In Silico Study to Predict the Structural and Functional Consequences of SNPs on Biomarkers of Ovarian Cancer (OC) and BPA Exposure-Associated OC

Abstract

Background: Recently, we have shown that seven genes, namely GBP5, IRS2, KRT4, LINCOO707, MRPL55, RRS1 and SLC4A11, have prognostic power for the overall survival in ovarian cancer (OC).

Methods: We present an analysis on the association of these genes with any phenotypes and mutations indicative of involvement in female cancers and predict the structural and functional consequences of those SNPS using in silico tools.

Results: These seven genes present with 976 SNPs/mutations that are associated with human cancers, out of which 284 related to female cancers. We have then analysed the mutation impact on amino acid polarity, charge and water affinity, leading to the identification of 30 mutations in gynaecological cancers where amino acid (aa) changes lead to opposite polarity, charges and water affinity. Out of these 30 mutations identified, only a missense mutation (i.e., R831C/R804C in uterine corpus endometrial carcinomas, UCEC) was suggestive of structural damage on the SLC4A11 protein.

Conclusions: We demonstrate that the R831C/R804C mutation is deleterious and the predicted ΔΔG values suggest that the mutation reduces the stability of the protein. Future in vitro studies should provide further insight into the role of this transporter protein in UCEC.

Keywords: SLC4A11; missense mutations; protein modelling; uterine corpus endometrial carcinoma.

Figure 1

Venn diagram showing the possible mutations/SNPs associated with seven biomarkers in cBioPortal and UCSC Xena repository. (a) Mutations in human cancers. (b) Mutations in female cancers.

Figure 2

(a) Bar plot representing types of SNPs/mutations associated with seven biomarkers in human cancers. (b) Pie chart demonstrating the percentage distribution of 976 SNPs for 7 biomarkers in human cancers, where red colour represents the number of mutations in each gene.

Figure 3

(a) Bar plot indicating different types of mutations associated with seven biomarkers in female cancers. (b) Pie chart specifying the percentage distribution of 284 SNPs for 7 biomarkers in female cancers, where red colour represents the number of mutations in each gene.

Figure 4

(a) Bar plot showing the sample size and percentage of mutation in seven biomarkers in each human cancer type, (b) with emphasis on female cancers.

Figure 5

Amino acid change/SNP selection criteria according to the change in amino acid polarity and charge.

Figure 6

(a) Aligned structure of solute carrier family 4, sodium borate transporter, member 11 protein wildtype (918 aa, grey colour) and energy-minimised wildtype (cyan colour). (b) Aligned structure of SLC4A11 protein mutant (grey colour) and energy-minimised mutant (red colour). (c) Aligned structure of energy-minimised solute carrier family 4, sodium borate transporter, member 11 protein wildtype (cyan) and energy-minimised mutant (red). (d) Surface view of aligned structure of energy-minimised solute carrier family 4, sodium borate transporter, member 11 protein wildtype (cyan) and energy-minimised mutant (red).

Figure 7

(a) Aligned structure of solute carrier family 4, sodium borate transporter, member 11 protein wildtype (891 aa, grey colour) and energy-minimised wildtype (cyan colour). (b) Aligned structure of SLC4A11 protein mutant type (grey colour) and energy-minimised mutant type (red colour). (c) Aligned structure of energy-minimised solute carrier family 4, sodium borate transporter, member 11 protein wildtype (cyan) and energy-minimised mutant type (red). (d) Surface view of aligned structure of energy-minimised SLC4A11 protein wildtype (cyan) and energy-minimised mutant type (red).

Figure 8

(a) An electrostatic potential surface of wildtype solute carrier family 4, sodium borate transporter, member 11 protein indicating amino acid residue ARG at position 831/804. (b) An electrostatic potential surface of mutant-type protein indicating amino acid residue CYS at position 831/804. In the colour legend, the red colour indicates negative potential, the blue colour indicates positive potential of the protein surface and the white regions correspond to fairly neutral potentials. Yellow arrow indicates towards the mutation site at position 831/804.