[Comparison of hereditary breast and ovarian cancer syndrome and sporadic ovarian cancer in ovarian cancer BRCA mutations].

Objective: To study the difference between BRCA gene mutations in hereditary breast and ovarian cancer syndrome (HBOC) and in sporadic ovarian cancer (SOC). Methods: This study was for exploratory research, the inclusion criteria were 284 patients with ovarian cancer admitted at Shanxi Provincial Cancer Hospital from November 2018 to December 2019, with high-throughput DNA sequencing including the full coding regions and exon-intron link regions of BRCA1 and BRCA2 gene. Pathogenic mutations in the BRCA gene of patients with ovarian cancer were collected and mutation site analysis was performed to compare phenotypic differences in pathogenic mutations between HBOC syndrome and SOC patients. Results: (1) Of the 284 ovarian cancer patients, seventy-seven had BRCA pathogenic mutations with a mutation rate of 27.1% (77/284), with BRCA1 mutation rate of 19.7% (56/284), BRCA2 gene 6.7% (19/284) and BRCA1/2 common mutation rate of 0.7% (2/284). Of the 284 patients with ovarian cancer, the pathogenic mutation rate in the BRCA gene in HBOC syndrome patients was 43.8% (32/73), which were significantly higher than that in SOC patients [21.3% (45/211); χ²=13.905, P<0.01]. Among BRCA1 gene mutation, the mutation rate in HBOC syndrome was higher than that of SOC [87.5% (28/32) vs 62.2% (28/45)], the BRCA2 gene mutation rate in patients with HBOC syndrome was lower than that in SOC patients [6.2% (2/32) vs 37.8% (17/45)], and there were statistically significant differences (all P<0.05). Two of the 77 patients with pathogenic mutations in the BRCA gene were multisite mutations, including one simultaneous two site mutation, one simultaneous three site mutation. There were 80 mutation sites with frameshift deletion mutations (55.0%, 44/80) and nonsense mutations (31.2%, 25/80). (2) Of the 73 patients with HBOC syndrome, 32 cases had pathogenic mutations in BRCA gene, including 28 cases in BRCA1, mainly in exon 11 and 24 (9 and 7 cases, respectively), and only two cases in BRCA2, both in exon 11; another two had multiple locus mutations. Of the 211 patients with SOC, 45 cases had pathogenic mutants in BRCA gene, including 28 cases in BRCA1, mainly in exon 11 and 24 (15 and 2 cases, respectively), and 17 cases in BRCA2, mainly in exon 11 (11 cases). (3) Thirty-four pathogenic mutation sites in BRCA gene were found newly, twenty of them were located in the BRCA1 gene, including a locus located on the intron 6, 301+1G>A, and the remaining 19 sites were located on the exons, including 283_286delCTTG, 68_69delAG, 132C>T, 514_547+3del37, 742delA, 1126_1129delAATA, 1196delA, 1352_1364del, 1465G>T, 2171delC, 2341G>T, 3359_3363delTTAAT, 4085_4086ins11, 4161_4162delTC, 4165_4166delAG, 4258G>T, 4338_4339del8insAGAA, 4468G>T, and 4783delA; fourteen sites were located in the BRCA2 gene, including a locus located on the intron 7, 631+1G>A, and the remaining 13 sites were located on the exons, including 2648delT, 2914A>T, 2950_2951insG, 4357+1G>A, 5054C>T, 5257A>T, 5291_5292insTC, 5913delT, 3593delA, 6091_6092insA, 6135_6136delTT, 7452delT, 9097_9098insA. A tal of 28 repeat mutations were located in the BRCA1 gene; among them, the site 5470_5477del8 was repeated 6 times, while 3 times in 981_982delAT. Conclusions: Patients with HBOC syndrome have a significantly higher rate of pathogenic mutation in the BRCA gene than that in patients with SOC. BRCA gene pathogenic mutation sites in HBOC syndrome patients occur commonly in exon 11 and 24 of BRCA 1 gene, while SOC patients occur mainly in exon 11 and 24 of BRCA1 gene and exon 11 of BRCA2 gene. The two loci of BRCA1∶5470_5477del8, BRCA1∶981_982delAT may be ancestor mutations in Chinese ovarian cancer patients, and 34 newly discovered pathogenic mutations in the BRCA gene, enriching the BRCA gene mutation spectrum in the Chinese population.目的： 探讨BRCA基因致病性突变表型在遗传性乳腺癌-卵巢上皮性癌（卵巢癌；HBOC）综合征与散发性卵巢癌（SOC）患者中的差异。 方法： 本研究为探索性研究，纳入标准是2018年11月至2019年12月山西省肿瘤医院收治的284例未经选择（指连续性病例）的卵巢癌患者，行高通量DNA测序，测序范围包括BRCA1和BRCA2基因全编码区、外显子-内含子连接区、非翻译区、启动子区。收集BRCA基因致病性突变的卵巢癌患者，进行突变位点分析，比较HBOC综合征与SOC患者BRCA基因致病性突变表型的差异。 结果： （1）284例卵巢癌患者中，BRCA基因致病性突变者77例，突变率为27.1%（77/284），其中BRCA1基因突变率为19.7%（56/284）、BRCA2基因突变率为6.7%（19/284）、BRCA1/2基因共同突变率为0.7%（2/284）。284例卵巢癌患者中，73例HBOC综合征患者的BRCA基因致病性突变率为43.8%（32/73），显著高于211例SOC患者的突变率［21.3%（45/211）；χ2=13.905，P<0.01］；其中，BRCA1基因突变率HBOC综合征患者高于SOC患者［分别为87.5%（28/32）、62.2%（28/45）］，BRCA2基因突变率HBOC综合征患者低于SOC患者［分别为6.2%（2/32）、37.8%（17/45）］，分别比较，差异均有统计学意义（P均<0.05）。77例BRCA基因致病性突变患者中，75例患者为1个位点突变，2例为多个位点突变（包括1例同时2个位点突变、1例同时3个位点突变），共有突变位点80个，突变类型以移码突变（55.0%，44/80）和无义突变（31.2%，25/80）为主。（2）73例HBOC综合征患者中，存在BRCA基因致病性突变者32例，其中突变发生于BRCA1基因者28例，主要位于BRCA1基因外显子11和24（分别为9、7例）；而突变发生于BRCA2基因者仅2例，均位于BRCA2基因外显子11；另有2例为多个位点突变。211例SOC患者中，存在BRCA基因致病性突变者45例，其中突变发生于BRCA1基因者28例，主要位于BRCA1基因为外显子11和24（分别为15、2例）；突变发生于BRCA2基因者17例，主要位于BRCA2基因外显子11（11例）。（3）本研究新发现BRCA基因致病性突变位点34个，其中位于BRCA1基因20个，包括1个位点位于内含子6，为301+1G>A，其余19个位点位于外显子，为283_286delCTTG、68_69delAG、132C>T、514_547+3del37、742delA、1126_1129delAATA、1196delA、1352_1364del、1465G>T、2171delC、2341G>T、3359_3363delTTAAT、4085_4086ins11、4161_4162delTC、4165_4166delAG、4258G>T、4338_4339del8insAGAA、4468G>T、4783delA；位于BRCA2基因14个，包括1个位点位于内含子7，为631+1G>A，其余13个位点位于外显子，为2648delT、2914A>T、2950_2951insG、4357+1G>A、5054C>T、5257A>T、5291_5292insTC、5913delT、3593delA、6091_6092insA、6135_6136delTT、7452delT、9097_9098insA。重复突变共有28例，均位于BRCA1基因，其中位点5470_5477del8重复6次，981_982delAT重复3次，这两个位点可能是卵巢癌患者的始祖突变。 结论： HBOC综合征患者的BRCA基因致病性突变率显著高于SOC患者；HBOC综合征患者的BRCA基因致病性突变位点好发于BRCA1基因外显子11和24，而SOC患者主要发生于BRCA1基因外显子11和24以及BRCA2基因外显子11。BRCA1∶5470_5477del8、BRCA1∶981_982delAT两个位点可能是中国卵巢癌患者的始祖突变，新发现的BRCA基因致病性突变位点34个，丰富了中国人群BRCA基因突变谱。.