散发性乳腺癌中BRCA1基因突变

为探讨散发性乳腺癌发生的分子机理与ＢＲＣＡ１基因异常的关系，应用聚合酶链反应（ＰＣＲ）结合单链构象多态性分析（ＳＳＣＰ）和核酸序列分析方法，研究了２０例散发性乳腺癌组织和６例正常人外周血样品中ＢＲＣＡ１基因外显子５、１１区域的突变情况。结果显示：２０例散发性乳腺癌组织中，２例在外显子１１（ｎｔ３５５２－ｎｔ３８０４区域）发生突变；１例在ｎｔ３６６７发生Ａ→Ｇ点突变；另一例在该区域上发生约３５０ｂｐ的大片段插入突变。表明编码区基因突变引起的ＢＲＣＡ１失活可能至少与少部分散发性乳腺癌的发生有关，同时也证实了ＢＲＣＡ１基因对乳腺癌的肿瘤抑制功能，为乳腺癌的病因学研究提供了有用的资料。     

中国福建遗传性乳腺癌BRCA1基因突变分析

目的研究福建遗传性乳腺癌患者BRCA1基因突变位点及携带情况。方法对20例遗传性乳腺癌患者血液标本进行检测,对其BRCA1基因第11号外显子全序列进行DNA测序。结果20例标本中检出5患者存在共计9种BRCA1基因突变,其中3个为新发现位点（错义突变1159T〉C,4071A〉C;同义突变4122C〉T）;其它6个已报道位点中2个（2201C〉T,2430T〉C）为同义突变,其余4个（2685T〉C,2731C〉T,3232A〉G,3667A〉G）属错义突变,本研究中BRCA1突变率为25%。结论福建遗传性乳腺癌患者BRCA1基因突变具有地域性特征,开展BRCA1基因突变检测有助于本地区女性患癌风险评估和早期诊断。     

维吾尔族及汉族早发性乳腺癌 BRCA1基因突变分析

目的研究维吾尔族及汉族早发性乳腺癌患者BRCA1突变情况及突变位置。方法选取35例维吾尔族及汉族早发性乳腺癌根治标本（其中维吾尔族早发性乳腺癌22例,汉族乳腺癌13例）,对照组为32例维汉族乳腺良性病变（纤维腺病及纤维腺瘤）及乳腺癌旁非癌组织;运用PCR—SSCP和DNA序列测定的方法检测BRCA1基因突变。结果（1）35例新疆早发性乳腺癌（≤35岁）BRCA1突变率为22．86％（8／35）,22例维吾尔族早发性乳腺癌BRCA1突变率为31．82％（7／22）。（2）35例新疆早发性乳腺癌中发现8例BRCA1突变的12个新位点,其中2例突变位点IVS20-68insA均为维吾尔族早发性乳腺癌患者。（3）35例新疆早发性乳腺癌中发现7例BRCA1基因核苷酸多态性,对照组32例维吾尔族及汉族乳腺癌旁非癌组织及乳腺良性病变中仅发现1例BRCA1基因核苷酸的多态性。结论BRCA1突变可能与新疆早发性乳腺癌尤其是维吾尔族早发性乳腺癌密切相关,其突变位点IVS20—68insA可能是新疆维吾尔族早发性乳腺癌的遗传易感性位点,尚需扩大样本进一步研究证实。     

中国乳腺癌患者BRCA1基因突变的研究

目的　在中国乳腺癌患者 BRCA1基因外显子 2、2 0和 11部分序列中寻找突变位点 ,探讨其与乳腺癌发病的关系。方法收集 86例无血缘关系的乳腺癌患者 ,用聚合酶链反应 -双链四色荧光标记的方法 ,分析 BRCA1基因的外显子 2和 2 0的全长序列和外显子 11的部分序列。结果　外显子 2、2 0和 11的序列中均未发现有突变 ,仅在外显子 11A的序列上有一个 C/ T多态 ,基因型频率高达 4 2 %。对这个高频单核苷酸多态 (single nucleotide ploymorphism,SNP)位点 ,先作了 Hardy- Weinberg检测 ,P>0 .0 5 ,确定这个 SNP的频率不受杂合性缺失的影响。再进行 χ2检测 ,与正常对照组进行比较 ,P>0 .1,两者差异无显著性。结论　这个高频 SNP位点与乳腺癌的发生无显著相关 ;在中国人群中没有发现其他乳腺癌患者人群中普遍存在的这几个突变热点 ,说明外显子 2、2 0和 11上的这部分序列对中国人群的乳腺癌发生影响不大。     

早发性乳腺癌/卵巢癌BRCA1基因突变分析

目的探讨中国北方地区汉族人群早发性乳腺癌和卵巢癌与BRCA1基因的关系.方法应用聚合酶链反应-单链构象多态性分析和DNA直接测序法检测BRCA1基因外显子2和外显子11部分序列.结果对12例早发性乳腺癌/卵巢癌患者PCR-SSCP的检测中,在外显子2发现1例突变,经DNA测序证实突变为第166碱基插入碱基"C".结论 BRCA1基因突变可能与北方地区汉族人群早发性乳腺癌有关.     

山东半岛地区家族性和早发性乳腺癌BRCA2基因突变研究

目的 研究山东半岛地区家族性和早发性乳腺癌中乳腺癌易感基因BRCA2的突变位点及携带情况.方法 应用PureGene DNA纯化系统提取52例家族性和早发性乳腺癌患者的外周血单核细胞DNA,对BRCA2基因的全部编码序列及内含子和外显子拼接区进行扩增,扩增产物用变性高效液相色谱进行初筛,对发现异常片段经重新扩增后进行DNA测序证实.结果 在52例乳腺癌患者中发现3个(5.8%)BRCA2的致病性突变(2001delTTAT,4099＞T,5873C＞A).其中,家族性乳腺癌突变率达到12%(3/25),在单纯早发性乳腺癌病例中未发现致病性突变.结论 在家族性乳腺癌患者中,BRCA2基因突变可能具有重要作用,在此人群中有必要进行相关的基因检测.     

新疆地区维吾尔族乳腺癌BRCA1基因突变分析

目的研究新疆地区维吾尔族乳腺癌患者BRCA1基因突变情况及突变位置。方法选取70例维吾尔族乳腺癌根治标本,对照组为32例维汉族乳腺良性病变（纤维腺病及纤维腺瘤）及乳腺癌旁非癌组织;应用PCR-单链构象多态性和DNA序列测定的方法检测BRCA1基因突变。结果（1）70例维吾尔族乳腺癌中发现9例BRCA1突变的12个新位点。（2）70例维吾尔族乳腺癌BRCA1的突变率为12.86%（9/70）,22例维吾尔族早发性乳腺癌（≤35岁）BRCA1突变率为31.82%（7/22）。维吾尔族早发性乳腺癌BRCA1突变率（7/22）高于维吾尔族晚发性乳腺癌（2/48）,差异有统计学意义（χ^2=10.295,P〈0.01）。（3）70例维吾尔族乳腺癌中发现9例BRCA1基因核苷酸多态性位点,其中8例多态性位点均为3232A〉G。（4）2例双侧乳腺癌中均检测出BRCA1基因的突变。结论BRCA1突变可能与新疆维吾尔族乳腺癌尤其是维吾尔族早发性乳腺癌及双侧乳腺癌的发生密切相关。     

中国福建遗传性乳腺癌BRCAl基因突变分析

目的 研究福建遗传性乳腺癌患者BRCAI基因突变位点及携带情况.方法 对20例遗传性乳腺癌患者血液标本进行检测,对其BRCA1基因第11号外显子全序列进行DNA测序.结果 20例标本中检出5患者存在共计9种BRCA1基因突变,其中3个为新发现住点(错义突变1159T>C,4071A>C;同义突变4122C>T);其它6个已报道位点中2个(2201C>T,2430T>C)为同义突变,其余4个(2685T>C,2731C>T,3232A>G,3667A>G)属错义突变,本研究中BRCA1突变率为25%.结论 福建遗传性乳腺癌患者BRCA1基因突变具有地域性特征,开展BRCA1基因突变检测有助于本地区女性患癌风险评估和早期诊断.     

维吾尔族和汉族散发性乳腺癌患者BRCA1/2基因突变的检测

目的探讨新疆维吾尔族和汉族散发性乳腺癌患者乳腺癌易感基因1/2(BRCA1/2)突变情况及与临床病理参数的关系。方法采用PCR和DNA直接测序法,对新疆地区230例散发性乳腺癌患者(维吾尔族、汉族各115例)石蜡组织进行BRCA1基因第2、11(11A和11B)、20号外显子和BRCA2基因第11号部分外显子,共5对引物进行突变检测。结果 230例乳腺癌患者中,BRCA基因突变率为6.96%(16/230),其中1例BRCA1基因-5 382位点的突变及7例新发突变位点;维吾尔族和汉族患者中BRCA基因突变检出率分别为7.83%(9/115)和6.09%(7/115);BRCA基因突变组发病年龄均≤50岁;突变组16例患者中绝经前患者(13例)的突变率明显高于绝经后患者(3例)(P0.05)。结论 BRCA1基因突变可能与新疆地区散发性乳腺癌发生相关。     

中国乳腺癌患者BRCA1基因的频发突变5589del8

目的研究在中国大陆乳腺癌人群中是否存在BRCAI／2基因突变的“热点”。方法研究对象为来自全国4个乳腺癌医疗中心的177例家族性和早发性乳腺癌患者和426例散发性乳腺癌患者,根据前期研究中已发现的BRCAI／2基因突变位点,应用变性高效液相色谱分析和DNA测序技术对这些患者进行已知位点的突变检测。结果在前期研究的70例家族性和早发性乳腺癌患者和本研究的177例患者（共247例）中,共发现3例BRCAl5589del8突变的携带者,在426例散发性乳腺癌患者中也发现了2例BRCAl5589del8突变的携带者。单倍型分析的结果显示这5例患者具有相近甚至相同的单倍型。结论BRCAl5589del8突变是中国人群中BRCAl基因的频发突变,它是否是中国人群中的“始祖突变”仍需进一步研究证实。     

Contribution of BRCA1 and BRCA2 germline mutations to the incidence of early-onset breast cancer in Cyprus

In Cyprus, the prevalence of breast cancer associated with BRCA1 and BRCA2 mutations in young women is unknown. In this study, we present the results of mutational analysis of the BRCA1 and BRCA2 genes in 26 Cypriot women diagnosed with breast cancer by the age of 40. The entire coding regions, including splice sites, of the BRCA1 and BRCA2 genes were sequenced using cycle sequencing. We identified four pathogenic mutations: two in BRCA1 [c.1840A>T (K614X), c.5310delG (5429delG)] and two in BRCA2 [c.3531-3534delCAGC (3758del4), c.8755delG (8984delG)] in six of 26 unrelated patients. The BRCA2 mutation c.3531-3534delCAGC (3758del4) is novel and the BRCA1 mutation c.1840A>T (K614X) is reported for the first time in Cypriot patients. The BRCA2 Cypriot founder mutation c.8755delG (8984delG) was detected in three unrelated patients. Additionally, we identified one novel BRCA1 missense mutation, two novel polymorphisms and three novel intronic variants of which BRCA1 c.4185+3A>G (IVS12+3A>G) may be pathogenic. Of the six BRCA1/2 mutation carriers, only four had a family history. These results show that the prevalence of BRCA1 and BRCA2 mutations in Cypriot women diagnosed with early-onset breast cancer is high. We conclude that Cypriot women with early-onset breast cancer should be offered BRCA1/2 testing irrespective of their family history.     

中国上海家族性乳腺癌BRCA1和BRCA2基因的突变

目的研究上海地区家族性乳腺癌中BRCA1／BRCA2基因的突变位点及携带情况。方法研究对象来自35个汉族家族性乳腺癌家系，家系中至少有一个一级亲属乳腺癌患病史。共35例患者，其中13例发病年龄≤加岁。由静脉血提取基因组DNA，对BRCA1／BRCA2基因的全部编码序列进行扩增。扩增产物突变分析先由变性高效液相色谱分析进行筛查，之后进行DNA直接测序证实。结果在BRCA1基因中发现有4个突变位点，其中2个为新发现位点——拼接点突变（IVS17-1G〉T；IVS21＋1G〉C）；另两个为已报道的致病突变位点——移码突变（1100delAT；5640delA）。BRCA2基因的1个致病突变位点位于11号外显子上，为移码突变（5802delAATT）。另外，共发现有12个新的单核苷重复多态位点，都未引起氨基酸编码改变；其中，8个在BRCA1基因上，4个在BRCA2基因上。在家族性乳腺癌中，BRCA1突变频率（11．4％）高于BRCA2基因（2．9％）。结论新发现的2个BRCA1基因的拼接点突变可能是中国上海人群家族性乳腺癌的特有突变位点；在我国上海地区人群中，BRCA1基因突变起着比BRCA2基因更大的作用；该研究丰富了中国人群中BRCA基因的突变谱，并为未来的临床基因检测提供了筛查模式。     

ATM germline mutations in Spanish early-onset breast cancer patients negative for BRCA1/BRCA2 mutations

Heterozygous carriers of ATM (ataxia telangiectasia mutated gene) mutations have increased risk of breast cancer (BC). We have estimated the prevalence of mutations in the ATM gene among Spanish patients with early-onset BC. Forty-three patients diagnosed with BC before the age of 46 years, and negative for BRCA1 and BRCA2 mutations, were analysed for the presence of ATM mutations. A total of 34 ATM sequence variants were detected: 1 deleterious mutation, 10 unclassified variants and 23 polymorphisms. One patient (2.3%) carried the ATM deleterious mutation (3802delG that causes ataxia telangiectasia in the homozygous state) and 13 patients carried the 10 ATM unclassified variants. The truncating mutation 3802delG and eight of the rare variants were not detected in a control group of 150 individuals. Different bioinformatic sequence analysis tools were used to evaluate the effects of the unclassified ATM changes on RNA splicing and function protein. This in silico analysis predicted that the missense variants 7653 T>C and 8156 G>A could alter the splicing by disrupting an exonic splicing enhancer motif and the 3763 T>G, 6314 G>C, and 8156 G>A variants would affect the ATM protein function. These are the initial results concerning the prevalence of germline mutations in the ATM gene among BC cases in a Spanish population, and they suggest that ATM mutations can confer increased susceptibility to early-onset BC.     

BRCA1 and BRCA2 mutation analysis of early-onset and familial breast cancer cases in Mexico

The entire coding regions of BRCA1 and BRCA2 were screened for mutations by heteroduplex analysis in 51 Mexican breast cancer patients. One BRCA1 and one BRCA2 truncating mutation each was identified in the group of 32 (6%) early-onset breast cancer patients (< or =35 years). Besides these two likely deleterious mutations, eight rare variants of unknown significance, mostly in the BRCA2 gene, were detected in six of 32 (19%) early-onset breast cancer cases and in three of 17 (18%) site-specific breast cancer families, one containing a male breast cancer case. No mutations or rare sequence variants have been identified in two additional families including each an early-onset breast cancer case and an ovarian cancer patient. The two truncating mutations (BRCA1 3857delT; BRCA2 2663-2664insA) and six of the rare variants have never been reported before and may be of country-specific origin. The majority of the alterations appeared to be distinct, with only one of them being observed in more than one family.     

三阴性乳腺癌患者BRCA1和BRCA2基因突变的临床特征及预后因素

目的:探究三阴性乳腺癌患者BRCA1和BRCA2基因突变检测的临床意义及预后因素分析.方法:研究对象选取为2003年1月至2015年12月之间的三阴性乳腺癌156例,所有患者均通过PCR法和DNA序列测定检验BRCA1和BRCA2基因突变情况,分析乳腺癌患者BRCA1和BRCA2基因突变特点.应用Log-Rank检验对BRCA1和/或BRCA2基因突变的三阴性乳腺癌患者的各项指标如年龄、ECOG状态、临床分期、淋巴结阳性数、月经状态和给药方式进行单因素分析.应用Cox风险比例回归模型分析患者年龄、ECOG状态、临床分期、淋巴结阳性数、肿瘤大小、月经状态和给药方式等多因素分析.结果:三阴乳腺癌患者发生基因突变21例,总体发生率13.46％,BRCA1突变15例,BRCA2突变6例.Log-Rank检验结果显示,发病年龄越大,ECOG评分越高,临床分期越晚,淋巴结阳性数越多,预后越差(P＜0.05),而发病时月经状态和给药方式与预后无关.COX风险比例回归模型显示,肿瘤大小(相对危险度,3.163;95％CI:1.455～9.287;P＜0.05)和淋巴结转移数(相对危险度,1.859;95％CI:1.254～6.875;P＜0.05)是BRCA基因突变三阴性乳腺癌独立的预后因素.结论:BRCA1和BRCA2基因突变可能与乳腺癌尤其是三阴乳腺癌可能有着密切的相关性,发病年龄、ECOG评分,临床分期和淋巴结阳性数及肿瘤大小与BRCA基因突变的三阴乳腺癌预后有关.     

BRCA1 mutations in Algerian breast cancer patients: high frequency in young, sporadic cases

Breast cancer rates and median age of onset differ between Western Europe and North Africa. In Western populations, 5 to 10 % of breast cancer cases can be attributed to major genetic factors such as BRCA1 and BRCA2, while this attribution is not yet well defined among Africans. To help determine the contribution of BRCA1 mutations to breast cancer in a North African population, we analysed genomic DNA from breast cancer cases ascertained in Algiers. Both familial cases (at least three breast cancers in the same familial branch, or two with one bilateral or diagnosed before age 40) and sporadic cases less than 38 years of age were studied. Complete sequencing plus quantitative analysis of the BRCA1 gene was performed. 9.8 % (5/51) of early-onset sporadic and 36.4 % (4/11) of familial cases were found to be associated with BRCA1 mutations. This is in contrast 10.3 % of French HBOC families exhibiting a BRCA1 mutation. One mutation, c.798_799delTT, was observed in two Algerian families and in two families from Tunisia, suggesting a North African founder allele. Algerian non-BRCA1 tumors were of significantly higher grade than French non-BRCA tumors, and the age at diagnosis for Algerian familial cases was much younger than that for French non-BRCA familial cases. In conclusion, we observed a much higher frequency of BRCA1 mutations among young breast cancer patients than observed in Europe, suggesting biological differences and that the inclusion criterea for analysis in Western Europe may not be applicable for the Northern African population.     

The contribution of founder mutations in BRCA1 to breast cancer in Belarus

Uglanitsa N, Oszurek O, Uglanitsa K, Savonievich E, Lubiński J, Cybulski C, Debniak T, Narod SA, Gronwald J. The contribution of founder mutations in BRCA1 to breast cancer in Belarus. Mutations in the BRCA1 gene increase susceptibility to both breast and ovarian cancer. In some countries, including several in Eastern Europe, founder mutations in the BRCA1 gene are responsible for a significant proportion of breast cancer cases. To estimate the hereditary proportion of breast cancer in Belarus, we sought the presence of any of three founder mutations in BRCA1 (4153delA, 5382insC and C61G) in 500 unselected cases of breast cancer. These mutations have previously been identified in breast/ovarian cancer families from Belarus and from other Slavic countries, including Poland and Russia. One of the three founder mutations in BRCA1 was present in 38 of 500 unselected cases of breast cancer (7.6%). A mutation was found in 12.6% of women diagnosed before age 50 and 5.6% of women diagnosed after age 50. A mutation was identified in 2 of 251 newborn controls (0.8%). The hereditary proportion of breast cancers in Belarus is among the highest of any countries studied to date.