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Pharmacogenet Genomics. 2018 Feb;28(2):49-55. doi: 10.1097/FPC.0000000000000318.

Genome-wide meta-analyses identifies novel taxane-induced peripheral neuropathy-associated loci.

Author information

1
The Ohio State University, Columbus.
2
Mayo Clinic, Rochester, Minnesota.
3
SWOG Statistical Center.
4
Cleveland Clinic, Cleveland, Ohio.
5
University of Southern California, Los Angeles.
6
Roswell Park Cancer Institute, Buffalo.
7
Alliance Statistics and Data Center, Duke University Medical Center.
8
Duke University, Durham, North Carolina.
9
Columbia University, New York, New York.
10
Loyola University Chicago Cardinal Bernardin Cancer Center, Maywood, Illinois.
11
University of Michigan, Ann Arbor, Michigan.
12
Baystate Medical Center, Springfield, Massachusetts.
13
Georgetown University, Washington, District of Columbia.
14
Allan Blair Cancer Centre, Regina, Saskatchewan, Canada.
15
Seattle Cancer Care Alliance, Seattle.
16
MD Anderson Cancer Center, Houston, Texas.
17
Arizona Cancer Center, Tucson, Arizona, USA.
18
University of California San Francisco, San Francisco, California.

Abstract

OBJECTIVE:

Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN.

PATIENTS AND METHODS:

Women with high-risk breast cancer enrolled in SWOG 0221 were genotyped using the Illumina 1M chip. Genome-wide analyses were performed in relation to ≥grade 3 Common Terminology Criteria for Adverse Events (CTCAE) neuropathy in European and African Americans. Data were meta-analyzed with GW associations of CTCAE ≥grade 3 versus <grade 3 in CALGB 40101 assuming a fixed effects model.

RESULTS:

The percentage of ≥grade 3 TIPN in 1269 European Americans and 139 African Americans in S0221, was 11.6 and 22.3%, respectively. CALGB 40101 ≥grade 3 TOPN was 7.2%. The most significant association with ≥grade 3 TIPN was the G allele of rs1858826 in GNGT1 (Pmeta=1.1×10), which showed a decrease in risk of ≥grade 3 TIPN (odds ratio=0.29, 95% confidence interval: 0.18-0.46).

CONCLUSION:

The genetic variants associated with ≥grade 3 TIPN are hypothesized to have biochemical functions and reside in and near genes involved in diabetes and diabetic neuropathy. This finding is consistent with results from CALGB 40101 pathway analyses. Larger homogeneous trials with similar dosing and criteria for defining neuropathy are needed to properly assess the relationship of genomics with the neuropathy spectrum.

PMID:
29278617
PMCID:
PMC5824720
[Available on 2019-02-01]
DOI:
10.1097/FPC.0000000000000318
[Indexed for MEDLINE]

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