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Polymorphic markers associated with severe oxaliplatin‐induced, chronic peripheral neuropathy in colon cancer patients
Author(s) -
Won HongHee,
Lee Jeeyun,
Park Joon Oh,
Park Young Suk,
Lim Ho Yeong,
Kang Won Ki,
Kim JongWon,
Lee SooYoun,
Park Se Hoon
Publication year - 2011
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.26614
Subject(s) - medicine , oxaliplatin , peripheral neuropathy , colorectal cancer , peripheral , cancer , oncology , gastroenterology , endocrinology , diabetes mellitus
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. Cancer 2011;. © 2011 American Cancer Society .