Role of Single-Nucleotide Polymorphisms in Genes Implicated in Capecitabine Pharmacodynamics on the Effectiveness of Adjuvant Therapy in Colorectal Cancer
, Almudena Sánchez-MartÃn 1, Noelia Márquez-Pete 1, Encarnación González-Flores 2,3, Fernando MartÃnez-MartÃnez 4, Cristina Pérez-RamÃrez 5,*,†and Alberto Jiménez-Morales 1,†
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis manuscript describes the effect of genetic polymorphisms on the outcome of adjuvant capecitabine from pharmacodynamic (not pharmacokinetic) perspective in 142 CRC patients.
Known genotypes were examined in TYMS, ENOSF1, MTHFR, ERCC1/2, and XRCC1/3.
The study demonstrated that ENOSF1 related to better survival, which is an implicative result. The authors discussed that ENOSF1 is involved in the regulation of the expression of TYMS, thus affecting the outcomes, which is a currently accepted consideration.
The manuscript is well written and will add value to pharmacogenetics of capacitabine in CRC..
Line 105: HWE should be spelled out here.
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Reviewer 2 Report
Comments and Suggestions for AuthorsI have read the results contained in the article and although they are very interesting, a few issues require clarification:
1. The study group is small and this is a very big limitation in drawing conclusions. However, what seems to me much more important is the complete lack of a reference group, i.e. people belonging to the Spanish population and the distribution of these polymorphic changes in this population. Only a comparison with the distribution in this population can allow us to draw reliable conclusions.
2. Authors must adapt the notation of gene names to the applicable nomenclature. For example, in line 67 of the manuscript.
3. The description of the methodology in section 4.3.3 Genotyping is very simplified and does not include any examples of raw data. They are also missing in the supplementary materials.
4. Please provide reviewers with an example of an anonymized signed consent to perform genetic testing.
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Reviewer 3 Report
Comments and Suggestions for AuthorsIdentification of new SNPs associated with severe toxicity and adverse reaction to capecitabine and the identification of new genetic variants to select additional groups of SNP tags in genes associated with the pharmacodynamics of fluoropyrimidines is a rather rich area of study.
The authors had already identified some SNPs as possible biomarkers. In the present work, they extensively present the validation as a genetic biomarker of ENOSF1 rs2612091-TT, a gene already deeply studied for its toxicity and effectiveness of FP-based therapy.
The aim of their study was to explore the significance of SNPs associated with capecitabine pharmacodynamics in predicting treatment survival. The results of their investigation showed that the ENOSF1 rs2612091-TT genotype and the TYMS/ENOSF1 ACT haplotype were linked to increased duration of disease-free survival in colorectal cancer patients receiving adjuvant capecitabine-based therapy.
ENOF1 (the gene is ENOSF1) is a protein with catalytic activity in mitochondria whose molecular mechanisms are little known. Active 1: Apparently, the literature reports that ENOF1 (the gene ENOSF1) interacts with about fifteen different interactors (NPL, THOC1, COLEC12, DPH5, SNX20, TYMS, CLUL1, TMEM14C, and so on). However, when we thoroughly evaluate these interactions and the literature describing them, we discover that all of them are statistically insignificant or indirect and almost never have biochemical or biophysical experimental validations.
The most damning proof is that if we go to STRING, one of the best and most appreciated interactomics platforms, and try to calculate an interactome model of ENOF1 by using an extremely significant score (score 0.9) we discover that even if we try with an enrichment directed with 500 or more proteins, ENOF1 extracts no functional relationships from the human proteome. Only TYMS Thymidylate synthase appears to be involved, but not by direct physical interaction. This indicates the absence of reliable scientific information concerning the functional mechanisms of this protein.
The authors have successfully capitalized on the available opportunities, i.e., observational data from CRC, such as clinical data from populations and genotyping. To the limitations of their study, I would also add that they used only European patients.
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