@article{3165924,
    title = "Immune Response Gene Expression in Colorectal Cancer Carries Distinct
Prognostic Implications According to Tissue, Stage and Site: A
Prospective Retrospective Translational Study in the Context of a
Hellenic Cooperative Oncology Group Randomised Trial",
    author = "Pentheroudakis, George and Raptou, Georgia and Kotoula, Vassiliki and and Wirtz, Ralph M. and Vrettou, Eleni and Karavasilis, Vasilios and and Gourgioti, Georgia and Gakou, Chryssa and Syrigos, Konstantinos N. and and Bournakis, Evangelos and Rallis, Grigorios and Varthalitis, Ioannis and and Galani, Eleni and Lazaridis, Georgios and Papaxoinis, George and and Pectasides, Dimitrios and Aravantinos, Gerasimos and Makatsoris, Thomas and and Kalogeras, Konstantine T. and Fountzilas, George",
    journal = "PLOS ONE",
    year = "2015",
    volume = "10",
    number = "5",
    publisher = "Public Library of Science",
    doi = "10.1371/journal.pone.0124612",
    abstract = "Background
Although host immune response is an emerging prognostic factor for
colorectal cancer, there is no consensus on the optimal methodology,
surrogate markers or tissue for study.
Patients and Methods
Tumour blocks were prospectively collected from 344 patients with stage
II/III colorectal cancer (CRC) treated with adjuvant chemotherapy. Whole
section lymphocytic infiltration was studied along with mRNA expression
of CD3Z, CD8, CD4, CXCL9, CXCL13, IGHM, FOXP3, SNAI2 and ESR1 by
qRT-qPCR in tissue microarray (TMA) cores from the centre of tumour,
invasive margin and adjacent normal mucosa.
Results
Lymphocytic infiltration, deficient MMR (10.9%), KRAS (40.7%) and BRAF
(4.9%) mutations or single mRNA gene expression were not prognostic.
Tumour ESR1 gene expression (Hazard Ratio [HR] for relapse 2.33, 95%
CI 1.35-4.02; HR for death 1.74, 95% CI 1.02-2.97) and absence of
necrosis (HR for relapse 1.71, 95% CI 1.05-2.71; HR for death 1.98,
95% CI 1.14-3.43) were adverse prognostic features. We used CD3Z and
CD8 expression in order to devise the mRNA-based Immune Score (mIS) and
proceeded to partitioning analysis in 267 patients, with age, stage,
tumour site (Right vs Left CRC), KRAS mutation and tumour mIS as input
factors. Only in patients with stage III right-sided colon cancer, a low
immune response was associated with inferior disease-free survival
(mIS-low, HR for relapse 2.28, 95% CI 1.05-8.02). No prognostic
significance was seen for tumour mIS in any other stage or site of CRC,
or for a similar mIS score derived from adjacent normal mucosa.
Independent adverse prognostic significance was retained in
multivariable analysis for absence of necrosis, tumour ESR1 expression
in all patients and low tumour mIS in stage III right-sided CRC.
Conclusions
In localised CRC, mRNA-based CD3Z/CD8 profiling of tumour immune
response may have stage, site and tissue-specific prognostic
significance, along with ESR1 expression."
}