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An In Vitro System to Study Tumor Dormancy and the Switch to Metastatic Growth

An In Vitro System to Study Tumor Dormancy and the Switch to Metastatic Growth

Published on: August 11, 2011

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

Sofía Del Carmen¹, José María Sayagués², Oscar Bengoechea¹

¹Department of Pathology and IBSAL, University Hospital of Salamanca, Salamanca, Spain.

|October 23, 2018

Abstract:

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.

Insights

Activating mutations in KRAS and NRAS genes impact anti-EGFR therapy response in metastatic colorectal cancer (mCRC). Analyzing primary tumors and metastases reveals differing mutation profiles, suggesting comprehensive mutational analysis is crucial for effective treatment decisions.

Area of Science:

Oncology
Genetics
Molecular Biology

Background:

Activating mutations in KRAS and NRAS genes are known predictors of poor response to anti-EGFR therapies in metastatic colorectal cancer (mCRC).
A significant proportion of patients with wild-type KRAS colorectal cancer also do not respond to these therapies, potentially due to undetected mutations in metastatic sites.

Purpose of the Study:

To investigate the mutational profiles of KRAS, NRAS, BRAF, and PI3KCA genes in paired primary tumors, lymph nodes, and liver metastases from mCRC patients.
To determine if clonal evolution occurs, leading to differing mutation profiles between primary tumors and their metastases.
To assess the clinical implication of these findings for anti-EGFR therapy decisions.

Main Methods:

Low-density microarray technology was employed to analyze gene mutations.
Samples from 26 untreated mCRC patients, including paired primary tumors (n=26), lymph nodes (n=16), and liver metastases (n=34), were analyzed (total 76 samples).
Mutational status of KRAS, NRAS, BRAF, and PI3KCA genes was assessed in all collected samples.

Main Results:

KRAS and PI3KCA were the most frequent mutations in primary tumors (15% each).
Lymph node metastases showed higher frequencies of KRAS (25%) and NRAS (19%) mutations compared to primary tumors.
Liver metastases exhibited the highest prevalence of KRAS mutations (35%), followed by PI3KCA (9%) and BRAF (6%).
Discordant mutation profiles between primary tumors and metastases were observed in 11 out of 26 patients (48%), indicating spatial and temporal clonal evolution.

Conclusions:

Significant differences in mutational profiles exist between primary colorectal tumors and their lymph node and liver metastases.
Clonal evolution, leading to divergent genetic landscapes, is a notable phenomenon in a subset of mCRC patients.
Comprehensive mutational analysis of all available tumor samples (primary and metastatic) is recommended before initiating anti-EGFR therapy to optimize treatment selection.

Read full analysis

Keywords:

anti-EGFR clonal evolution colorectal cancer mutational profile tumor heterogeneity

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