Spatio-temporal tumor heterogeneity in metastatic CRC tumors: a mutational-based approach.

Autor:	Del Carmen S; Department of Pathology and IBSAL, University Hospital of Salamanca, Salamanca, Spain., Sayagués JM; Cytometry Service-NUCLEUS, Department of Medicine, Cancer Research Center (IBMCC-CSIC/USAL) and IBSAL, University Hospital of Salamanca, Salamanca, Spain., Bengoechea O; Department of Pathology and IBSAL, University Hospital of Salamanca, Salamanca, Spain., Anduaga MF; General and Gastrointestinal Surgery Service and IBSAL, University Hospital of Salamanca, Salamanca, Spain., Alcazar JA; General and Gastrointestinal Surgery Service and IBSAL, University Hospital of Salamanca, Salamanca, Spain., Gervas R; Department of Pathology and IBSAL, University Hospital of Salamanca, Salamanca, Spain., García J; General and Gastrointestinal Surgery Service and IBSAL, University Hospital of Salamanca, Salamanca, Spain., Orfao A; Cytometry Service-NUCLEUS, Department of Medicine, Cancer Research Center (IBMCC-CSIC/USAL) and IBSAL, University Hospital of Salamanca, Salamanca, Spain., Bellvis LM; General and Gastrointestinal Surgery Service and IBSAL, University Hospital of Salamanca, Salamanca, Spain., Sarasquete ME; Hematology Service, University Hospital of Salamanca, Salamanca, Spain., Del Mar Abad M; Department of Pathology and IBSAL, University Hospital of Salamanca, Salamanca, Spain.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2018 Sep 28; Vol. 9 (76), pp. 34279-34288. Date of Electronic Publication: 2018 Sep 28 (Print Publication: 2018).
DOI:	10.18632/oncotarget.26081
Abstrakt:	It is well known that activating mutations in the KRAS and NRAS genes are associated with poor response to anti-EGFR therapies in patients with metastatic colorectal cancer (mCRC). Approximately half of the patients with wild-type (WT) KRAS colorectal carcinoma do not respond to these therapies. This could be because the treatment decision is determined by the mutational profile of the primary tumor, regardless of the presence of small tumor subclones harboring RAS mutations in lymph nodes or liver metastases. We analyzed the mutational profile of the KRAS , NRAS , BRAF and PI3KCA genes using low-density microarray technology in samples of 26 paired primary tumors, 16 lymph nodes and 34 liver metastases from 26 untreated mCRC patients (n=76 samples). The most frequent mutations found in primary tumors were KRAS (15%) and PI3KCA (15%), followed by NRAS (8%) and BRAF (4%). The distribution of the mutations in the 16 lymph node metastases analyzed was as follows: 4 (25%) in KRAS gene, 3 (19%) in NRAS gene and 1 mutation each in PI3KCA and BRAF genes (6%). As expected, the most prevalent mutation in liver metastasis was in the KRAS gene (35%), followed by PI3KCA (9%) and BRAF (6%). Of the 26 cases studied, 15 (58%) displayed an overall concordance in the mutation status detected in the lymph node metastases and liver metastases compared with primary tumor, suggesting no clonal evolution. In contrast, the mutation profiles differed in the primary tumor and lymph node/metastases samples of the remaining 11 patients (48%), suggesting a spatial and temporal clonal evolution. We confirm the presence of different mutational profiles among primary tumors, lymph node metastases and liver metastases. Our results suggest the need to perform mutational analysis in all available tumor samples of patients before deciding to commence anti-EGFR treatment. Competing Interests: CONFLICTS OF INTEREST The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Databáze:	MEDLINE
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