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Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Association of candidate single nucleotide polymorphisms with somatic mutation of the epidermal growth factor
Samuel Wormald1, Liz Milla, Liam O'Connor
1Division of Systems Biology and Personalized Medicine, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. wormald@wehi.edu.au.
Background:
Tumour growth in colorectal cancer and other solid cancers is frequently supported by activating mutations in the epidermal growth factor receptor (EGFR) signaling pathway (Patholog Res Int 2011:932932, 2011). Treatment of metastatic colorectal cancer with targeted anti-EGFR therapeutics such as cetuximab extends survival in only 25% of patients who test wild-type for KRAS, while the majority of patients prove resistant (J Clin Oncol 28(7):1254-1261, 2010).Prediction of cetuximab responsiveness for KRAS wild-type colorectal cancers is currently not well defined, and prognostic biomarkers would help tailor treatment to individual patients. Somatic mutation of the EGFR signalling pathway is a prevalent mechanism of resistance to cetuximab (Nature 486(7404):532-536, 2012). If the human genome harbours variants that influence susceptibility of the EGFR pathway to oncogenic mutation, such variants could also be prognostic for cetuximab responsiveness.
Methods:
We assessed whether patient genetic variants may associate with somatic mutation of the EGFR signalling pathway. We combined tumour mutation data from the Cancer Genome Atlas with matched patient genetic data, and tested for germline variants that associate with somatic mutation of the EGFR pathway (including EGFR, KRAS, BRAF, PTEN and PIK3CA).
Results:
Two single nucleotide polymorphisms (SNPs) located 90 kb upstream of the TERT oncogene associated with somatic mutation of the EGFR pathway beyond the threshold of genome-wide significance: rs7736074 (P = 4.64 × 10-9) and rs4975596 (P = 5.69 × 10-9). We show that allelic variants of rs7736074 and rs4975596 modulate TERT expression levels in multiple cancer types, and exhibit preliminary prognostic value for response to cetuximab.
Conclusions:
We have identified two germline SNPs that associate with somatic mutation of the EGFR pathway, and may be prognostic for cetuximab responsiveness. These variants could potentially contribute to a panel of prognostic biomarkers for assessing whether metastatic colorectal cancer patients are likely to derive benefit from cetuximab treatment. Genotyping of a large cohort of cetuximab-treated colorectal cancer patients is called for to further clarify the association.
Insights
Two germline SNPs, rs7736074 and rs4975596, associate with epidermal growth factor receptor (EGFR) pathway mutations. These variants may predict response to cetuximab treatment in colorectal cancer patients.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Activating mutations in the epidermal growth factor receptor (EGFR) signaling pathway drive tumor growth in colorectal cancer.
- Cetuximab treatment improves survival in only 25% of KRAS wild-type patients, with resistance being a significant challenge.
- Predictive biomarkers for cetuximab responsiveness in KRAS wild-type colorectal cancer are needed to personalize treatment.
Purpose of the Study:
- To investigate whether patient germline genetic variants are associated with somatic mutations in the EGFR signaling pathway.
- To identify potential prognostic biomarkers for cetuximab responsiveness in colorectal cancer.
Main Methods:
- Combined tumor mutation data from The Cancer Genome Atlas with matched patient genetic data.
- Tested for germline variants associated with somatic mutations in key EGFR pathway genes (EGFR, KRAS, BRAF, PTEN, PIK3CA).
Main Results:
- Two single nucleotide polymorphisms (SNPs), rs7736074 and rs4975596, located upstream of the TERT oncogene, showed a significant association with EGFR pathway somatic mutations.
- These SNPs (rs7736074 and rs4975596) were found to modulate TERT expression levels across multiple cancer types.
- Preliminary evidence suggests these variants possess prognostic value for cetuximab response.
Conclusions:
- Identified two germline SNPs (rs7736074 and rs4975596) associated with EGFR pathway somatic mutations.
- These SNPs may serve as prognostic biomarkers for cetuximab responsiveness in metastatic colorectal cancer.
- Further validation in a large cohort of cetuximab-treated patients is warranted to confirm their clinical utility.
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