In:
PLOS ONE, Public Library of Science (PLoS), Vol. 16, No. 12 ( 2021-12-31), p. e0262198-
Abstract:
Colorectal cancer (CRC) is a leading cause of cancer-related deaths, with a 5% 5-year survival rate for metastatic disease, yet with limited therapeutic advancements due to insufficient understanding of and inability to accurately capture high-risk CRC patients who are most likely to recur. We aimed to improve high-risk classification by identifying biological pathways associated with outcome in adjuvant stage II/III CRC. Methods and findings We included 1062 patients with stage III or high-risk stage II colon carcinoma from the prospective three-arm randomized phase 3 AVANT trial, and performed expression profiling to identify a prognostic signature. Data from validation cohort GSE39582, The Cancer Genome Atlas, and cell lines were used to further validate the prognostic biology. Our retrospective analysis of the adjuvant AVANT trial uncovered a prognostic signature capturing three biological functions—stromal, proliferative and immune—that outperformed the Consensus Molecular Subtypes (CMS) and recurrence prediction signatures like Oncotype Dx in an independent cohort. Importantly, within the immune component, high granzyme B (GZMB) expression had a significant prognostic impact while other individual T-effector genes were less or not prognostic. In addition, we found GZMB to be endogenously expressed in CMS2 tumor cells and to be prognostic in a T cell independent fashion. A limitation of our study is that these results, although robust and derived from a large dataset, still need to be clinically validated in a prospective study. Conclusions This work furthers our understanding of the underlying biology that propagates stage II/III CRC disease progression and provides scientific rationale for future high-risk stratification and targeted treatment evaluation in biomarker defined subpopulations of resectable high-risk CRC. Our results also shed light on an alternative GZMB source with context-specific implications on the disease’s unique biology.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0262198
DOI:
10.1371/journal.pone.0262198.g001
DOI:
10.1371/journal.pone.0262198.g002
DOI:
10.1371/journal.pone.0262198.g003
DOI:
10.1371/journal.pone.0262198.g004
DOI:
10.1371/journal.pone.0262198.s001
DOI:
10.1371/journal.pone.0262198.s002
DOI:
10.1371/journal.pone.0262198.s003
DOI:
10.1371/journal.pone.0262198.s004
DOI:
10.1371/journal.pone.0262198.s005
DOI:
10.1371/journal.pone.0262198.s006
DOI:
10.1371/journal.pone.0262198.s007
DOI:
10.1371/journal.pone.0262198.s008
DOI:
10.1371/journal.pone.0262198.s009
DOI:
10.1371/journal.pone.0262198.s010
DOI:
10.1371/journal.pone.0262198.s011
DOI:
10.1371/journal.pone.0262198.s012
DOI:
10.1371/journal.pone.0262198.s013
DOI:
10.1371/journal.pone.0262198.s014
DOI:
10.1371/journal.pone.0262198.s015
DOI:
10.1371/journal.pone.0262198.s016
DOI:
10.1371/journal.pone.0262198.s017
DOI:
10.1371/journal.pone.0262198.s018
DOI:
10.1371/journal.pone.0262198.s019
DOI:
10.1371/journal.pone.0262198.s020
DOI:
10.1371/journal.pone.0262198.s021
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2267670-3
Permalink