title: Plastin polymorphisms predict gender- and stage-specific colon cancer recurrence after adjuvant chemotherapy.
abstract: Tumor recurrence after curative resection remains a major problem in patients with locally advanced colorectal cancer treated with adjuvant chemotherapy. Genetic single-nucleotide polymorphisms (SNP) may serve as useful molecular markers to predict clinical outcomes in these patients and identify targets for future drug development. Recent in vitro and in vivo studies have demonstrated that the plastin genes PLS3 and LCP1 are overexpressed in colon cancer cells and play an important role in tumor cell invasion, adhesion, and migration. Hence, we hypothesized that functional genetic variations of plastin may have direct effects on the progression and prognosis of locally advanced colorectal cancer. We tested whether functional tagging polymorphisms of PLS3 and LCP1 predict time to tumor recurrence (TTR) in 732 patients (training set, 234; validation set, 498) with stage II/III colorectal cancer. The PLS3 rs11342 and LCP1 rs4941543 polymorphisms were associated with a significantly increased risk for recurrence in the training set. PLS3 rs6643869 showed a consistent association with TTR in the training and validation set, when stratified by gender and tumor location. Female patients with the PLS3 rs6643869 AA genotype had the shortest median TTR compared with those with any G allele in the training set [1.7 vs. 9.4 years; HR, 2.84; 95% confidence interval (CI), 1.32-6.1; P = 0.005] and validation set (3.3 vs. 13.7 years; HR, 2.07; 95% CI, 1.09-3.91; P = 0.021). Our findings suggest that several SNPs of the PLS3 and LCP1 genes could serve as gender- and/or stage-specific molecular predictors of tumor recurrence in stage II/III patients with colorectal cancer as well as potential therapeutic targets.
authors.affiliation: Corresponding Author: Heinz-Josef Lenz, Norris Comprehensive Cancer Center, Keck School of Medicine, 1441 Eastlake Avenue, Suite 3456, University of Southern California, Los Angeles, CA 90089. lenz@usc.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ning
authors.forename: Armin
authors.initials: A
authors.lastname: Gerger
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.forename: Diana L
authors.initials: DL
authors.lastname: Hanna
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.forename: Thomas
authors.initials: T
authors.lastname: Winder
authors.forename: Takeru
authors.initials: T
authors.lastname: Wakatsuki
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Labonte
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stintzing
authors.forename: Nico
authors.initials: N
authors.lastname: Volz
authors.forename: Yu
authors.initials: Y
authors.lastname: Sunakawa
authors.forename: Stefan
authors.initials: S
authors.lastname: Stremitzer
authors.forename: Rita
authors.initials: R
authors.lastname: El-Khoueiry
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000368:Aged; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012737:Sex Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C047262:LCP1 protein, human; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; C026742:plastin; D005472:Fluorouracil