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.

Topical interventions for preventing hand-foot syndrome resulting from antineoplastic therapy: A scoping review

“…Another study ( 77 ) , whose sample consisted of patients with advanced colon cancer treated with capecitabine and oxaliplatin (XELOX), investigated the rs6783836 variant in ST6GAL1 (ST6 β-galactoside α-2,6-sialyltransferase), a gene that plays a role in inflammation and development of type 2 diabetes, and concluded that the gene was associated with the development of HFS, showing to be a promising biomarker of the syndrome ( 77 ) . Furthermore, an important study ( 78 ) revealed a novel mechanism of individual genetic susceptibility to capecitabine-associated HFS, with implications for clinically relevant risk prediction.…”

Intervenções tópicas para prevenção de síndrome mão-pé decorrente de terapia antineoplásica: revisão de escopo

“…Outro estudo (77) , cuja amostra foi composta por pacientes com câncer de cólon avançado tratados com capecitabina e oxaliplatina (XELOX), investigou a variante rs6783836 em ST6GAL1 (ST6 β-galactoside α-2,6-sialyltransferase), um gene que tem papel na inflamação e no desenvolvimento de diabetes tipo 2, e concluiu que o gene foi associado ao desenvolvimento de SMP, mostrando ser um promissor biomarcador da síndrome (77) . Além disso, importante estudo (78) revelou um novo mecanismo de suscetibilidade genética individual à SMP associada à capecitabina, com implicações para a previsão de risco clinicamente relevante.…”