Research Papers:

Prognostic significance of tumor genotypes and CD8+ infiltrates in stage I-III colorectal cancer

Elena Fountzilas _, Vassiliki Kotoula, Ioannis Tikas, Kyriaki Manousou, Kyriaki Papadopoulou, Christos Poulios, Vasilios Karavasilis, Ioannis Efstratiou, Dimitrios Pectasides, Kleo Papaparaskeva, Ioannis Varthalitis, Christos Christodoulou, George Papatsibas, Sofia Chrisafi, Georgios K. Glantzounis, Amanda Psyrri, Gerasimos Aravantinos, Georgia-Angeliki Koliou, George K. Koukoulis, George E. Pentheroudakis and George Fountzilas

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Oncotarget. 2018; 9:35623-35638. https://doi.org/10.18632/oncotarget.26256

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Elena Fountzilas1, Vassiliki Kotoula2,3, Ioannis Tikas3, Kyriaki Manousou4, Kyriaki Papadopoulou3, Christos Poulios2, Vasilios Karavasilis5, Ioannis Efstratiou6, Dimitrios Pectasides7, Kleo Papaparaskeva8, Ioannis Varthalitis9, Christos Christodoulou10, George Papatsibas11, Sofia Chrisafi3, Georgios K. Glantzounis12, Amanda Psyrri13, Gerasimos Aravantinos14, Georgia-Angeliki Koliou4, George K. Koukoulis15, George E. Pentheroudakis16 and George Fountzilas3,17

1Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

2Department of Pathology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

3Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece

4Section of Biostatistics, Hellenic Cooperative Oncology Group, Athens, Greece

5Department of Medical Oncology, Papageorgiou Hospital, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

6Department of Pathology, Papageorgiou Hospital, Thessaloniki, Greece

7Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, Greece

8Department of Pathology, Konstantopouleio Agia Olga General Hospital, Athens, Greece

9Oncology Department, General Hospital of Chania, Crete, Greece

10Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece

11Oncology Department, University General Hospital of Larissa, Larissa, Greece

12Department of Surgery, University Hospital of Ioannina and School of Medicine, University of Ioannina, Greece

13Division of Oncology, Second Department of Internal Medicine, Attikon University Hospital, Athens, Greece

14Second Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece

15Department of Pathology, Faculty of Medicine, University of Thessaly, Larissa, Greece

16Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece

17Aristotle University of Thessaloniki, Thessaloniki, Greece

Correspondence to:

Elena Fountzilas, email: [email protected]

Keywords: targeted NGS; CD8; MMR; BRCA1; ARID1A

Received: June 29, 2018     Accepted: October 08, 2018     Published: November 02, 2018


Background: We explored the clinical significance of tumor genotypes and immunophenotypes in non-metastatic colorectal cancer (CRC).

Methods: In primary tumors (paraffin blocks) from 412 CRC patients treated with adjuvant chemotherapy, we examined pathogenic mutations (panel NGS; 347 informative); mismatch repair (MMR) immunophenotype (360 informative); and CD8+ lymphocyte density (high – low; 412 informative). The primary outcome measure was disease-free survival (DFS).

Results: We evaluated 1713 pathogenic mutations (median: 3 per tumor; range 0-49); 118/412 (28.6%) tumors exhibited high CD8+ density; and, 40/360 (11.1%) were MMR-deficient. Compared to MMR-proficient, MMR-deficient tumors exhibited higher CD8+ density (chi-square, p<0.001) and higher pathogenic mutation numbers (p=0.003). High CD8+ density was an independent favorable prognosticator (HR=0.49, 95%CI 0.29-0.84, Wald’s p=0.010). Pathogenic BRCA1 and ARID1A mutations were inversely associated with each other (p<0.001), were not associated with MMR-deficiency or CD8+ density, but both independently predicted for unfavorable DFS (HR=1.98, 95%CI 1.12-3.48, p=0.018 and HR=1.99, 95%CI 1.11-3.54, p=0.020, respectively).

Conclusion: In non-metastatic CRC, high CD8+ lymphocyte density confers a favorable prognosis and may be developed as a single marker in routine diagnostics. The unfavorable prognostic effect of pathogenic BRCA1 and ARID1A mutations is a novel observation that, if further validated, may improve treatment selection.

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