Genetic variation in ST6GAL1 is a determinant of capecitabine and oxaliplatin induced hand-foot syndrome

Abstract

Cancer patients treated with capecitabine and oxaliplatin (XELOX) often develop hand-foot syndrome (HFS) or palmar-plantar erythrodysesthesia. Genetic variation in ST6GAL1 is a risk factor for type-2 diabetes (T2D), a disease also associated with HFS. We analysed genome-wide association data for 10 toxicities in advanced colorectal cancer (CRC) patients from the COIN and COIN-B trials. One thousand and fifty-five patients were treated with XELOX ± cetuximab and 745 with folinic acid, fluorouracil and oxaliplatin ± cetuximab. We also analysed rs6783836 in ST6GAL1 with HFS in CRC patients from QUASAR2. Using UK Biobank data, we sought to confirm an association between ST6GAL1 and T2D (17 384 cases, 317 887 controls) and analysed rs6783836 against markers of diabetes, inflammation and psoriasis. We found that 68% of patients from COIN and COIN-B with grade 2-3 HFS responded to treatment as compared to 58% with grade 0-1 HFS (odds ratio [OR] = 1.1, 95% confidence interval [CI] = 1.02-1.2, P = 2.0 × 10^-4 ). HFS was also associated with improved overall survival (hazard ratio = 0.92, 95% CI = 0.84-0.99, P = 4.6 × 10^-2 ). rs6783836 at ST6GAL1 was associated with HFS in patients treated with XELOX (OR = 3.1, 95% CI = 2.1-4.6, P = 4.3 × 10^-8 ) and was borderline significant in patients receiving capecitabine from QUASAR2, but with an opposite allele effect (OR = 0.66, 95% CI = 0.42-1.03, P = .05). ST6GAL1 was associated with T2D (lead SNP rs3887925, OR = 0.94, 95% CI = 0.92-0.96, P = 1.2 × 10^-8 ) and the rs6783836-T allele was associated with lowered HbA1c levels (P = 5.9 × 10^-3 ) and lymphocyte count (P = 2.7 × 10^-3 ), and psoriasis (P = 7.5 × 10^-3 ) beyond thresholds for multiple testing. In conclusion, HFS is a biomarker of treatment outcome and rs6783836 in ST6GAL1 is a potential biomarker for HFS with links to T2D and inflammation.

Keywords: ST6GAL1; XELOX; chemotherapy; colorectal cancer; genetics; toxicity.

FIGURE 1

Kaplan‐Meier plot showing the relationship between hand‐foot syndrome (HFS) and overall survival (OS). The y‐axis represents survival probability and the x‐axis represents time (days). The blue line represents patients with G0‐1 HFS and the red line patients with G2‐3 HFS. Dotted lines show the median OS (596 days in those with G2‐3 HFS and 503 days in those with G0‐1 HFS). The P‐value was calculated using a cox proportional hazard regression [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Regional plots for the association of rs6783836 with hand‐foot syndrome (HFS). (A) Manhattan plot of the association between single‐nucleotide polymorphism (SNP) genotype and HFS in patients treated with capecitabine and oxaliplatin. The red line corresponds to a P = 5.0 × 10⁻⁸ and the blue line P = 1.0 × 10⁻⁵. (B) Locus zoom plot shows results of the analysis for SNPs and recombination rates. −log₁₀(P) (y axis) of the SNPs are shown according to their chromosomal positions (x axis). The sentinel SNP (purple) is labelled by its rsID. The colour intensity of each symbol reflects the extent of linkage disequilibrium with the sentinel SNP, deep blue (r ² = 0) through to dark red (r ² = 1.0). Genetic recombination rates, estimated using 1000 Genomes Project samples, are shown with a blue line. Physical positions are based on NCBI build 37 of the human genome. Also shown are the relative positions of genes and transcripts mapping to the region of association. Genes have been redrawn to show their relative positions; therefore, maps are not to physical scale. Fine‐mapping identified a credible set of 3 SNPs with rs6783836 having the highest posterior probability of 0.53 [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

Layered locus zoom plot showing single‐nucleotide polymorphisms (SNPs) in ST6GAL1 associated with hand‐foot syndrome (HFS) and type‐2 diabetes (T2D). Plot shows results of the analysis for SNPs and recombination rates. −log₁₀(P) (y axis) of the SNPs are shown according to their chromosomal positions (x axis). The dashed line corresponds to a P = 5.0 × 10⁻⁸. Genetic recombination rates, estimated using 1000 Genomes Project samples, are shown with a blue line. Physical positions are based on NCBI build 37 of the human genome. Lead SNPs for HFS and T2D are indicated by their rsIDs. Also shown is the relative coding region of ST6GAL1 and chromatin state annotations from ENCODE [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 4

Relationship between rs6783836 and (A) continuous and (B) ordinal phenotypes. The x axis shows phenotype and respective UK Biobank ID, and the y axis shows SD change or odds ratio. Only lymphocyte count and glycated haemoglobin (HbA1c) were significantly associated with rs6783836 after Bonferroni correction for eight tests (P < 6.3 × 10⁻³) [Color figure can be viewed at wileyonlinelibrary.com]