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。     

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。     

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.     

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。     

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.     

中国早发性乳腺癌患者中BRCA1基因突变分析

目的研究中国早发性乳腺癌患者中BRCA1基因致病性突变的发生情况以及家族史在突变携带者识别中的作用。方法研究对象为来自中国4个乳腺癌临床医疗中心的188例早发性乳腺癌病例(发病年龄≤40岁),其中39例(20.1%)有乳腺/卵巢癌家族史。从外周静脉血提取基因组DNA,对BRCA1基因的全部编码区和外显子/内含子拼接区进行PCR扩增。其中22例通过单链构象多态方法进行突变初筛,166例用变性高效液相色谱分析进行初筛;对发现的异常片段通过DNA直接测序的方法进行确认。对发现重复出现突变的样本,选取5个与BRCA1基因连锁的标记(D17S855、D17S1322、D17S1323、D17S1326和D17S1327)进行等位基因型分析。结果在15例(8.0%)患者中发现有12个BRCA1基因的致病性突变,其中BRCA11100delAT和5589del8突变分别在3个和2个患者中发现。在39例同时伴有乳腺/卵巢癌家族史的病例中共发现有9例(23.1%)携带突变。有(无)乳腺癌家族史的早发性乳腺癌病例间BRCA1基因的突变率的差异有统计学意义(P=0.001)。重复出现的突变在所有检测病例中出现的频率为2.7%,在所有检测到的突变中占33.3%。两个来自中国北方的BRCA11100delAT突变携带病例有相同的等位基因型,而与来自上海地区的此突变携带者的等位基因型在D17S1322位点上有所差异。两例5589del8突变携带者在所检测的5个STR位点上有完全相同的等位基因型。结论这是到目前为止较大规模的关于中国早发性乳腺癌人群的BRCA1基因突变的研究,有助于增加对中国早发性乳腺癌人群中BRCA1基因致病性突变分布的全面认识。在中国早发性乳腺癌人群中,BRCA1基因致病性突变在肿瘤的发生中有比较重要的意义,尤其在伴有乳腺/卵巢癌家族史病例中该基因突变的意义尤为突出。两个重复出现的突变可能在中国人群中有始祖效应,在进行全基因检测前对其先进行检测可能非常合算。     

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。     

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.     

海南西部地区乳腺癌患者 BRCA1 / 2 基因突变状态分析

目的 不同的区域及种族的 BRCA1 / 2 基因突变频率差异较大, 着重分析海南西部地区乳腺癌患 者 BRCA1 / 2 基因的突变状态及对患者预后的影响。 方法 选取 2015 年 10 月 ~ 2020 年 12 月在海南西部中 心医院住院并确诊为原发性乳腺癌的 256 例患者为研究对象, 采用变性高效液相色谱法 ( denaturing high performance liquid chromatography, DHPLC) 筛查乳腺癌患者是否存在 BRCA1 / 2 基因突变, 分析 BRCA1 / 2 基 因突变状态及 BRCA1 / 2 基因突变患者的临床特征, 并随访分析患者 5 年生存情况, COX 回归分析影响患者 预后的因素。 结果 256 例乳腺癌患者中共检出 53 例患者发生 BRCA1 / 2 基因突变, 其中 BRCA1 突变率 12. 11 % (31 / 256), BRCA2 突变率 8. 59 % (22 / 256), 其中有害变异率为 7. 03 % (18 / 256)。 BRCA1 / 2 基 因突变患者家族病史、 妇科疾病史、 乳腺疾病史、 雌激素受体 (estrogen receptor, ER)、 原癌基因 (CerbB2) 蛋白阳性比例以及临床病理分级、 临床分期与未突变患者比较差异有统计学意义 (P< 0. 05)。 患者总 体生存率为 83. 59 % , BRCA1 / 2 基因突变者生存率低于未突变者 (P< 0. 05), COX 回归分析显示, BRCA1 / 2 基因突变、 乳腺疾病史、 临床分期、 CerbB-2 阳性、 CEA、 CA199 均是影响乳腺癌患者生存的危险因素 (P< 0. 05)。 结论 通过 DHPLC 可有效筛查海南西部地区乳腺癌患者 BRCA1 / 2 基因的有害变异, BRCA1 / 2 基因突变与临床病理特征及预后密切相关。     

CHEK2基因c.1100delC与中国人遗传性乳腺癌易感性的关联研究

目的研究上海地区非BRCA1／2基因突变的遗传倾向乳腺癌中CHEK2基因c．1100delC突变的携带情况及可能的作用。方法研究对象来自114例遗传倾向性乳腺癌，包括家族性乳腺癌76例，其中8例发病年龄低于40岁；38例单纯早发性乳腺癌（发病年龄〈40岁）。对照组为121名无乳腺癌的健康女性，静脉血中提取基因组DNA，对CHEK2基因的第10～14外显子进行长片段PCR扩增，PCR产物再进行含突变的第10外显子的扩增。突变分析全部由DNA直接测序进行鉴定。结果研究人群和对照人群中都没有发现c．1100delC的突变；在3例（3／114，2．6％）家族性乳腺癌中发现邻近c．1100delC的新的错义突变位点1111C〉T（p-His371 Tyr），对照组中则无此突变发现。结论CHEK2基因c．1100delC突变可能是中国人群罕见的突变位点，在中国人乳腺癌遗传易感性中的作用非常有限；1111C〉T可能与中国上海地区遗传倾向乳腺癌低度外显的易感性有关，需要进行进一步研究确认。     

BRCA1 and BRCA2 founder mutations in patients with bilateral breast cancer

Bilateral breast cancer is traditionally considered an indirect indicator of inherited predisposition to cancer. To appreciate the contribution of genetic determinants to bilateral breast cancer in Jewish women we genotyped 55 such women for the three predominant mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) that account for the overwhelming majority of BRCA mutations in high-risk Jewish families. Among women with bilateral breast cancer, 17 mutation carriers (17/55; 29.6%) were identified. Individual mutation frequencies were 18.5% (10/55) for 185delAG, 3.7% (2/55) for 5382insC and 7.4% (5/55) for 6174delT. Carrier rate was significantly higher (P < 0.0016) in women with bilateral breast cancer whose first tumour was diagnosed at or before 42 years of age (82%; 14/17) than in women diagnosed after 42 years of age (7.9%; 3/38). Among patients with bilateral breast cancer and positive family history 45% (14/31) carried a BRCA mutation. Of these 86% (12/14) had one breast cancer diagnosed at or before 42 years of age. Our results suggest that bilateral breast cancer per se, in most cases, does not reflect genetic predisposition, unless associated with early age of onset (first tumour diagnosed at or before 42 years of age). Although the relationship between young age and carrier state in women with bilateral breast cancer is strong, no significant association between family history and carrier state was found. We can thus speculate that women with early onset breast cancer who carry a BRCA1 or BRCA2 mutation are prone to acquire a second breast tumour.     

The analysis of BRCA1 mutations in eastern Chinese patients with early onset breast cancer and affected relatives

To study the BRCA1 mutations in eastern Chinese patients with early onset breast cancer and affected relatives, 41 patients' genomic DNA from peripheral mononuclear blood cells was studied by using single strand conformational polymorphism (SSCP) and DNA sequencing. The BRCA1 mutations were detected in the whole gene sequence. Three novel disease-causing mutations (c.582C>T, c.735C>T and c.2790delT) occurred in all the patients. Two occurred in the patients younger than 35 years old (9.1%) and one in the patients with affected relatives (5%). Additional sequence variants identified included a novel missense mutation of unknown significance and six polymorphisms. The prevalence of BRCA1 mutations in Chinese patients in Shanghai with early onset breast cancer is similar to that observed in western women, but the incidence of mutations in breast cancer patients in Shanghai with affected relatives isn't as high as that in western women.     

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。     

Characterization of ten novel and 13 recurring BRCA1 and BRCA2 germline mutations in Italian breast and/or ovarian carcinoma patients. Mutations in brief no. 178. Online

Germline mutations in the BRCA1 and BRCA2 genes are associated with approximately 80% of families with a high incidence of breast and/or ovarian cancers (OMIM database reference numbers: 113705, 600185). Furthermore, constitutional mutations in the these genes have been reported in women with early-onset breast carcinoma and without family history of cancer. We analyzed by protein truncation test (PTT) and single strand conformation polymorphism (SSCP) followed by sequence analysis, BRCA1 exons 11 and 20 and BRCA2 exons 10 and 11 in 142 Italian cancer patients. These included six male breast cancer cases, 61 women with breast carcinoma diagnosed before 36 years old and selected independently of family history of breast cancer and 75 familial breast and/or ovarian cancer patients. In a previous report, we described 11 different BRCA1 mutations in a subset of 70 cases. Here, we report the characterization of 23 additional mutations, 14 in BRCA1 and 9 in BRCA2, subsequently identified. Ten mutations were not previously described, while the other 13 were recurrent. Of the 61 women with early-onset breast cancer, 11 carried a germline mutation in BRCA1 (18.0%) and four in BRCA2 (6.6%). These frequencies indicate that BRCA1/BRCA2 genetic tests should be advised to women with breast cancer diagnosed at early age, independently of family history of cancer.     

Germline mutations in the BRCA1 and BRCA2 genes in Turkish breast/ovarian cancer patients

In this study we genotyped Turkish breast/ovarian cancer patients for BRCA1/BRCA2 mutations: protein truncation test (PTT) for exon 11 BRCA1 of and, multiplex PCR and denaturing gradient gel electrophoresis (DGGE) for BRCA2, complemented by DNA sequencing. In addition, a modified restriction assay was used for analysis of the predominant Jewish mutations: 185delAG, 5382InsC, Tyr978X (BRCA1) and 6174delT (BRCA2). Eighty three breast/ovarian cancer patients were screened: twenty three had a positive family history of breast/ovarian cancer, ten were males with breast cancer at any age, in eighteen the disease was diagnosed under 40 years of age, one patient had ovarian cancer in addition to breast cancer and one patient had ovarian cancer. All the rest (n=30) were considered sporadic breast cancer cases. Overall, 3 pathogenic mutations (3/53-5.7%) were detected, all in high risk individuals (3/23-13%): a novel (2990insA) and a previously described mutation (R1203X) in BRCA1, and a novel mutation (9255delT) in BRCA2. In addition, three missense mutations [two novel (T42S, N2742S) and a previously published one (S384F)] and two neutral polymorphisms (P9P, P2532P) were detected in BRCA2. Notably none of the male breast cancer patients harbored any mutation, and none of the tested individuals carried any of the Jewish mutations. Our findings suggest that there are no predominant mutations within exon 11 of the BRCA1 and in BRCA2 gene in Turkish high risk families.     

The contribution of founder mutations to early-onset breast cancer in French-Canadian women

In an ethnically‐homogeneous population, it is valuable to identify founder mutations in cancer‐predisposing genes. Founder mutations have been found in four breast‐cancer‐predisposing genes in French‐Canadian breast cancer families. The frequencies of the mutant alleles have been measured neither in a large series of unselected breast cancer patients from Quebec, nor in healthy controls. These estimates are necessary to measure their contribution to the hereditary burden of breast cancer in Quebec and to help develop genetic screening policies which are appropriate for the province. We studied 564 French‐Canadian women with early‐onset invasive breast cancer who were treated at a single Montreal hospital. Patients had been diagnosed at age 50 or less, and were ascertained between 2004 and 2008. We screened all 564 patients for nine founder mutations: four in BRCA1, three in BRCA2 and one each in PALB2 and CHEK2. We also studied 6433 DNA samples from newborn infants from the Quebec City area to estimate the frequency of the nine variant alleles in the French‐Canadian population. We identified a mutation in 36 of the 564 breast cancer cases (6.4%) and in 35 of 6443 controls (0.5%). In the breast cancer patients, the majority of mutations were in BRCA2 (54%). However, in the general population (newborn infants), the majority of mutations were in CHEK2 (54%). The odds ratio for breast cancer to age 50, given a BRCA1 mutation, was 10.1 (95% CI: 3.7–28) and given a BRCA2 mutation was 29.5 (95% CI: 12.9–67). The odds ratio for breast cancer to age 50, given a CHEK2 mutation, was 3.6 (95% CI: 1.4–9.1). One‐half of the women with a mutation had a first‐ or second‐degree relative diagnosed with breast or ovarian cancer. Thus, it can be concluded that a predisposing mutation in BRCA1, BRCA2, CHEK2 or PALB2 is present in approximately 6% of French‐Canadian women with early‐onset breast cancer. It is reasonable to offer screening for founder mutations to all French‐Canadian women with breast cancer before age 50. The frequency of these mutations in the general population (0.5%) is too low to advocate population‐based screening.     

Prevalence of BRCA1 gene mutation in breast cancer patients in Guangxi,China

Objective: The prevalence of breast cancer susceptibility gene 1 mutation in breast cancer patients of south China has not been well revealed. This study was to invest the prevalence of BRCA1 gene mutation in breast cancer patients in Guangxi, China, and to try reflecting its relevance in genetic counseling of breast cancer. Methods: In this study, 463 breast cancer patients and 30 healthy women (control group) were involved. Entire sequence and splicing sites of BRCA1 genes were detected by PCR-DNA sequencing. Results: About 8.9% (41/463) patients were with 22 BRCA1 mutations (all in exon 10). The average hospitalized age of BRCA1-associated breast cancer cases was significantly younger (t = -2.965, P = 0.003). The nuclear grade (U = 2321.0, P = 0.030), ER (U = 4343.5, P = 0.041) and CerbB-2 (U = 3894.0, P = 0.038) expression levels, and triple negative breast cancer diagnosing rate (χ² = 4.719, P = 0.03) were disclosed more in BRCA1-associated patients. Conclusions: The four most frequent BRCA1 mutation (2798 T > C, 3971 G > A, 3971 G > A and 624 C > T) found in female breast cancer cases in Guangxi are all located in exon 10. BRCA1-associated breast cancer cases have earlier onset age, higher nuclear grade and negative ER and CerbB-2 expression.