BRCA1/2 Germline Mutations In Ovarian Malignant Tumors In Yunnan Province

Research purposes:To study the carrying status of the germline BRCA1/2 mutation?gBRCAm?in patients with ovarian malignant tumors in Yunnan Province,and provide evidence for the research and early prevention of heredity ovarian cancer in Yunnan Province.Research methods:According to the principle of informed consent,three hundred twenty-seven unselected ovarian malignant tumors patients in total from September 2016 to June 2017 were collected samples of peripheral blood and enrolled,which were tested for gBRCAm status by using the next-generation sequencing approach.There are two hundred ninety-two unselected ovarian malignant tumors patients from the Third Affiliated Hospital of Kunming Medical University of Yunnan Province,nineteen unselected ovarian malignant tumors patients from the Lincang People's Hospital of Yunnan Province,two unselected ovarian malignant tumors patients from the Lijiang People's Hospital of Yunnan Province,eleven unselected ovarian malignant tumors patients from the First Affiliated Hospital of Kunming Medical University of Yunnan Province,one unselected ovarian malignant tumors patients from the Honghe People's Hospital of Yunnan Province,four unselected ovarian malignant tumors patients from the Traditional Chinese Medicine Hospital of Yunnan Province,three unselected ovarian malignant tumors patients from the Second People's Hospital of Yunnan Province,two unselected ovarian malignant tumors patients from the First People's Hospital of Yunnan Province.Collect relevant clinical information of patients.Research result:1.Among 327 patients with ovarian malignant tumors,the rate of pathogenic/likely pathogenic gBRCA1/2m is 21.4%,of which gBRCAlm rate is 15.6%,gBRCA2m rate is 4.0%,both gBRCAlm and gBRCA2m simultaneously rate is 1.8%.2.Among 327 patients with ovarian malignant tumors,219?67.0%?patients were found to have benign gBRCAl/2m,and 14?4.3%?patients were found to have likely benign gBRCAl/2m,thirty patients?9.2%?were found to have VUS gBRCA1/2m,eighteen patients?5.5%?were found to have a likely pathogenic gBRCAl/2m,and forty-six patients?14.1%?were to have a pathogenic gBRCAl/2m.3.Six?1.8%?patients carried both gBRCAlm and gBRCA2m simultaneously.Seven mutations have not been referred in ClinVar database.The pathogenic site was c.5468₁G>A in gBRCA1.The likely pathogenic mutations were c.954dupT in gBRCA1,c.1583delA,c.2884₂890del in gBRCA2.The VUS mutations were c.G1593T,c.G2345T in gBRCA1,c.C1478A in gBRCA2.Four mutations have been recorded in ClinVar database,the pathogenic mutation was c.310dupA in gBRCA1.The VUS mutations were c.9106C>G,c.5606G>A,c.9925G>A in gBRCA2.Both OC119 and OC261 are both gBRCA1/2m and the same sites mutations.4.Two?0.6%?carcinosarcoma patients were found to carry pathogenic gBRCAm.c.5194-12G>A in gBRCA1 of OC189 patient,c.954dupT in gBRCA1 of OC232 patient and c.9925G>A in gBRCA2.5.The proportion of exon 10 in gBRCAlm was higher,and the proportion of exon 11 in gBRCA2m was higher.6.A total of 9 sites with two or more mutation frequencies have been recorded in the ClinVar database of VUS and pathogenic gBRCA1/2m were found in this study.Frequency three mutations were found in c.5114T>C,c,3770₃771del AG,tc.2799delT in gBRCA1 and c.5606G>A in gBRCA2.Frequency two mutations were found in c.5521delA,c.3756₃759de1GTCT,c.220C>T,c.5470₅477delATTGGGCA in gBRCA1 and c.3165₃168deITCAA in gBRCA2.c.5470₅477de1ATTGGGCA in gBRCA1 is a hot spot mutation in the Chinese population found in this study consistent with previous reports.7.Twenty-five novel mutations that has not been referred in ClinVar database were identified,including three cases of pathogenic gBRCAl/2m,seven cases of likely pathogenic gBRCA1/2m,and fifteen cases of VUS gBRCAl/2m.Among the three cases of pathogenic gBRCA1/2m,there were two cases of c.2591C>A in gBRCA1 and one case of c.5468₁G>A in gBRCA1 and one case of c.C3405A in gBRCA2.Among the seven cases of likely pathogenic gBRCA1/2m,there were two cases of c.3101dupA and c.954dupT and c.139delT in gBRCA1,one case of c.3286dupC and c.5068₅074+1dupAAAACAGG in gBRCA1,two cases of c.2884₂890del in gBRCA2,one case of c.1583delA in gBRCA2.Among the fifteen cases of VUS gBRCA1/2m,there were three cases of c.5062G>T in gBRCA1,two cases of c.G2345T and c.3646T>G in gBRCA1,one case of c.5062G>C,c.5152+2₅152+3insCCCT,c.4484+1G>C,c.3752₃753delGT,c.G748T,c.G1593T,c.G5092T,c.G2402T,c.G1593T in gBRCA1,one case of c.9587A>G,c.10209₁0214del,c.C1478A in gBRCA2.8.Patients with pathogenic gBRCAlm tended to be diagnosed at younger ages than carriers of gBRCA2m?mean age at diagnosis:50.0 vs.55.8 years,P=0.023?.9.The age?P=0.324?and grade?P=0.063?of non-pathogenic gBRCAl/2m and pathogenic gBRCA1/2m were not significantly different.The histology?P=0.025?,FIGO stage?P=0.040?,HBOC-related tumor?P=0.002?,personal history of cancer?P=0.024?,tumor in first relatives?P<0.001?,tumor in second relatives?P<0.001?of non-pathogenic gBRCAl/2m and pathogenic gBRCA1/2m were significantly different.10.There were forty-one cases of Yunnan ethnic minorities in this study.No pathogenic gBRCA1/2m was found in Hani ethnic group,Dai nationality,Lisu nationality,Tibetan.Six of which had pathogenic gBRCA1/2m.Three novel mutations have not been referred in ClinVar database,three mutations were gecorded in the ClinVar database were identified.Among the three novel mutations have not been referred in ClinVar database,the c.3286dupC and c.5068₅074+1dupAAAACAGG in likely pathogenic gBRCA1m were only found in the Bai nationality,the C.C3405A in pathogenic gBRCA2m was only found in Yi people.Among the three mutations were recorded in the ClinVar database,the c.134+2T>C in pathogenic gBRCA1m was only found in Yi people,the c.5089T>C in likely pathogenic gBRCA1m was only found in Zhuang nationality,the c.2799delT in pathogenic gBRCA1m was found in the Hui and Han nationality.11.In this study,more than five cases of gBRCA1/2m were found in Kunming City,Dali Bai Autonomous Prefecture,Lincang City,Yuxi City and Qujing City of Yunnan Province.No gBRCA1/2m were found in Diqing Tibetan Autonomous Prefecture,Xishuangbanna Dai Autonomous Prefecture,Lijiang City,Nujiang Lisu Autonomous Prefecture in the Yi Autonomous Prefecture.One case in the Hui and Han nationalities was found that ClinVar has been recorded the c.2799delT in pathogenic gBRCAlm,which was from the Honghe Hani and Yi Autonomous Prefecture of Yunnan Province.12.Under the same conditions,the patients with serous cancer and personal history of cancer and family history for cancer the risk of carrying gBRCA1/2m is 3.950 times,3.744 times,2.390 times respectively.In conclusion:1.Among 327 patients with ovarian malignant tumors,the rate of pathogenic/likely pathogenic gBRCA1/2m is 21.4%,of which gBRCAlm rate is 15.6%,gBRCA2m rate is 4.0%,both gBRCAlm and gBRCA2m simultaneously rate is 1.8%.2.Among 327 patients with ovarian malignant tumors,219?67.0%?patients were found to have benign mutations in the gBRCA1/2,and 14?4.3%?patients were found to have likely benign mutations in the gBRCA 1/2,thirty patients?9.2%?were found to have VUS mutations in the gBRCAl/2,eighteen patients?5.5%?were found to have a likely pathogenic mutation in the gBRCA1/2,and forty-six patients?14.1%?were to have a pathogenic mutation in the gBRC A1/2.3.Two?0.6%?carcinosarcoma patients were found to carry pathogenic gBRCAm.c.5194-12G>A in gBRCAl of OC189 patient,c.954dupT in gBRCAl of OC232 patient and c.9925G>A in gBRCA2.4.The proportion of exon 10 in gBRCA1m was higher,and the proportion of exon 11 in gBRCA2m was higher.5.A total of 9 sites with two or more mutation frequencies have been recorded in the ClinVar database of VUS and pathogenic gBRCAl/2m were found in this study.Frequency three mutations were found in c.5114T>C,c.3770₃771delAG,tc.2799delT in gBRCA1 and c.5606G>A in gBRCA2.Frequency two mutations were found in c.5521 delA,c.3756₃759delGTCT,c.220C>T,c.5470₅477delATTGGGCA in gBRCA1 and c.3165₃168delTCAA in gBRCA2.c.5470₅477delATTGGGCA in gBRCA1 is a hot spot mutation in the Chinese population found in this study consistent with previous reports.The above sites may be potential hot spots in the Chinese population.6.Twenty-five novel mutations that has not been referred in ClinVar database were identified,including three cases of pathogenic gBRCA1/2m,seven cases of likely pathogenic gBRCA1/2m5 and fifteen cases of VUS gBRCA1/2m.Among the three cases of pathogenic gBRCA1/2m,there were two cases of c.2591C>A in gBRCA1 and one case of c.5468₁G>A in gBRCA1 and one case of C.C3405A in gBRCA2.Among the seven cases of likely pathogenic gBRCA1/2m,there were two cases of c.3101dupA and c.954dupT and c.139de1T in gBRCA1,one case of c.3286dupC and c.5068₅074+ldupAAAACAGG in gBRCA1,two cases of c.2884₂890del in gBRCA2,one case of c.1583delA in gBRCA2.Among the fifteen cases of VUS gBRCA1/2m,there were three cases of c.5062G>T in gBRCA1,two cases of C.G2345T and c.3646T>G in gBRCA1,one case of c.5062G>C,c.5152+2₅152+3insCCCT,c.4484+1G>C,c.3752₃753delGT,c.G748T,c.G1593T,c.G5092T,c.G2402T,c.G1593T in gBRCA1,one case of c.9587A>G,c.10209₁0214del,c.C1478A in gBRCA2.These novel mutations may be unique mutation sites in Yunnan.7.This study found that there are differences in the mutations of different ethnic groups,and the same mutations exist in different ethnic groups in the same region,suggesting that the pathogenic gBRCA1/2m and the likely pathogenic gBRCA1/2m may exist in regions and ethnic differences.8.In this study,gBRCA1/2m was not found in the ?30-year-old age group.Patients with pathogenic gBRCA1m tended to be diagnosed at younger ages than carriers of gBRCA2m?mean age at diagnosis:50.0 vs.55.8 years,P=0.023?.Ovarian cancer onset in carriers with pathogenic gBRCA2m variants is an average of 5.8 years later than in carriers with pathogenic gBRCA1m.9.The age?P=0.324?and grade?P=0.063?of non-pathogenic gBRCA1/2m and pathogenic gBRCA1/2m were not significantly different.The histology?P=0.025?,FIGO stage?P=0.040?,HBOC-related tumor?P=0.002?,personal history of cancer?P=0.024?,tumor in first relatives?P<0.001?,tumor in second relatives?P<0.001?of non-pathogenic gBRCAl/2m and pathogenic gBRCA1/2m were significantly different.10.The patients with serous cancer and personal history of cancer and family history for cancer have a higher risk of carrying gBRCA1/2m,and the gBRCA1/2m embryoid processes was autosomal dominant,the pathogenic gBRCAl/2m carriers have a higher cancer risk of lifetime.It is recommended that patients with serous cancer and personal history of cancer and family history for cancer and their families undergo gBRCA1/2m detection.The pathogenic gBRCA1/2m carriers go to relevant genetic counseling clinics for cancer risk assessment and preventive treatment.