Study On BRCA1/2 Germline Mutation In Chinese Patients With HER-2 Negative Metastatic Breast Cancer

Research Background and Purpose:Breast cancer is the most common malignant tumor in women and the leading cause of cancer in women worldwide.It is estimated that more than 1.9 million women worldwide will be diagnosed with breast cancer by 2020,an increase of approximately 18.4% over 2012.About 5%~10% of breast cancer cases are inherited in all breast cancer patients,and up to 25% of hereditary breast cancers are associated with specific gene mutations.The most studied genes are the BRCA1 and BRCA2 genes.BRCA1 and BRCA2 are two different tumor suppressor genes that play an integral role in DNA repair processes by responding to cellular stress activation.Studies have shown that BRCA1/2 mutations greatly increase the risk of breast and ovarian cancer,BRCA1/2 mutations in women with lifetime breast cancer is 45% ~75%,respectively.At present,countries in Europe and the United States have included BRCA1/2 gene mutation detection in breast cancer into the NCCN guidelines,and established a corresponding database,while China's breast cancer BRCA1/2 gene standardization screening is still in its infancy,mostly single-center small sample size studies,and Genetic testing methods vary.Therefore,in this study,BRCA1/2 mutation was detected in 66 cases of breast cancer patients,and the BRCA1/2 gene detection articles published in 2005~2017 in all Chinese breast cancer patients were reviewed.The characteristics of BRCA1/2 mutation in Chinese were summarized.Research Objects and Methods:The subjects studied were patients with HER-2 negative metastatic breast cancer at the Cancer Center of Jilin University First Hospital.Entry criteria: Histologically or cytologically confirmed breast cancer with evidence of metastases,immunohistochemistry indicated positive or negative estrogen(ER)and/or progesterone(PR)receptors,and negative HER-2 expression.A total of 66 women with breast cancer were included.The Sanger sequencing method was used to detect the full-coded exon sequences of BRCA1 and BRCA2 genes to determine whether there was a pathogenic BRCA1/2 gene mutation.All the information included in the patient's history,histopathologic types,immunohistochemical characteristics,and disease-free survival(DFS)were reviewed to analyze the clinicopathological features of BRCA1/2 mutation-associated breast cancer patients and whether BRCA1/2 germline mutations were present.Impact on the prognosis.Statistical methods: Comparison of pathological features of BRCA1/2 gene mutations between HER-2 negative metastatic breast cancer patients by chi-square test or Fisher's exact test,P<0.05 statistically significant.The univariate and multivariate analyses were performed to analyze the factors affecting the patient's DFS using the Cox model.Significance test level ?=0.05.Results:1.In this study,the pathogenic mutation rate of BRCA1/2 in metastatic HER-2 negative breast cancer patients was 18.18%(12/66),the pathogenic mutation rate of BRCA1 was 7.58%(5/66),and BRCA2 was 10.60.%(7/66).2.The total mutation rate of BRCA1/2 in Chinese breast cancer patients was 12.08%,the BRCA1 gene mutation rate was 5.32%(116/2178),and the BRCA2 gene mutation rate was 6.76%(130/1921).The BRCA1/2 mutation is characterized by a higher frequency of BRCA2 mutations than BRCA1 mutations.3.BRCA1 mutations are commonly found in exons 11,10,and 24,and BRCA2 mutations are commonly found in exons 11,10,18,and 22,which are quite different from those in European and American populations.4.The most common BRCA1 mutation sites in Chinese population are 1100delAT(exon 11),3478del5(exon 11),5470-5477del8(exon 23),and 5640delA(exon 24).The most common BRCA2 mutation sites are 3109C>T(exon #11),2060C>A(exon #11),and 6819delTG(exon #11).The 5470-5477del8(exon 23)mutation in the BRCA1 gene may be an ancestral mutation in the Chinese population.5.The breast cancer patients with BRCA1/2 gene-pathogenic germline mutations are mainly characterized by non-menopause and negative ER expression at the time of onset.The molecular typing is mostly triple-negative breast cancer.It is recommended that breast cancer patients with the above pathological features be screened for BRCA1/2 mutations early to guide treatment.6.In this study,patients with negative expression of PR,histological grade III,and primary tumors greater than 2 cm have poor DFS.Whether or not there is a BRCA mutation is not statistically significant in this study because of the small sample size,but it may still indicate a poor prognosis.Conclusion:1.According to available data,the total mutation rate of BRCA1/2 gene in breast cancer patients in China was 12.08%,BRCA1 gene mutation rate was 5.32%,and BRCA2 gene mutation rate was 6.76%.The frequency of BRCA2 mutation in Chinese population is higher than that of BRCA1 mutation.2.BRCA1/2 mutations have large racial differences.We should continue to explore and enrich the BRCA1/2 mutation database in China.3.It is recommended that breast cancer patients with non-menopausal,ER-negative,and triple-negative molecular types at the time of onset be screened for BRCA1/2 mutations early to guide treatment and assess prognosis.4.The impact of BRCA1/2 mutation on the prognosis of breast cancer is currently inconclusive and needs further exploration.