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

Watts, Katie, Wills, Christopher, Madi, Ayman, Palles, Claire, Maughan, Timothy S., Kaplan, Richard, Al-Tassan, Nada A., Kerr, Rachel, Kerr, David J., Houlston, Richard S., Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483 and Cheadle, Jeremy P. ORCID: https://orcid.org/0000-0001-9453-8458 2022. Genetic variation in ST6GAL1 is a determinant of capecitabine and oxaliplatin induced hand-foot syndrome. International Journal of Cancer 151 (6) , pp. 957-966. 10.1002/ijc.34046

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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 ten toxicities in advanced colorectal cancer (CRC) patients from the COIN and COIN-B trials. 1,055 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=2.0x10-4). HFS was also associated with improved overall survival (Hazard Ratio=0.92, 95%CI=0.84-0.99, P=4.6x10-2). rs6783836 at ST6GAL1 was associated with HFS in patients treated with XELOX (OR=3.1, 95%CI=2.1-4.6, P=4.3x10-8) 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=0.05). ST6GAL1 was associated with T2D (lead SNP rs3887925, OR=0.94, 95%CI=0.92-0.96, P=1.2x10-8) and the rs6783836-T allele was associated with lowered HbA1c levels (P=5.9x10-3) and lymphocyte count (P=2.7x10-3), and psoriasis (P=7.5x10-3) 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Wiley
ISSN:	0020-7136
Date of First Compliant Deposit:	29 March 2022
Date of Acceptance:	28 March 2022
Last Modified:	11 Oct 2023 22:02
URI:	https://orca.cardiff.ac.uk/id/eprint/148940

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