| Objective:(1)For testing of BRCA1/2gene mutation with the genetic background ofXinjiang multi national area of breast cancer patients, to understand the mutation ofBRCA1/2gene and distribution in these populations, to investigate the BRCA1/2gene ofpathogenic mutations and hereditary breast cancer.(2)Analysis of BRCA1/2gene mutationin patients with breast cancer clinical and pathological features, using Logistic regressionmethod, we established the Xinjiang multi-national area has the genetic susceptibility tobreast cancer patients with mutations in BRCA risk model.(3)For the BRCA1/2mutationnegative breast cancer patients, we proceed to the PALB2, BRIP1, CHEK2gene mutationdetection, the purpose is to understand the3genes in the genetic background of thepatients with breast cancer mutations and distribution, and to explore its relationship withhereditary breast cancer.Methods:(1)In the Xinjiang area to select214cases of patientswith high risk breast cancer mutations as the research object, and100cases of nonmalignant tumor history and family history of healthy subjects served as a controlgroup,From the study of peripheral venous blood5ml, the extraction of target genomicDNA and PCR amplification. Select all exons of BRCA1/2gene, exon and intron junctionand the shear point sequence, using PCR-DHPLC method for screening, mutation resultsfor DNA sequencing and confirmed.(2)Collected214cases of complete BRCA1/2genemutation detection in breast cancer patients with clinical and pathological data of familyrelated information, through the single factor and multi factor analysis, found breastcancer patients with the clinical pathology and hereditary factors associated withBRCA1/2gene mutation.164cases of these patients, their information as the modelsample, using Logistic to establish BRCA1/2gene mutation risk prediction model of regression equation. The remaining50patients with individual and family information,verification of the overall accuracy of the model, and compared with the BRCApro andthe existing BOADICEA model.(3)Select the BRCA1/2mutation negative high geneticrisk of breast cancer patients112patients as the research object, and100cases of nonmalignant tumor history and family history of healthy subjects served as a controlgroup,from the study of peripheral venous blood5ml, the extraction of target genomicDNA and PCR amplification.On BRIP1, PALB2, and CHEK2all exons, exon and intronjunction sequences and shear mutation detection, and on the basis of the study found thatBRIP1, PALB2, CHEK2gene of certain mutations, in the control group were the site ofsequencing, comparing the mutation frequency.Results:(1)Of the214patients, themutation rate of BRCA1/2was16.8%, in which the BRCA1gene mutation rate was9.8%,BRCA2gene mutation rate was7%.In these patients98patients had a family history ofbreast cancer and ovarian cancer, their BRCA1/2gene mutation rate was20.4%(BRCA19.2%, BRCA211.2%). BRCA1/2gene has a family history of ovarian cancer in thesepatients and the mutation rate was35.7%, higher than the13.8%mutation rate without afamily history of patients;In these patients there were36cases of bilateral breast cancerpatients, the mutation rate of BRCA1/226.3%(where BRCA1mutation rate was13.2%,BRCA2mutation rate2.6%), higher than the14.6%mutation rate in patients withunilateral breast cancer (P=0.054);88cases were triple negative breast cancer in thepatients, the BRCA1/2mutation rate was28.4%(BRCA1mutation rate was20.4%,BRCA2mutation rate8%), higher than non-triple negative breast cancer mutation ratewas8.7%(P<0.05);In3cases of male breast cancer,1cases were detected BRCA2mutation, BRCA mutation rate was33.3%;In these patients, different ethnic groups ofBRCA mutation rates were14.2%,19%,25%,27.3%,25%, there was no significantdifference.In this study, we found no BRCA gene mutation hot spots, these mutationsthroughout the entire gene, but more than half of mutation in exon10and11. At the sametime, we detected43function unknown mutations in139patients, the mutation of BRCA121, BRCA222.(2)After analysis, we found that BRCA1/2mutations in breast cancerpatients are more likely to histologic grade III, and easier to hormone receptornegative,lymph node metastasis. pathological type of medullary carcinoma showedBRCA1mutation.Patients with BRCA1/2mutations in breast cancer incidence familymost light with an average age of37.97, significantly lower than that in the family ofbreast cancer incidence in the light with an average age of42.08years, the incidence ofbreast cancer in the family of light each additional1years of age, a4.4%lower risk of BRCA1/2mutation. For each additional family breast cancer population1people,1.781times increased risk of BRCA1/2mutation.Through single factor and clinical analysis, wechoose the following factors as modeling factors: the minimum age of breast cancer infamily, ovarian cancer family history, breast cancer number in the family, bilateralprimary breast cancer and triple negative breast cancer.We put the model developed in thisstudy with the BRCApro and BOADICEA models are compared, results show, theirsensitivity is respectively1,0.5,0.5, specificity was0.771,0.812,0.833, the negativepredictive value was1,0.975,0.976, the area under the curve were0.885,0.656,0.667.(3)Through the112cases of breast cancer in BRCA1/2mutation negative, mutationscreening of PALB2, BRIP1and CHEK2gene, the mutation rates were respectively2.7%,1.8%and0%.Mutations in the PALB2gene testing, detected a3294delTCGTC frameshiftmutation, insertion of1039insA frameshift mutations and2386G>T nonsense mutation,BRIP1gene detected1795G>A splice site mutation.The PALB21039insA frameshiftmutation, BRIP1gene1795G>A splice site mutation for new mutations, associated withthe risk of breast cancer, may be Chinese population specific mutation.Patients with thePALB2mutation and BRCA1/2mutation in patients with breast cancer havecharacteristics similar to pathology. In this study, the CHEK2gene was not detectedpathogenic mutation.Conclusions:(1)In the minority areas of Xinjiang have a high risk ofbreast cancer patients with mutations in BRCA1/2gene mutation detection is feasible.Especially for a family history of ovarian cancer and three negative breast cancerrecommend screening the gene.According to the results of this study show that themutation characteristics, recommended for BRCA gene mutation testing, first detectionthe hot fragments. For triple negative patients or bilateral primary breast cancers in BRCAtesting, first detection BRCA1, may improve the detection efficiency, reduce the cost oftesting.(2)China breast cancer population is different from other ethnic groups in breastcancer BRCA gene mutations, we should establish the model according to the geneticcharacteristics China population, mutations of BRCA gene for risk assessment in patientswith genetic susceptibility to breast cancer in order to better, and the result is better thanthe existing BRCApro and BOADICEA model.(3)PALB2, BRIP1gene mutation increasesthe risk of breast cancer, BRCA1/2mutation testing negative breast cancers suggestcontinued PALB2, BRIP1gene mutation testing. |
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