高危家族卵巢癌和散发性卵巢癌患者BRCA1/2基因突变的研究及临床意义探讨
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摘要
背景和目的：
卵巢上皮性癌(卵巢癌)是病死率最高的妇科恶性肿瘤,家族史则被认为是最有力的肿瘤预测因素之一。研究表明,卵巢癌患者约5%～10%为遗传性,其中,遗传性卵巢癌患者中约有80～90%伴有易感基因BRCA1/2的突变。目前, BRCA1/2基因的检测已成为卵巢癌高危人群重要的筛查方法。在中国,有关高危家族卵巢癌患者和散发性卵巢癌患者的外周血BRCA1/2基因突变的研究并不深入,中国卵巢癌人群的BRCA1/2基因突变情况还未得到很好阐明。因此,为了进一步明确中国卵巢癌人群的BRCA1/2基因突变情况,本课题对高危家族卵巢癌患者和散发性卵巢癌患者进行了BRCA1/2基因全序列突变检测并进行对照分析,以了解两个基因在两组卵巢癌患者中的突变情况及差异；分析伴有BRCA1/2基因突变的卵巢癌患者的临床特点及病理学特征,以比较不同遗传背景的卵巢癌患者临床生物学的特点及差异；同时还对四个卵巢癌高危家族的女性成员进行了外周血BRCA1/2基因全序列突变检测和家系分析。
对象和方法：
研究的入选标准：(1)高危家族卵巢癌患者：①家族中至少有两个一级或二级亲属患原发性卵巢癌或卵巢癌和乳腺癌；②家族中至少有一名成员患乳腺-卵巢双原发癌,伴或不伴有直系三代血亲内其他成员患卵巢癌或乳腺癌。(2)散发性卵巢癌：没有乳腺癌／卵巢癌家族史和乳腺癌个人史的卵巢癌患者。所有卵巢癌患者的诊断均为病理诊断。最后入选的高危家族卵巢癌患者39例,散发性卵巢癌患者32例。
研究方法：(1)提取外周血单个核细胞DNA,应用变性高效液相色谱分析(DHPLC)+DNA测序,对每名患者均进行了BRCA1和BRCA2基因全外显子以及外显子内含子拼接区的突变检测；(2)对高危家族卵巢癌患者与散发性卵巢癌患者进行发病年龄、病理类型、肿瘤分期和分级、化疗敏感性等生物学特点进行统计,分析比较；(3)本研究收集了4个完整的家族性乳腺癌-卵巢癌家系,将家系中所有符合条件的女性成员进行DHPLC分析+DNA测序,并对家系的BRCA1和BRCA2基因突变特点进行分析。
结果：
共有来自35个独立高危家族的39例卵巢癌患者和32例散发性卵巢癌患者纳入本研究中。在这71例患者中,共有20例患者携带了BRCA1或BRCA2基因致病性突变,BRCA基因的总突变率为28.2%,其中BRCA1突变22.5%(16例),BRCA 2突变5.6%(4例),两种基因的突变率有显著性差异(P=0.004)。在39例高危家族卵巢癌患者中,有41.0%(16例)携带BRCA1或BRCA2基因致病性突变,而在32例散发性卵巢癌患者中,只有12.5%(4例)携带BRCA1或BRCA2基因致病性突变,两组比较有显著性差异(P=0.008)。20例携带的BRCA基因突变分为4种突变类型,75%(15例)的致病性基因突变为移码突变,其中碱基丢失12例和碱基插入3例；其他的基因突变分别为无义突变2例、内含子突变2例和错义突变1例。20例BRCA基因突变分布于16个不同位点,50%(8／16)的致病性突变位点为首次发现,未在乳腺癌信息中心(BIC)数据库中记录,5种位于BRCA1,3种位于BRCA2。BRCA1 5589del8在本研究中重复出现于3个相互独立的高危家族卵巢癌患者中,且之前曾在中国人群中有过报道,考虑可能为中国人群的热点突变,具有部分始祖效应。本研究的BRCA基因致病性突变以BRCA1外显子11最为常见,而非致病性基因变异的热点区域也集中于BRCA1和BRCA2两个基因的外显子11,今后应将外显子11作为BRCA基因热点区域加以研究。
本研究对高危家族卵巢癌患者与散发性卵巢癌患者、携带和未携带BRCA基因突变患者的发病年龄进行统计,没有发现明显差异。卵巢癌病理分化方面来看,低分化者占散发性卵巢癌患者的65.6%(19／32)；而在高危家族卵巢癌患者中占76.9%(32／39)；携带BRCA基因致病性突变的20例患者,低分化者达到85%(17／20),而未携带BRCA基因突变的仅66.7%(34／51),各组间的差异均有统计学意义(P<0.05)。高危家族卵巢癌患者术前血CA125水平也明显高于散发性卵巢癌患者(3018.8U／MLvs 1120.4U/ML),差异具有统计学意义；但是,两组化疗后血CA125下降的满意率和耐药率之间并没有统计学差异。高危家族卵巢癌患者比散发性卵巢癌患者总体复发时间晚,总体生存期长；携带BRCA基因致病性突变患者比未携带的患者,总体复发时间晚。本研究中,有10例乳腺-卵巢双原发癌患者,其首发肿瘤均为乳腺癌,与卵巢癌的发病间隔平均为13.1年,乳腺癌平均发病年龄仅为44.4岁。在有乳腺癌／卵巢癌家族史的患者中,肿瘤均有明显的后代发病更早的趋势；高危家族中,家族恶性肿瘤发病人数越多,携带突变机率可能越大,且消化道肿瘤的聚发较常见。
在家系分析中,来自4个独立卵巢癌高危家族的42位女性成员中,有2个家族的11个成员分别携带了BRCA基因致病性突变,突变携带率为26.2%,均位于BRCA1基因。另有一些未明意义的变异在这些家系中的分布有一定的规律：(1)携带率较高的未明意义变异点均位于BRCA1基因,而多态性位点则均位于BRCA2基因,BRCA1基因在卵巢癌高危的发病中起着较为重要的作用。(2) BRCA1 P1099Q、V1181I和IVS13+117C＞A等位点出现变异的频率较高,分别达到28.6%、7.1%和4.8%,其中,BRCA1 P1099Q分布最广,见于家族一、二、四共三个家族成员中,可能为中国人群的频发变异。(3)BRCA基因突变和变异表现为家族特异性和家族聚发现象, BRCA1 P1099Q、ⅣS13+117C＞A和BRCA2 N854K等变异均未在BIC数据库报道,值得进一步研究。(4)高危家系中的卵巢癌患者的发病年龄较小,手术病理分期偏晚,低分化和浆液性腺癌的比例较高,但对化疗敏感性较好、复发间隔较长。
结论：
本课题是目前例数最多的针对中国大陆地区高危家族卵巢癌患者和散发性卵巢癌患者BRCA1/2基因全序列的突变的对比研究。研究认为：(1)发现了一些新的致病性BRCA基因突变和尚不明意义的变异位点,其中BRCA1 5589del8重复出现,并可能具有部分始祖效应；(2)高危家族卵巢癌患者的BRCA1/2基因突变率明显高于散发性卵巢癌患者,其发病也有后代早发的趋势,因此,对于有乳腺癌-卵巢癌家族史的人群进行BRCA1/2基因突变检测是非常必要的,有利于卵巢癌／乳腺癌的预测和早期干预；(3) BRCAl基因在中国遗传性卵巢癌/乳腺癌的发病中,可能起着更为重要的作用；(4)高危家族卵巢癌患者和携带BRCA1/2基因突变的患者,虽然其肿瘤恶性程度较高,但对化疗较为敏感,预后似乎较好,仍需要大宗病例的随机对照研究给予证实；(5)不同遗传背景的患者,其肿瘤发病的遗传基础可能不同；一些未知意义的BRCA基因频发变异点很可能是中国人群特有的变异,值得进一步深入研究,以明确其临床意义。
Background & Objective:Ovarian cancer has the highest mortality rate in gynecological malignancies, and family history is one of the most important risk factors for epithelial ovarian cancer.5% to 10% of ovarian cancer is inherited, and 80% to 90% of hereditary ovarian cancer is due to the mutations of BRCA1 or BRCA2. Currently, genetic testing for BRCA1 and BRCA2 in women with a strong family history of ovarian and/or breast cancer are accepted as the most effective method for the screening of hereditary ovarian cancer. All exons of BRCA1/2 were analyzed in this study, in order to assess the prevalence of BRCA1/2 mutations among clinic-based patients from families at risk of hereditary ovarian cancer and patients with sporadic ovarian cancer in mainland China, and to compare the clinical features of patients with ovarian cancer from different genetic background.
Subjects & Methods:The inclusion criteria were:(1) patients from family at risk of hereditary ovarian cancer:①at least two first or second degree relatives with ovarian cancer and/or breast cancer in the family;②at least one relative with double primary ovarian and breast cancer; (2) patients with sporadic ovarian cancer:patient with ovarian cancer, who has no family history of ovarian and breast cancer in her first and second degree relatives, and has no breast cancer history herself. There were 71 patients from 67 independent families enrolled in our study, of which 39 patients were from families at risk of hereditary ovarian cancer, and 32 patients were sporadic.
Methods:(1) DNA was abstracted from peripheral blood, and all exons of BRCA1/2 were analyzed using DHPLC followed by direct sequencing; (2) clinical features of patients from families at risk of hereditary ovarian cancer and sporadic patients were compared by statistical analysis; (3) pedigree studies were carried out in four families at risk of hereditary ovarian cancer, and all the female members of these four families accepted DHPLC+DNA direct sequencing after informed consent were signed.
Results:Pathogenic mutations were detected in 20 of 71 patients, as the mutation rate was 28.2%, and the frequency of BRCA1 and BRCA2 mutation was 22.5% and 5.6%, respectively. The mutation rates between these two genes were of statistically significant (P=0.004). The differences of BRCA mutation rates between sporadic patients and patients from families at risk of hereditary ovarian cancer were statistically significant, too (12.5% v.s. 41.0%, P=0.008). Sixteen different pathogenic mutations sites were detected in this study and 50% of them were novel. BRCA1 5589del8 was identified in three independent families. It has been reported as a recurrent mutation in Chinese, and may be partial "founder effect" in Chinese people. Both exon 11 of BRCA1/2 have been found to be hotspots of germline mutations.
The average onset age of patients with ovarian cancer was similar between each group (patients from families at risk of hereditary ovarian cancer v.s. sporadic patients, patients with and without pathogenic mutations). The differentiation of tumor was worse but the sensitivity of chemotherapy was better in patients with pathogenic mutations and patients from families at risk of hereditary ovarian cancer. There were 10 patients with double primary ovarian and breast cancer in our study. We found that all the first primary tumor of them was breast cancer, and the average onset age was 44.4 years. The average interval between breast and ovarian cancer was 13.1 years. For the families at risk of hereditary ovarian cancer, the more family members with malignancy, the more chance for the family to carry pathogenic mutations, and gastrointestinal malignancies were also common in these families.11 out of 42 female members from the four families in our pedigree analysis were detected to have pathogenic mutations.
There were 42 female members from four independent families who accepted BRCA 1/2 gene screening in our pedigree analysis.11 members from two families carried two kinds of BRCA1 pathogenic mutations, and the mutation rate was 26.2%. Several SNPs were found on BRCA2 gene. Several mutations with a high carrier rate in the four families, which clinical importance were still unknown, were all on BRCA1 gene BRCA1 P1099Q, which had a highest carrier rate (28.6%), was detected in three families, and may be unique in Chinese. BRCA mutation with no clinical importance seems to be specificity and accumulation. BRCA1 P1099Q、IVS13+117C＞A and BRCA2 N854K were not reported in BIC database, and we need more research to prove their clinical importance in Chinese people. The patients from families at risk of hereditary ovarian cancer had younger onset age, higher grades and advanced FIGO stage tumors, but better sensitivity to chemotherapy and longer disease-free survival intervals.
Conclusions:We performed the comprehensive mutation screening of BRCA1/2 gene in sporadic patients and patients from families at risk of hereditary ovarian cancer. The mutation rate of patients from families at risk of hereditary ovarian cancer is higher than the sporadic ones, and the onset age of patients with ovarian/breast cancer may be younger in the offspring. Therefore, the genetic screening and clinical intervention is necessary and has to be performed as early as possible for the members from families at risk of hereditary ovarian cancer. BRCA1 gene may make greater impact on ovarian cancer in Chinese population. The patients with BRCA pathogenic mutations and patients from families at risk of hereditary ovarian cancer have higher grades and advanced FIGO stage tumor, but better sensitivity to chemotherapy and better prognosis. All the known pathogenic mutations cannot explain the high morbidity of some families. The etiology may be different in patients with different genetic background. The clinical importance of some amount of BRCA gene mutations detected in our research is still unknown. We need further study to confirm their clinical importance.
卵巢上皮性癌(卵巢癌)是病死率最高的妇科恶性肿瘤,家族史则被认为是最有力的肿瘤预测因素之一。研究表明,卵巢癌患者约5%～10%为遗传性,其中,遗传性卵巢癌患者中约有80～90%伴有易感基因BRCA1/2的突变。目前, BRCA1/2基因的检测已成为卵巢癌高危人群重要的筛查方法。在中国,有关高危家族卵巢癌患者和散发性卵巢癌患者的外周血BRCA1/2基因突变的研究并不深入,中国卵巢癌人群的BRCA1/2基因突变情况还未得到很好阐明。因此,为了进一步明确中国卵巢癌人群的BRCA1/2基因突变情况,本课题对高危家族卵巢癌患者和散发性卵巢癌患者进行了BRCA1/2基因全序列突变检测并进行对照分析,以了解两个基因在两组卵巢癌患者中的突变情况及差异；分析伴有BRCA1/2基因突变的卵巢癌患者的临床特点及病理学特征,以比较不同遗传背景的卵巢癌患者临床生物学的特点及差异；同时还对四个卵巢癌高危家族的女性成员进行了外周血BRCA1/2基因全序列突变检测和家系分析。
对象和方法：
研究的入选标准：(1)高危家族卵巢癌患者：①家族中至少有两个一级或二级亲属患原发性卵巢癌或卵巢癌和乳腺癌；②家族中至少有一名成员患乳腺-卵巢双原发癌,伴或不伴有直系三代血亲内其他成员患卵巢癌或乳腺癌。(2)散发性卵巢癌：没有乳腺癌／卵巢癌家族史和乳腺癌个人史的卵巢癌患者。所有卵巢癌患者的诊断均为病理诊断。最后入选的高危家族卵巢癌患者39例,散发性卵巢癌患者32例。
研究方法：(1)提取外周血单个核细胞DNA,应用变性高效液相色谱分析(DHPLC)+DNA测序,对每名患者均进行了BRCA1和BRCA2基因全外显子以及外显子内含子拼接区的突变检测；(2)对高危家族卵巢癌患者与散发性卵巢癌患者进行发病年龄、病理类型、肿瘤分期和分级、化疗敏感性等生物学特点进行统计,分析比较；(3)本研究收集了4个完整的家族性乳腺癌-卵巢癌家系,将家系中所有符合条件的女性成员进行DHPLC分析+DNA测序,并对家系的BRCA1和BRCA2基因突变特点进行分析。
结果：
共有来自35个独立高危家族的39例卵巢癌患者和32例散发性卵巢癌患者纳入本研究中。在这71例患者中,共有20例患者携带了BRCA1或BRCA2基因致病性突变,BRCA基因的总突变率为28.2%,其中BRCA1突变22.5%(16例),BRCA 2突变5.6%(4例),两种基因的突变率有显著性差异(P=0.004)。在39例高危家族卵巢癌患者中,有41.0%(16例)携带BRCA1或BRCA2基因致病性突变,而在32例散发性卵巢癌患者中,只有12.5%(4例)携带BRCA1或BRCA2基因致病性突变,两组比较有显著性差异(P=0.008)。20例携带的BRCA基因突变分为4种突变类型,75%(15例)的致病性基因突变为移码突变,其中碱基丢失12例和碱基插入3例；其他的基因突变分别为无义突变2例、内含子突变2例和错义突变1例。20例BRCA基因突变分布于16个不同位点,50%(8／16)的致病性突变位点为首次发现,未在乳腺癌信息中心(BIC)数据库中记录,5种位于BRCA1,3种位于BRCA2。BRCA1 5589del8在本研究中重复出现于3个相互独立的高危家族卵巢癌患者中,且之前曾在中国人群中有过报道,考虑可能为中国人群的热点突变,具有部分始祖效应。本研究的BRCA基因致病性突变以BRCA1外显子11最为常见,而非致病性基因变异的热点区域也集中于BRCA1和BRCA2两个基因的外显子11,今后应将外显子11作为BRCA基因热点区域加以研究。
本研究对高危家族卵巢癌患者与散发性卵巢癌患者、携带和未携带BRCA基因突变患者的发病年龄进行统计,没有发现明显差异。卵巢癌病理分化方面来看,低分化者占散发性卵巢癌患者的65.6%(19／32)；而在高危家族卵巢癌患者中占76.9%(32／39)；携带BRCA基因致病性突变的20例患者,低分化者达到85%(17／20),而未携带BRCA基因突变的仅66.7%(34／51),各组间的差异均有统计学意义(P<0.05)。高危家族卵巢癌患者术前血CA125水平也明显高于散发性卵巢癌患者(3018.8U／MLvs 1120.4U/ML),差异具有统计学意义；但是,两组化疗后血CA125下降的满意率和耐药率之间并没有统计学差异。高危家族卵巢癌患者比散发性卵巢癌患者总体复发时间晚,总体生存期长；携带BRCA基因致病性突变患者比未携带的患者,总体复发时间晚。本研究中,有10例乳腺-卵巢双原发癌患者,其首发肿瘤均为乳腺癌,与卵巢癌的发病间隔平均为13.1年,乳腺癌平均发病年龄仅为44.4岁。在有乳腺癌／卵巢癌家族史的患者中,肿瘤均有明显的后代发病更早的趋势；高危家族中,家族恶性肿瘤发病人数越多,携带突变机率可能越大,且消化道肿瘤的聚发较常见。
在家系分析中,来自4个独立卵巢癌高危家族的42位女性成员中,有2个家族的11个成员分别携带了BRCA基因致病性突变,突变携带率为26.2%,均位于BRCA1基因。另有一些未明意义的变异在这些家系中的分布有一定的规律：(1)携带率较高的未明意义变异点均位于BRCA1基因,而多态性位点则均位于BRCA2基因,BRCA1基因在卵巢癌高危的发病中起着较为重要的作用。(2) BRCA1 P1099Q、V1181I和IVS13+117C＞A等位点出现变异的频率较高,分别达到28.6%、7.1%和4.8%,其中,BRCA1 P1099Q分布最广,见于家族一、二、四共三个家族成员中,可能为中国人群的频发变异。(3)BRCA基因突变和变异表现为家族特异性和家族聚发现象, BRCA1 P1099Q、ⅣS13+117C＞A和BRCA2 N854K等变异均未在BIC数据库报道,值得进一步研究。(4)高危家系中的卵巢癌患者的发病年龄较小,手术病理分期偏晚,低分化和浆液性腺癌的比例较高,但对化疗敏感性较好、复发间隔较长。
结论：
本课题是目前例数最多的针对中国大陆地区高危家族卵巢癌患者和散发性卵巢癌患者BRCA1/2基因全序列的突变的对比研究。研究认为：(1)发现了一些新的致病性BRCA基因突变和尚不明意义的变异位点,其中BRCA1 5589del8重复出现,并可能具有部分始祖效应；(2)高危家族卵巢癌患者的BRCA1/2基因突变率明显高于散发性卵巢癌患者,其发病也有后代早发的趋势,因此,对于有乳腺癌-卵巢癌家族史的人群进行BRCA1/2基因突变检测是非常必要的,有利于卵巢癌／乳腺癌的预测和早期干预；(3) BRCAl基因在中国遗传性卵巢癌/乳腺癌的发病中,可能起着更为重要的作用；(4)高危家族卵巢癌患者和携带BRCA1/2基因突变的患者,虽然其肿瘤恶性程度较高,但对化疗较为敏感,预后似乎较好,仍需要大宗病例的随机对照研究给予证实；(5)不同遗传背景的患者,其肿瘤发病的遗传基础可能不同；一些未知意义的BRCA基因频发变异点很可能是中国人群特有的变异,值得进一步深入研究,以明确其临床意义。
Background & Objective:Ovarian cancer has the highest mortality rate in gynecological malignancies, and family history is one of the most important risk factors for epithelial ovarian cancer.5% to 10% of ovarian cancer is inherited, and 80% to 90% of hereditary ovarian cancer is due to the mutations of BRCA1 or BRCA2. Currently, genetic testing for BRCA1 and BRCA2 in women with a strong family history of ovarian and/or breast cancer are accepted as the most effective method for the screening of hereditary ovarian cancer. All exons of BRCA1/2 were analyzed in this study, in order to assess the prevalence of BRCA1/2 mutations among clinic-based patients from families at risk of hereditary ovarian cancer and patients with sporadic ovarian cancer in mainland China, and to compare the clinical features of patients with ovarian cancer from different genetic background.
Subjects & Methods:The inclusion criteria were:(1) patients from family at risk of hereditary ovarian cancer:①at least two first or second degree relatives with ovarian cancer and/or breast cancer in the family;②at least one relative with double primary ovarian and breast cancer; (2) patients with sporadic ovarian cancer:patient with ovarian cancer, who has no family history of ovarian and breast cancer in her first and second degree relatives, and has no breast cancer history herself. There were 71 patients from 67 independent families enrolled in our study, of which 39 patients were from families at risk of hereditary ovarian cancer, and 32 patients were sporadic.
Methods:(1) DNA was abstracted from peripheral blood, and all exons of BRCA1/2 were analyzed using DHPLC followed by direct sequencing; (2) clinical features of patients from families at risk of hereditary ovarian cancer and sporadic patients were compared by statistical analysis; (3) pedigree studies were carried out in four families at risk of hereditary ovarian cancer, and all the female members of these four families accepted DHPLC+DNA direct sequencing after informed consent were signed.
Results:Pathogenic mutations were detected in 20 of 71 patients, as the mutation rate was 28.2%, and the frequency of BRCA1 and BRCA2 mutation was 22.5% and 5.6%, respectively. The mutation rates between these two genes were of statistically significant (P=0.004). The differences of BRCA mutation rates between sporadic patients and patients from families at risk of hereditary ovarian cancer were statistically significant, too (12.5% v.s. 41.0%, P=0.008). Sixteen different pathogenic mutations sites were detected in this study and 50% of them were novel. BRCA1 5589del8 was identified in three independent families. It has been reported as a recurrent mutation in Chinese, and may be partial "founder effect" in Chinese people. Both exon 11 of BRCA1/2 have been found to be hotspots of germline mutations.
The average onset age of patients with ovarian cancer was similar between each group (patients from families at risk of hereditary ovarian cancer v.s. sporadic patients, patients with and without pathogenic mutations). The differentiation of tumor was worse but the sensitivity of chemotherapy was better in patients with pathogenic mutations and patients from families at risk of hereditary ovarian cancer. There were 10 patients with double primary ovarian and breast cancer in our study. We found that all the first primary tumor of them was breast cancer, and the average onset age was 44.4 years. The average interval between breast and ovarian cancer was 13.1 years. For the families at risk of hereditary ovarian cancer, the more family members with malignancy, the more chance for the family to carry pathogenic mutations, and gastrointestinal malignancies were also common in these families.11 out of 42 female members from the four families in our pedigree analysis were detected to have pathogenic mutations.
There were 42 female members from four independent families who accepted BRCA 1/2 gene screening in our pedigree analysis.11 members from two families carried two kinds of BRCA1 pathogenic mutations, and the mutation rate was 26.2%. Several SNPs were found on BRCA2 gene. Several mutations with a high carrier rate in the four families, which clinical importance were still unknown, were all on BRCA1 gene BRCA1 P1099Q, which had a highest carrier rate (28.6%), was detected in three families, and may be unique in Chinese. BRCA mutation with no clinical importance seems to be specificity and accumulation. BRCA1 P1099Q、IVS13+117C＞A and BRCA2 N854K were not reported in BIC database, and we need more research to prove their clinical importance in Chinese people. The patients from families at risk of hereditary ovarian cancer had younger onset age, higher grades and advanced FIGO stage tumors, but better sensitivity to chemotherapy and longer disease-free survival intervals.
Conclusions:We performed the comprehensive mutation screening of BRCA1/2 gene in sporadic patients and patients from families at risk of hereditary ovarian cancer. The mutation rate of patients from families at risk of hereditary ovarian cancer is higher than the sporadic ones, and the onset age of patients with ovarian/breast cancer may be younger in the offspring. Therefore, the genetic screening and clinical intervention is necessary and has to be performed as early as possible for the members from families at risk of hereditary ovarian cancer. BRCA1 gene may make greater impact on ovarian cancer in Chinese population. The patients with BRCA pathogenic mutations and patients from families at risk of hereditary ovarian cancer have higher grades and advanced FIGO stage tumor, but better sensitivity to chemotherapy and better prognosis. All the known pathogenic mutations cannot explain the high morbidity of some families. The etiology may be different in patients with different genetic background. The clinical importance of some amount of BRCA gene mutations detected in our research is still unknown. We need further study to confirm their clinical importance.
引文
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[1]Nelson HD, Huffman LH, Fu R, et al. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility:systematic evidence review for the U.S. Preventive Services Task Force [J]. Ann Intern Med,2005,143(5):362-79.
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[1]Lynch HT, Snyder CL, Lynch JF, et al. Hereditary breast-ovarian cancer at the bedside:role of the medical oncologist [J]. J Clin Oncol,2003,21:740-753.
[2]Szabo CI, King MC. Inherited breast and ovarian cancer [J]. Hum Mol Genet 1995; 4: 1811-1817.
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[2]Dimitrios H Roukos, Evangelos Briasoulis. Individualized preventive and therapeutic management of hereditary breast ovarian cancer syndrome [J]. Nature Clinical Practice Oncology,2007,4(10):578-90.
[3]Neuhausen S, Gilewski T, Norton L, et al. Recurrent BRCA26174delT mutations in Ashkenazi Jewish women affected by breast cancer[J]. Nat Genet,1996,13(1):126-128.
[4]Struewing JP, Abeliovich D, Peretz T et al. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals [J]. Nat Genet 1995; 11(2):198-200.
[5]Loman N, Johannsson O, Kristoffersson U, et al. Family history of breast and ovarian cancers and BRCA1 and BRCA2.mutations in a population-based series of early-onset breast cancer [J]. J Natl Cancer Inst,2001,93(16):1215-1223.
[6]Nanda R, Schumm LP, Cummings S, et al. Genetic testing in an ethnically diverse cohort of high-risk women:a comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry [J]. JAMA,2005,294(15): 1925-1933.
[7]Warner E, Foulkes W, Goodwin P, et al. Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unseleeted Ashkenazi Jewish women with breast cancer [J]. J Natl Caneer Inst,1999,91(14):1241-1247.
[8]Ikeda N, Miyoshi Y, Yoneda K, et al. Frequency of BRCA1 and BRCA2 germline mutations in Japanese breast cancer families [J]. Int J Cancer,2001,91(1):83-88.
[9]Gayther SA, Harrington P, Russell P, et al. Frequently occurring germ-line mutations of the BRCA1 gene in ovarian cancer families from Russia [J]. Am J Hum Genet,1997, 60(5):1239-1242.
[10]Roa BB, Boyd AA, Volcik K, et al. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2 [J]. Nat Genet,1996,14(2):185-187.
[11]Neuhausen S, Gilewski T, Norton L, et al. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer [J]. Nat Genet,1996; 13(1): 126-128.
[12]Thorlacius S, Olafsdottir G, Tryggvallottir L, et al. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes [J]. Nat Genet,1996, 13(1):117-9.
[13]Sekine M, Nagata H, Tsuji S, et al.Mutational Analysis of BRCA1 and BRCA2 and clinicopathologic analysis of ovarian cancer in 82 ovarian cancer families:Two common founder mutations of BRCA1 in Japanese population[J]. Clin Caner Res,2001,7(10): 3144-50.
[14]Tang NL, Pang CP, Yeo W, et al. Prevalence of mutations in the BRCA1 gene among Chinese patients with breast cancer [J]. J Natl Cancer Inst,1999,91(10):882-885.
[15]Khoo US, Chan KY, Cheung AN, et al. Recurrent BRCA1 and BRCA2 germline mutations in ovarian cancer:A founder mutation of BRCA1 identified in the Chinese population [J]. Hum Mutat,2002,19(3):307-8.
[16]Kwong A, Wong LP, Wong HN, et al. A BRCA2 founder mutation and seven novel deleterious BRCA mutations in southern Chinese women with breast and ovarian cancer [J]. Breast Cancer Res Treat,2009,117(3):683-6.
[17]Sng JH, Chang J, Feroze F, et al. The Prevalence of BRCA1 mutations in Chinese patients with early onset breast cancer and affected relatives [J]. Br J Cancer,2000,82(3): 538-42.
[18]Li SS, Tseng HM, Yang TP, et al. Molecular charaeterization of germline mutations in the BRCA1 and BRCA2 genes from breast cancerf amilies in Taiwan [J]. Hum Genet, 1999,104(3):201-4.
[19]饶南燕,周婕,赵林等,219例中国汉族遗传性乳腺癌患者BRCA1和BRCA2突变的研究[J].中国癌症杂志,2008,18(5)：370-375.
[20]Miki Y, Swensen J, Shattuck Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1 [J]. Science,1994,266(5182):66-71.
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