Impact of Kras/Nras Mutational Heterogeneity On Clinical Outcomes In Colorectal Cancer

<p><strong>Introduction:</strong> Mutations in <em>KRAS/NRAS</em> (<em>RAS</em>) predict a lack of benefit from anti-EGFR agents in metastatic colorectal cancer (mCRC). As next generation sequencing (NGS) has advanced, we are discovering atypical and low allele frequency mutations. We aimed to evaluate how NGS can optimally define <em>RAS</em> mutant CRC and the role of relative mutant allele frequency (rMAF) as a biomarker.</p> <p><strong>Methods: </strong>Using institutional and public cohorts of mCRC patients with NGS results, we described the prevalence and clinical impact of atypical (not in current guidelines) and low rMAF <em>RAS</em> mutations (RAS MAF by the MAF of the mutated gene with the highest allele frequency to normalize for tumor content. Functional annotation of 113 <em>RAS</em> mutations was performed and functionality of mutations was compared to rMAF.</p> <p><strong>Results: </strong><em>RAS</em> mutations were noted in 4244/8609 patients (49.3%), with atypical mutations in 1.3% of patients. The most prevalent atypical mutations were <em>KRAS</em> Q22K (0.2%), <em>KRAS</em> D33E (0.1%) and <em>KRAS</em> T50I (0.1%). Of 113 functionally characterized <em>RAS</em> mutations, all 23 non-activating mutations were atypical, while every guideline cited mutation was activating. Atypical variants (HR 2.45, P=0.0092) and those that resulted in MAPK activity greater than <em>KRAS</em> exon 2 (HR 1.40, P=0.028) had a worse OS. A <em>RAS</em> rMAF >50% was associated with worse OS than rMAFRAS mutation was associated with a worse OS than wild-type patients. The rMAF of any mutated gene was also associated with functional significance in a clinically annotated database, yet the magnitude of difference in rMAF was not sufficient to warrant clinical utility in tissue cohorts. However, a cfDNA cohort did show striking results demonstrating rMAF was associated with a variants functional characterization.</p> <p><strong>Conclusions: </strong>Through a comprehensive atlas of <em>RAS</em> functional characterization, we show that several atypical variants appear clinically relevant. Although rMAF was not useful in characterizing variants as damaging, our findings that <em>RAS</em> rMAF is associated with prognosis suggests allele frequency may be useful information in standard clinical reports.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2017

Authors dc:creator

• Loree, Jonathan M
• <p>0000-0001-8189-2132</p>

Contributors dc:contributor

• Scott Kopetz
• Jeffrey Morris
• Russell Broaddus

• colorectal cancer
• biomarker
• next generation sequencing
• allele frequency
• mutation
• KRAS
• NRAS
• cfDNA
• Genetic Processes
• Medicine and Health Sciences
• Oncology
• Translational Medical Research

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/818

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1862