HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome
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....
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Nature Portfolio
2021
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oai:doaj.org-article:957481dcdc6e4e478acc8a847c3b62c12021-12-02T14:21:43ZHERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome10.1038/s41525-021-00177-w2056-7944https://doaj.org/article/957481dcdc6e4e478acc8a847c3b62c12021-02-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00177-whttps://doaj.org/toc/2056-7944Abstract 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.Mahdi GolkaramMichael L. SalmansShannon KaplanRaakhee VijayaraghavanMarta MartinsNafeesa KhanCassandra GarbuttAaron WiseJoyee YaoSandra CasimiroCatarina AbreuDaniela MacedoAna Lúcia CostaCecília AlvimAndré MansinhoPedro FilipePedro Marques da CostaAfonso FernandesPaula BorralhoCristina FerreiraFernando AldeiaJoão MalaquiasJim GodseyAlex SoTraci PawlowskiLuis CostaShile ZhangLi LiuNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-11 (2021) |
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DOAJ |
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DOAJ |
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EN |
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Medicine R Genetics QH426-470 |
| spellingShingle |
Medicine R Genetics QH426-470 Mahdi Golkaram Michael L. Salmans Shannon Kaplan Raakhee Vijayaraghavan Marta Martins Nafeesa Khan Cassandra Garbutt Aaron Wise Joyee Yao Sandra Casimiro Catarina Abreu Daniela Macedo Ana Lúcia Costa Cecília Alvim André Mansinho Pedro Filipe Pedro Marques da Costa Afonso Fernandes Paula Borralho Cristina Ferreira Fernando Aldeia João Malaquias Jim Godsey Alex So Traci Pawlowski Luis Costa Shile Zhang Li Liu HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome |
| description |
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. |
| format |
article |
| author |
Mahdi Golkaram Michael L. Salmans Shannon Kaplan Raakhee Vijayaraghavan Marta Martins Nafeesa Khan Cassandra Garbutt Aaron Wise Joyee Yao Sandra Casimiro Catarina Abreu Daniela Macedo Ana Lúcia Costa Cecília Alvim André Mansinho Pedro Filipe Pedro Marques da Costa Afonso Fernandes Paula Borralho Cristina Ferreira Fernando Aldeia João Malaquias Jim Godsey Alex So Traci Pawlowski Luis Costa Shile Zhang Li Liu |
| author_facet |
Mahdi Golkaram Michael L. Salmans Shannon Kaplan Raakhee Vijayaraghavan Marta Martins Nafeesa Khan Cassandra Garbutt Aaron Wise Joyee Yao Sandra Casimiro Catarina Abreu Daniela Macedo Ana Lúcia Costa Cecília Alvim André Mansinho Pedro Filipe Pedro Marques da Costa Afonso Fernandes Paula Borralho Cristina Ferreira Fernando Aldeia João Malaquias Jim Godsey Alex So Traci Pawlowski Luis Costa Shile Zhang Li Liu |
| author_sort |
Mahdi Golkaram |
| title |
HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome |
| title_short |
HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome |
| title_full |
HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome |
| title_fullStr |
HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome |
| title_full_unstemmed |
HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome |
| title_sort |
hervs establish a distinct molecular subtype in stage ii/iii colorectal cancer with poor outcome |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/957481dcdc6e4e478acc8a847c3b62c1 |
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