Transcriptomic profiling of adjuvant colorectal cancer identifies three key prognostic biological processes and a disease specific role for granzyme B.

Autor: Daemen A; Bioinformatics & Computational Biology, Genentech Inc., South San Francisco, California, United States of America., Udyavar AR; Bioinformatics & Computational Biology, Genentech Inc., South San Francisco, California, United States of America., Sandmann T; Bioinformatics & Computational Biology, Genentech Inc., South San Francisco, California, United States of America., Li C; Oncology Biomarker Development, Genentech Inc., South San Francisco, California, United States of America., Bosch LJW; Oncology Biomarker Development, Genentech Inc., South San Francisco, California, United States of America., O'Gorman W; OMNI Biomarker Development, Genentech Inc., South San Francisco, California, United States of America., Li Y; Oncology Biomarker Development, Genentech Inc., South San Francisco, California, United States of America., Au-Yeung A; Oncology Biomarker Development, Genentech Inc., South San Francisco, California, United States of America., Takahashi C; OMNI Biomarker Development, Genentech Inc., South San Francisco, California, United States of America., Kabbarah O; Oncology Biomarker Development, Genentech Inc., South San Francisco, California, United States of America., Bourgon R; Bioinformatics & Computational Biology, Genentech Inc., South San Francisco, California, United States of America., Hegde P; Oncology Biomarker Development, Genentech Inc., South San Francisco, California, United States of America., Bais C; Oncology Biomarker Development, Genentech Inc., South San Francisco, California, United States of America., Das Thakur M; Oncology Biomarker Development, Genentech Inc., South San Francisco, California, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2021 Dec 31; Vol. 16 (12), pp. e0262198. Date of Electronic Publication: 2021 Dec 31 (Print Publication: 2021).
DOI: 10.1371/journal.pone.0262198
Abstrakt: Background: 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.
Competing Interests: All authors were employees of, and may have been shareholders of, Genentech/Roche at the time this work was completed. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Databáze: MEDLINE
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