Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer.
OBJECTIVE
Thymidylate synthase (TS) is an important target enzyme for the fluoropyrimidines. TS gene promoter possesses regulatory tandemly repeated (TR) sequences that are polymorphic in humans, depending on ethnic factors. These polymorphisms have been reported to influence TS expression. TS expression levels affect tumor downstaging after preoperative fluoruracil (5-FU)-based chemoradiation. Tumor downstaging correlates with improved local control and disease-free survival. The aim of this study is to correlate TR polymorphisms with downstaging and disease-free survival.


METHODS
Sixty-five patients with rectal cancer underwent tumor resection after preoperative 5-FU-based chemoradiation. Tumor downstaging was evaluated by comparing the pretreatment T stage with the pathologic stage observed in the surgical specimen. TS polymorphism genotype was determined by polymerase chain reaction amplification of the corresponding TS promoter region, and products of amplification were electrophoresed, obtaining products of 220 bp (2/2), 248 bp (3/3), or both (2/3). The TS polymorphism genotype results were subsequently compared with the downstaging observed and with disease-free survival.


RESULTS
Patients who were homozygous for triple TR (3/3) had a lower probability of downstaging than patients who were homozygous with double TR or heterozygous patients (2/2 and 2/3): 22% versus 60% (P =.036; logistic regression). Furthermore, a trend toward improved 3-year disease-free survival was detected in the 2/2 and 2/3 groups, compared with that in the 3/3 group (81% v 41%; P =.17).


CONCLUSIONS
This preliminary study suggests that TS repetitive-sequence polymorphisms are predictive for tumor downstaging. TR sequences in TS promoter may be useful as a novel means of predicting response to preoperative 5-FU-based chemoradiation.
Villafranca
E
E
Department of Oncology, Clínica Universitaria, University of Navarre, Pamplona, Spain. evillafran@unav.es
Okruzhnov
Y
Y
Dominguez
M A
MA
García-Foncillas
J
J
Azinovic
I
I
Martínez
E
E
Illarramendi
J J
JJ
Arias
F
F
Martínez Monge
R
R
Salgado
E
E
Angeletti
S
S
Brugarolas
A
A
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic; D011300:Preoperative Care; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D020080:Tandem Repeat Sequences; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D013940:Thymidylate Synthase; D005472:Fluorouracil