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

Katie Watts, Christopher Wills, Ayman Madi, Claire Palles, Timothy S. Maughan, Richard Kaplan, Nada A. Al‐tassan, Rachel Kerr, David J. Kerr, Richard S. Houlston, Valentina Escott‐price, Jeremy P. Cheadle

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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.

Original languageEnglish
Pages (from-to)957-966
JournalInternational Journal of Cancer
Issue number6
Early online date25 Apr 2022
Publication statusE-pub ahead of print - 25 Apr 2022

Bibliographical note

Funding Information:
This work was supported by Cardiff University School of Medicine (to KW), Tenovus Cancer Care (to JPC and CW), KFSHRC (to NAA) and Cancer Research UK (grant number C1298/A8362 to RSH). The COIN and COIN‐B trials were funded by Cancer Research UK, the Medical Research Council and an unrestricted educational grant from Merck‐Serono and were conducted with the support of the National Institute of Health Research Cancer Research Network. None of the sponsors played a role in the study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the article for publication. Funding information

Timothy S. Maughan consults for AstraZeneca and receives personal fees from Pierre Fabre (IDMC services). Timothy S. Maughan received research funding from Merck KgAa and AstraZeneca. The institution where Timothy S. Maughan works receives funding from Bayer. David J. Kerr is a director of Oxford Cancer Biomarkers. All other authors have declared no conflicts of interest.

Publisher Copyright:
© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.


  • ST6GAL1
  • chemotherapy
  • colorectal cancer
  • genetics
  • toxicity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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