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| Home > Articles > Published articles > Copy-number intratumor heterogeneity increases the risk of relapse in chemotherapy-naive stage colon cancer |
| Home > Articles > Published articles > Copy-number intratumor heterogeneity increases the risk of relapse in chemotherapy-naive stage colon cancer |
(Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Universitat de Barcelona) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Universitat de Barcelona) (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
| Date: | 2022 |
| Abstract: | Optimal selection of high-risk patients with stage II colon cancer is crucial to ensure clinical benefit of adjuvant chemotherapy. Here, we investigated the prognostic value of genomic intratumor heterogeneity and aneuploidy for disease recurrence. We combined targeted sequencing, SNP arrays, fluorescence in situ hybridization, and immunohistochemistry on a retrospective cohort of 84 untreated stage II colon cancer patients. We assessed the clonality of copy-number alterations (CNAs) and mutations, CD8 + lymphocyte infiltration, and their association with time to recurrence. Prognostic factors were included in machine learning analysis to evaluate their ability to predict individual relapse risk. Tumors from recurrent patients displayed a greater proportion of CNAs compared with non-recurrent (mean 31. 3% versus 23%, respectively; p = 0. 014). Furthermore, patients with elevated tumor CNA load exhibited a higher risk of recurrence compared with those with low levels [ p = 0. 038; hazard ratio (HR) 2. 46], which was confirmed in an independent cohort (p = 0. 004; HR 3. 82). Candidate chromosome-specific aberrations frequently observed in recurrent cases included gain of the chromosome arm 13q (p = 0. 02; HR 2. 67) and loss of heterozygosity at 17q22-q24. 3 (p = 0. 05; HR 2. 69). CNA load positively correlated with intratumor heterogeneity (R = 0. 52; p < 0. 0001). Consistently, incremental subclonal CNAs were associated with an elevated risk of relapse (p = 0. 028; HR 2. 20), which we did not observe for subclonal single-nucleotide variants and small insertions and deletions. The clinico-genomic model rated an area under the curve of 0. 83, achieving a 10% incremental gain compared with clinicopathological markers (p = 0. 047). In conclusion, tumor aneuploidy and copy-number intratumor heterogeneity were predictive of poor outcome and improved discriminative performance in early-stage colon cancer. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. |
| Grants: | Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1035 Instituto de Salud Carlos III CPII18/00026 Instituto de Salud Carlos III FI18/00221 Instituto de Salud Carlos III PI17/01304 Instituto de Salud Carlos III PI20/00863 |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Stage II colon cancer ; Cancer genomics ; Copy-number alterations ; Mutational profiling ; Intratumor heterogeneity ; Machine learning |
| Published in: | The Journal of Pathology, Vol. 257, Num. 1 (April 2022) , p. 68-81, ISSN 1096-9896 |
