Genetic risk factors for VIPN in childhood acute lymphoblastic leukemia patients identified using whole-exome sequencing

被引：26

作者：

Abaji, Rachid ^{[1
,2
]}

Ceppi, Francesco ^{[3
,4
]}

Patel, Swati ^{[1
]}

Gagne, Vincent ^{[1
]}

Xu, Chang J. ^{[1
]}

Spinella, Jean-Francois ^{[1
]}

Colombini, Antonella ^{[5
]}

Parasole, Rosanna ^{[6
]}

Buldini, Barbara ^{[7
]}

Basso, Giuseppe ^{[7
]}

Conter, Valentino ^{[5
]}

Cazzaniga, Giovanni ^{[8
]}

Leclerc, Jean-Marie ^{[1
,9
]}

Laverdiere, Caroline ^{[1
,9
]}

Sinnett, Daniel ^{[1
,9
]}

Krajinovic, Maja ^{[1
,2
,8
]}

机构：

[1] CHU St Justine Res Ctr, Charles Bruneau Canc Ctr, Montreal, PQ H3T 1C5, Canada

[2] Univ Montreal, Dept Pharmacol & Physiol, Fac Med, Montreal, PQ H3C 3J7, Canada

[3] Univ Hosp Lausanne, Dept Woman Mother Child, Div Pediat, Pediat Hematol Oncol Unit, CH-1004 Lausanne, Switzerland

[4] Univ Hosp Lausanne, Dept Woman Mother Child, Div Pediat, Pediat Hematol Oncol Res Lab, CH-1004 Lausanne, Switzerland

[5] Univ Milano Bicocca, Dept Pediat, Osped S Gerardo, I-20835 Monza, Italy

[6] Santobono Pausilipon Hosp, Dept Pediat Hematooncol, I-80129 Naples, Italy

[7] Univ Padua, Dept Woman & Child Hlth, Lab Haematol Oncol, I-35128 Padua, Italy

[8] Univ Milano Bicocca, Dept Pediat, Ctr Ric Tettamanti, I-20835 Monza, Italy

[9] Univ Montreal, Dept Pediat, Fac Med, Montreal, PQ H4A 3J1, Canada

来源：

PHARMACOGENOMICS | 2018年 / 19卷 / 15期

基金：

加拿大健康研究院;

关键词：

acute lymphoblastic leukemia; adverse drug reactions; association study; cancer; genetics; pharmacogenetics; polymorphism; vincristine-induced peripheral neuropathy; whole-exome sequencing; INDUCED PERIPHERAL NEUROPATHY; MARIE-TOOTH DISEASE; MUSCULAR-DYSTROPHY; VINCRISTINE PHARMACOKINETICS; AXONAL NEUROPATHY; CHILDREN; NEUROTOXICITY; POLYMORPHISMS; ASSOCIATION; TOXICITY;

D O I：

10.2217/pgs-2018-0093

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Aim: To identify genetic markers associated with vincristine-induced peripheral neuropathy (VIPN) in childhood acute lymphoblastic leukemia. Patients & methods: Whole-exome sequencing data were combined with exome-wide association study to identify predicted-functional germline variants associated with high-grade VIPN. Genotyping was then performed for top-ranked signals (n =237), followed by validation in independent replication group (n =405). Results: Minor alleles of rs2781377/SYNE2 (p=0.01) and rs10513762/MRPL47 (p=0.01) showed increased risk, whereas that of rs3803357/BAHD1 had a protective effect (p=0.007). Using a genetic model based on weighted genetic risk scores, an additive effect of combining these loci was observed (p=0.003). The addition of rs1135989/ACTG1 further enhanced model performance (p=0.0001). Conclusion: Variants in SYNE2, MRPL47 and BAHD1 genes are putative new risk factors for VIPN in childhood acute lymphoblastic leukemia.

引用

页码：1181 / 1193

页数：13

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