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Pharmacogenomics. 2018 Oct;19(15):1181-1193. doi: 10.2217/pgs-2018-0093. Epub 2018 Sep 7.

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

Author information

1
Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, QC, H3T1C5, Canada.
2
Department of Pharmacology & Physiology, Faculty of Medicine, University of Montreal, Montreal, QC, H3C 3J7, Canada.
3
Pediatric Hematology-Oncology Unit & Pediatric Hematology-Oncology Research Laboratory, Division of Pediatrics, Department of Woman-Mother-Child, University Hospital of Lausanne, 1004 Lausanne, Switzerland.
4
Department of Pediatrics, University of Milano-Bicocca, Ospedale S Gerardo, 20835 Monza, Italy.
5
Department of Pediatric Hemato-Oncology, Santobono-Pausilipon Hospital, 80129 Naples, Italy.
6
Department of Woman & Child Health, Laboratory of Haematology-Oncology, University of Padova, 35128 Padova, Italy.
7
Centro Ricerca Tettamanti, Department of Pediatrics, University Milano Bicocca, 20835 Monza, Italy.
8
Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC, H4A 3J1, Canada.

Abstract

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.

KEYWORDS:

acute lymphoblastic leukemia; adverse drug reactions; association study; cancer; genetics; pharmacogenetics; polymorphism; vincristine-induced peripheral neuropathy; whole-exome sequencing

PMID:
30191766
DOI:
10.2217/pgs-2018-0093
[Indexed for MEDLINE]

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