challoner:2022:10.1101/2022.02.16.479224,
author = {Challoner, BR and Woolston, A and Lau, D and Buzzetti, M and Fong, C and Barber, LJ and Anandappa, G and Crux, R and Assiotis, I and Fenwick, K and Begum, R and Begum, D and Lund, T and Sivamanoharan, N and Sansano, HB and Domingo-Arada, M and Tran, A and Eccles, B and Ellis, R and Falk, S and Hill, M and Krell, D and Murugaesu, N and Nolan, L and Potter, V and Saunders, M and Shiu, K-K and Guettler, S and Alexander, JL and Lázare-Iglesias, H and Kinross, J and Murphy, J and Loga, KV and Cunningham, D and Chau, I and Starling, N and Ruiz-Bañobre, J and Dhillon, T and Gerlinger, M},
doi = {10.1101/2022.02.16.479224},
title = {Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer},
url = {http://dx.doi.org/10.1101/2022.02.16.479224},
year = {2022}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - <jats:title>Abstract</jats:title><jats:p>Mismatch repair deficient colorectal cancers have high mutation loads and many respond to immune checkpoint-inhibitors. We investigated how genetic and immune landscapes co-evolve in these tumors. All cases had high truncal mutation loads. Driver aberrations showed a clear hierarchy despite pervasive intratumor heterogeneity: Those in WNT/βCatenin, mitogen-activated protein kinase and TGFβ receptor family genes were almost always truncal. Immune evasion drivers were predominantly subclonal and showed parallel evolution. Pan-tumor evolution, subclonal evolution, and evolutionary stasis of genetic immune evasion drivers defined three MMRd CRC subtypes with distinct T-cell infiltrates. These immune evasion drivers have been implicated in checkpoint-inhibitor resistance. Clonality and subtype assessments are hence critical for predictive immunotherapy biomarker development. Cancer cell PD-L1 expression was conditional on loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and likely contributes to the high recurrence risk of MMRd CRCs with impaired CDX2 expression.</jats:p>
AU  - Challoner,BR
AU  - Woolston,A
AU  - Lau,D
AU  - Buzzetti,M
AU  - Fong,C
AU  - Barber,LJ
AU  - Anandappa,G
AU  - Crux,R
AU  - Assiotis,I
AU  - Fenwick,K
AU  - Begum,R
AU  - Begum,D
AU  - Lund,T
AU  - Sivamanoharan,N
AU  - Sansano,HB
AU  - Domingo-Arada,M
AU  - Tran,A
AU  - Eccles,B
AU  - Ellis,R
AU  - Falk,S
AU  - Hill,M
AU  - Krell,D
AU  - Murugaesu,N
AU  - Nolan,L
AU  - Potter,V
AU  - Saunders,M
AU  - Shiu,K-K
AU  - Guettler,S
AU  - Alexander,JL
AU  - Lázare-Iglesias,H
AU  - Kinross,J
AU  - Murphy,J
AU  - Loga,KV
AU  - Cunningham,D
AU  - Chau,I
AU  - Starling,N
AU  - Ruiz-Bañobre,J
AU  - Dhillon,T
AU  - Gerlinger,M
DO  - 10.1101/2022.02.16.479224
PY  - 2022///
TI  - Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer
UR  - http://dx.doi.org/10.1101/2022.02.16.479224
ER  -
Download