Base excision repair pathway: PARP1 genotypes as modulators of therapy response in cervical cancer patients.
BACKGROUND
Genetic polymorphisms in genes of the base excision repair (BER) pathway appear to modulate the therapy response of cancer patients. PARP1 protein recognizes the DNA strand damage and facilitates the subsequent recruitment of BER proteins. Few studies have reported an association between PARP1 Val762Ala polymorphism (rs1136410) and cancer therapy response.


OBJECTIVE
The purpose of our study was to determine whether PARP1 Val762Ala polymorphism have prognostic value in patients with cervical cancer.


METHODS
Two hundred and sixty adult patients, with histologically confirmed cervical cancer, at FIGO-stages IB2-IVA, primarily treated with concurrent chemotherapy (cisplatin) and radiotherapy. Overall survival (OS) and disease-free survival (DFS) were the primary end points of the analysis. The PARP1 Val762Ala genetic variants were analyzed by allelic discrimination by real-time PCR.


RESULTS
We observed that peri- and postmenopausal women carrying the C-allele present a statistically significant lower OS and DFS (log-rank test, p = 0.008 and p = 0.006, respectively) among those with early stage cervical cancer. Cox regression analysis confirmed these results, after adjustment for other prognostic factors (for OS: HR, 3.70; 95%CI, 1.32-10.38; p = 0.013 and for DFS: HR, 3.97; 95%CI, 1.59-9.93; p = 0.003).


CONCLUSIONS
This is the first study evaluating the effect of PARP1 Val762Ala polymorphism in treatment response in cervical cancer patients. PARP1 genotypes may contribute as an independent prognostic factor in cervical cancer, being useful in predicting the clinical outcome.
a Molecular Oncology and Viral Pathology Group - Research Center , Portuguese Institute of Oncology , Porto , Portugal.|b FMUP, Faculty of Medicine of Porto University , Porto , Portugal.|c Research Department , Portuguese League against Cancer (NRNorte) , Porto , Portugal.
Augusto
A
Nogueira
a Molecular Oncology and Viral Pathology Group - Research Center , Portuguese Institute of Oncology , Porto , Portugal.|b FMUP, Faculty of Medicine of Porto University , Porto , Portugal.
Joana
J
Assis
d Oncology Department , Portuguese Institute of Oncology , Porto , Portugal.
Ilda
I
Faustino
a Molecular Oncology and Viral Pathology Group - Research Center , Portuguese Institute of Oncology , Porto , Portugal.|d Oncology Department , Portuguese Institute of Oncology , Porto , Portugal.|e ICBAS , Abel Salazar Institute for the Biomedical Sciences , Porto , Portugal.
Deolinda
D
Pereira
a Molecular Oncology and Viral Pathology Group - Research Center , Portuguese Institute of Oncology , Porto , Portugal.
Raquel
R
Catarino
a Molecular Oncology and Viral Pathology Group - Research Center , Portuguese Institute of Oncology , Porto , Portugal.|c Research Department , Portuguese League against Cancer (NRNorte) , Porto , Portugal.|e ICBAS , Abel Salazar Institute for the Biomedical Sciences , Porto , Portugal.|f CEBIMED , Faculty of Health Sciences of Fernando Pessoa University , Porto , Portugal.
Rui
R
Medeiros
D000328:Adult; D002945:Cisplatin / Q000627:therapeutic use; D004260:DNA Repair / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics* / Q000502:physiology; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011878:Radiotherapy; D016019:Survival Analysis; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy
C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D002945:Cisplatin
Cervical cancer; DNA adducts/repair mechanisms; PARP1; genetic polymorphisms; prognosis