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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
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Atypical Exon 2/3 Mutants G48C, Q43K, and E37K Present Oncogenic Phenotypes Distinct from Characterized NRAS Variants

Mark Anthony G Fran1, Dominique Mickai G Leaño2, James Allen D de Borja2

  • 1The Graduate School, Thomas Aquinas Research Complex, University of Santo Tomas, España, Manila 1008, Philippines.

Cells
|October 25, 2024
PubMed

Insights

Novel NRAS mutants found in Filipino young-onset colorectal cancer patients significantly enhance cell proliferation and apoptosis resistance. These findings suggest mutation-specific effects on cancer aggressiveness and therapeutic response.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • NRAS mutations, though rare in colorectal cancer (CRC), are associated with poorer outcomes.
  • Previous NRAS mutants showed limited impact on cell proliferation.
  • Filipino young-onset CRC patients presented novel NRAS mutants: G48C, Q43K, and E37K.

Purpose of the Study:

  • To functionally characterize novel NRAS mutants (G48C, Q43K, E37K) identified in Filipino young-onset CRC patients.
  • To investigate the impact of these mutants on cell proliferation, apoptosis, migration, and GDP-binding affinity.
  • To understand the codon- and mutation-specific oncogenic effects of NRAS.

Main Methods:

  • Cell proliferation assays using HCT116 and NIH3T3 cell lines.
  • 3D spheroid assays to simulate in vivo cellular organization.
  • Apoptosis resistance assays and cellular migration studies.
  • Actin staining for motility and invasiveness assessment.
  • Molecular docking simulations to analyze GDP-binding affinity.

Main Results:

  • The novel NRAS mutants G48C, Q43K, and E37K significantly enhanced cell proliferation in both HCT116 and NIH3T3 cells.
  • G48C and E37K mutants conferred apoptosis resistance in both cell lines, while Q43K showed resistance in HCT116 cells.
  • G48C enhanced migration in HCT116 cells, and actin staining indicated altered cellular morphology related to motility.
  • Docking simulations revealed weaker GDP-binding affinity for all three mutants compared to wild-type NRAS.

Conclusions:

  • Oncogenic NRAS mutants exhibit codon- and mutation-specific effects on cancer cell behavior.
  • These novel mutants influence cancer aggressiveness, apoptosis resistance, and potentially therapeutic responses.
  • Understanding these specific mutations is crucial for predicting CRC patient outcomes and guiding treatment strategies.
Keywords:
NRASRas isoformepidermal growth factor receptoryoung-onset colorectal cancer (YO-CRC)

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