Polymorphic markers associated with severe oxaliplatin-induced, chronic peripheral neuropathy in colon cancer patients.
BACKGROUND
To identify potential genetic markers for severe oxaliplatin-induced chronic peripheral neuropathy (OXCPN), the authors performed a genome-wide association analysis of patients with colon cancer who received oxaliplatin-based chemotherapy.


METHODS
This was a prospective study in which DNA was purified in peripheral blood from patients with colon cancer who received oxaliplatin. The primary endpoint was the development of severe (grade 2 lasting for >7 days or grade 3) OXCPN. For the discovery set, genotyping was done for 96 patients who received adjuvant fluorouracil and oxaliplatin using the a genome-wide human single-nucleotide polymorphism (SNP) array. An association between polymorphisms and severe OXCPN was investigated. At the same time, 247 patients who received oxaliplatin-based, first-line chemotherapy for advanced disease were enrolled as a validation set.


RESULTS
Among the 32 genotyped candidate SNPs selected from the discovery set, 9 SNPs in 8 genes (tachykinin, precursor 1[TAC1]; forkhead box C1 [FOXC1]; integrin, alpha 1 [ITGA1]; acylphosphatase 2, muscle type [ACYP2]; deleted in lymphocytic leukemia, 7 [DLEU7]; B-cell translocation gene 4 [BTG4]; calcium/calmodulin-dependent protein kinase II inhibitor 1 [CAMK2N1]; and phenylalanyl-tRNA synthase 2 [FARS2]) had nominal replication (P < .05). The most significant association was observed at reference SNP number (rs)10486003 in TAC1 (P = 4.84 × 10(-7)) in combined data from 2 sets. Five SNPs (rs10486003, rs2338, rs830884, rs843748, and rs797519) were significant in a multiple regression analysis (P < .05). Overall prediction accuracy calculated by the regression model was 72.8% (95% confidence interval, 65.8%-79.9%) in the model development and 75.9% (95% confidence interval, 66.9%-84.9%) in the model evaluation.


CONCLUSIONS
The current results indicated that a genome-wide pharmacogenomic approach is useful for identifying novel polymorphism predictors of severe OXCPN that may be used in personalized chemotherapy.
Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, South Korea.
Hong-Hee
HH
Won
Jeeyun
J
Lee
Joon Oh
JO
Park
Young Suk
YS
Park
Ho Yeong
HY
Lim
Won Ki
WK
Kang
Jong-Won
JW
Kim
Soo-Youn
SY
Lee
Se Hoon
SH
Park
D000328:Adult; D000368:Aged; D015415:Biomarkers; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D015415:Biomarkers; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin