Abstract

Colorectal cancer (CRC) is one of the most lethal malignancies. The extreme heterogeneity in survival rate is driving the need for new prognostic biomarkers. Human endogenous retroviruses (hERVs) have been suggested to influence tumor progression, oncogenesis and elicit an immune response. We examined multiple next-generation sequencing (NGS)-derived biomarkers in 114 CRC patients with paired whole-exome and whole-transcriptome sequencing (WES and WTS, respectively). First, we demonstrate that the median expression of hERVs can serve as a potential biomarker for prognosis, relapse, and resistance to chemotherapy in stage II and III CRC. We show that hERV expression and CD8+ tumor-infiltrating T-lymphocytes (TILs) synergistically stratify overall and relapse-free survival (OS and RFS): the median OS of the CD8-/hERV+ subgroup was 29.8 months compared with 37.5 months for other subgroups (HR = 4.4, log-rank P < 0.001). Combing NGS-based biomarkers (hERV/CD8 status) with clinicopathological factors provided a better prediction of patient survival compared to clinicopathological factors alone. Moreover, we explored the association between genomic and transcriptomic features of tumors with high hERV expression and establish this subtype as distinct from previously described consensus molecular subtypes of CRC. Overall, our results underscore a previously unknown role for hERVs in leading to a more aggressive subtype of CRC.

Details

Title
HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome
Author
Golkaram Mahdi 1   VIAFID ORCID Logo  ; Salmans, Michael L 1 ; Kaplan, Shannon 1   VIAFID ORCID Logo  ; Vijayaraghavan Raakhee 1 ; Martins, Marta 2   VIAFID ORCID Logo  ; Khan Nafeesa 1 ; Garbutt Cassandra 1 ; Wise, Aaron 1 ; Yao Joyee 1 ; Casimiro, Sandra 2 ; Abreu Catarina 3 ; Macedo, Daniela 3 ; Costa, Ana Lúcia 3 ; Alvim Cecília 3 ; Mansinho André 4 ; Filipe, Pedro 3 ; Marques da Costa Pedro 5 ; Fernandes Afonso 2 ; Borralho Paula 6 ; Ferreira, Cristina 3 ; Aldeia Fernando 3 ; Malaquias João 3 ; Godsey, Jim 1 ; So, Alex 1 ; Pawlowski Traci 1 ; Costa, Luis 4 ; Zhang Shile 1 ; Liu, Li 1 

 Illumina Inc., San Diego, USA (GRID:grid.185669.5) (ISNI:0000 0004 0507 3954) 
 Universidade de Lisboa, Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Lisbon, Portugal (GRID:grid.9983.b) (ISNI:0000 0001 2181 4263) 
 Centro Hospitalar Universitário Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal (GRID:grid.411265.5) (ISNI:0000 0001 2295 9747) 
 Universidade de Lisboa, Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Lisbon, Portugal (GRID:grid.9983.b) (ISNI:0000 0001 2181 4263); Centro Hospitalar Universitário Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal (GRID:grid.411265.5) (ISNI:0000 0001 2295 9747) 
 Centro Hospitalar Universitário Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal (GRID:grid.411265.5) (ISNI:0000 0001 2295 9747); Universidade de Lisboa, Faculdade de Medicina, Lisbon, Portugal (GRID:grid.9983.b) (ISNI:0000 0001 2181 4263) 
 Universidade de Lisboa, Faculdade de Medicina, Lisbon, Portugal (GRID:grid.9983.b) (ISNI:0000 0001 2181 4263) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20567944
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2489438526
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.