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Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Molecular profiling of metastatic colorectal tumors using next-generation sequencing: a single-institution experience
Jun Gong1, May Cho1, Marvin Sy1
1Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.
Background:
Recent molecular characterization of colorectal tumors has identified several molecular alterations of interest that are considered targetable in metastatic colorectal cancer (mCRC).
Methods:
We conducted a single-institution, retrospective study based on comprehensive genomic profiling of tumors from 138 patients with mCRC using next-generation sequencing (NGS) via FoundationOne.
Results:
Overall, RAS mutations were present in 51.4% and RAF mutations were seen in 7.2% of mCRC patients. We found a novel KRASR68S1 mutation associated with an aggressive phenotype. RAS amplifications (1.4% KRAS and 0.7% NRAS), MET amplifications (2.2%), BRAFL597Ralterations (0.7%), ARAFS214F alterations (0.7%), and concurrent RAS+RAF (1.4%), BRAF+RAF1 (0.7%), and rare PTEN-PIK3CA-AKT pathway mutations were identified and predominantly associated with poor prognosis. ERBB2 (HER2) amplified tumors were identified in 5.1% and all arose from the rectosigmoid colon. Three cases (2.2%) were associated with a hypermutated profile that was corroborated with findings of high tumor mutational burden (TMB): 2 cases with MSI-H and 1 case with a POLE mutation.
Conclusions:
Comprehensive genomic profiling can uncover alterations beyond the well-characterized RAS/RAF mutations associated with anti-EGFR resistance. ERBB2 amplified tumors commonly originate from the rectosigmoid colon, are predominantly RAS/BRAF wild-type, and may predict benefit to HER2-directed therapy. Hypermutant tumors or tumors with high TMB correlate with MSI-H status or POLE mutations and may predict a benefit from anti-PD-1 therapy.
Insights
Comprehensive genomic profiling of metastatic colorectal cancer (mCRC) reveals targetable alterations beyond RAS/RAF mutations. ERBB2 amplification and high tumor mutational burden (TMB) indicate potential benefits from targeted therapies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Metastatic colorectal cancer (mCRC) harbors molecular alterations that can be targeted therapeutically.
- Recent advances in molecular characterization have identified several such alterations.
Purpose of the Study:
- To comprehensively analyze the genomic landscape of mCRC tumors.
- To identify novel molecular alterations and their prognostic significance.
- To explore potential therapeutic targets in mCRC.
Main Methods:
- Retrospective analysis of 138 mCRC patients.
- Comprehensive genomic profiling using next-generation sequencing (NGS).
- FoundationOne platform utilized for tumor profiling.
Main Results:
- RAS mutations (51.4%) and RAF mutations (7.2%) were common.
- Novel KRASR68S1 mutation linked to aggressive phenotype.
- ERBB2 (HER2) amplification found in 5.1% of tumors, originating from the rectosigmoid colon.
- High tumor mutational burden (TMB) observed in 2.2% of cases, associated with MSI-H or POLE mutations.
Conclusions:
- Genomic profiling identifies targets beyond RAS/RAF mutations, relevant for anti-EGFR resistance.
- ERBB2-amplified rectosigmoid tumors may benefit from HER2-directed therapy.
- Hypermutant/high TMB tumors suggest potential benefit from anti-PD-1 therapy.
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