Relationship Between Single Nucleotide Polymorphisms In Repair Gene XPD751, XPD312and Prognosis In Colorectal Carcinoma Patients

Object:With the development of the economy, life style, and the change of the diet,the incidence of colorectal cancer is higher and higher. In recent years for colorectalcancer prevention, diagnosis, treatment countermeasures has the corresponding change.People aware of drug sensitivity of tumor patients has obvious individual differences，So the individualized treatment is becoming a hot spot of research and practice.Platinum drugs is the common use of the colorectal cancer patients withchemotherapy.The affection of patient treated with platinum drugs sensitivity gene isDNA repair gene. In the known of five kinds of DNA damage repair pathways,the mostclosely relationship with mammals is nucleotide excision repair.And the singlenucleotide polymorphism of Nucleotide excision repair genes is closely related to thecurative effect of the platinum drugs.XPD is also called ERCC2, The gene singlenucleotide polymorphisms by influencing the repair gene transcription, translation, andvarious aspects of the stability of the mRNA and protein activity influence theexpression of gene product,and then affect the sensitivity of the tumor patients tochemotherapy drugs.The common genetic mutation of XPD gene are in751and 312.The XPD751. XPD312single nucleotide polymorphisms and colorectal cancerchemotherapy curative effect of the relationship between is not yet clear Currently. theresearch conclusions are inconsistent. FOLFOX is a commonly used chemotherapy inpatients with colorectal cancer. In view of the above, This test through studying the therelationship between gene XPD751and XPD312single nucleotide polymorphisms andlate-stage colorectal cancer on the basis of oxaliplatin, joint with5-Fluorouracil,Calcium Folinate,which namely FOLFOX chemotherapy curative effect, to furtherstudy XPD751, XPD312single nucleotide polymorphisms and disease control rates oflate-stage colorectal cancer patients after chemotherapy,and the progression-freesurvival.Methor:1)Collected from January1,2008-December31,2012patients withadvanced colorectal cancer in106cases,76patients cmplete the forecast and evaluation.In patients with male41cases, Women35cases, age29-76, the median age of57.41cases of colon cancer, rectal cancer,34cases of liver metastasis33cases,8cases ofpulmonary metastasis carcinoma and liver metastasis with lung metastasis,4cases ofpelvic metastasis8cases,22cases of peritoneal metastasis,1case with supraclavicularlymph node metastasis. All the cases were diagnosed by pathology, CT scan has ameasurable lesions. Before chemotherapy were performed routine blood, liver andkidney function, electrocardiogram (ecg) not seen obvious abnormity, ECOG score0to1.2) Chemotherapy regimens: All patients were performed FLOFOX chemotherapyregimens, specific for oxaliplatin into (L-OHP)85mg/m2, d1, calcium leucovorin (CF)300mg d1d2,5-fluorouracil (5-FU)400mg/m2d1, d2,5-fluorouracil (5-FU)600mg/m2d1,48h continuous intravenous drip into the second day, every three weeks for acycle.3) Specimen collection and experimental method: Admission prior tochemotherapy in patients with2ml peripheral venous blood, after sodium citrateanticoagulation treatment, in-20℃refrigerator, By extracting DNA, gene fragmentof upstream and downstream primer design purpose, use of polymerase chain polymer-restriction fragment length polymorphism (RFLP-PCR) technology to detect the singlenucleotide polymorphisms of DNA repair gene XPD751and XPD312. To compare different genotypes of the relationship between the prognosis of patients withchemotherapy.Result:1)The frequency of XPD751Lys/Lys was58cases（76.3%）、Lys/Gln+Gln/Glnwas18caese（23.7%），XPD312Asp/Asp was42cases（55.3%）、Asp/Asn+Asn/Asnwas34caese（44.7%）。2)The disease control rate(DCR) of FOLFOX chemotherapyamong patients with XPD751Lys/Lys was87.9%（51cases）, Lys/Gln+Gln/Glnwas66.7%（13caese），the difference between Lys/Lys and Lys/Gln+Gln/Gln wasstatistically significant,（X2=4.381，P=0.036）.3)XPD312Asp/Asp was64.2%（27cases）、Asp/Asn+Asn/Asn was79.41%（27caese）, the difference between Asp/Asp andAsp/Asn+Asn/Asn was no statistically significant,（X2=2.456，P=0.483）. Logisticregression analysis showed that carry Lys/Lys genotype patients accept FOLFOXscheme chemotherapy sensitivity is carrying Lys/Gln+Gln/Gln genotypes in patientswith3.5times.4)The MPFS of the76patients was9.68months,the MPFS was9.88months for patients with Asp/Asp gennetype of XPD312and8.41months for patientswith Asp/Asn+Asn/Asn gennetype, the difference between Asp/Asp andAsp/Asn+Asn/Asn was no statistically significant（X2=1.479，P>0.05）. the MPFS was9.96months for patients with Lys/Lys gennetype of XPD751and7.8months forpatients with Lys/Gln+Gln/Gln gennetype, the difference between Lys/Lys andLys/Gln+Gln/Gln was no statistically significant（X2=11.769，P=0.001）. The MPFSwas12.95months for patients with Lyn/Lyn simultaneously with Asp/Aspgenetype,8.36months for patients with Lyn/Lyn and Asp/Asn+Asn/Asn genetype,7.8months for patients with Lyn/Gln+Gln/Gln and Asp/Asp genetype,and7.14months forpatients with Lyn/Gln+Gln/Gln and Asp/Asn+Asn/Asn genetype. The differencebetween genetype above was statistically significant （X2=12.722，P=0.005）.5)COX regression analysis shows the correlation of progression-free surial in patientswith sex, age, area of tumor metastasis and four types of cross genotypes，onlygenotyping has the statistically significan（tP=0.000，RR=1.445）. Among the four kindsof cross genotype, only the XPD751Lyn/Lyn and the XPD312Asp/Asp genotypeassociated with progression-free surial of patients（P=0.006，RR=0.357）. Therefore, at the same time carry XPD751Lys/Lys, XPD312Asp/Asp genotype may be late predictorsof prognosis of patients with CRC. XPD751, XPD312both are wild type patients maybe more sensitive to FOLFOX chemotherapy.6)76cases of patients with major adversereactions is bone marrow suppression, White blood cells inhibit, platelet inhibition iswith Ⅱ degrees below, anemia is with Ⅰ degrees, Nausea and vomiting is with Ⅱdegree, But in both XPD312XPD751genotype no statistically significant differencewere observed in the adverse reactionsConclusions:1）XPD751may be related to the patients with colorectal cancerchemotherapy sensitivity of FOLFOX scheme, testing XPD751mononuclear nucleotidepolymorphism may be predicted to accept FOLFOX scheme is index of prognosis ofpatients with colorectal cancer after chemotherapy.2）XPD312gene may be related tocolorectal cancer patients with chemotherapy sensitivity no correlation withFOLFOX.3）Both XPD751, XPD312are wild type patients may be more sensitive toFOLFOX chemotherapy.