Germline BRCA1 mutations in Iranian women with breast cancer

BRCA1 is known as a familial early onset breast cancer gene located in the long arm of chromosome 17. Alterations in this gene have been reported in different populations, some of which are population-specific mutations showing a founder effect. In this study, which is the first report on the genetic testing of Iranian women, exon-2 of the BRCA1 gene was sequenced in 80 Iranian breast cancer patients and none of the patients showed the 185del AG mutation or any changes in the sequences of this exon. Among this population, 22 patients having one or more of any kind of tumor in their first-degree relatives were selected and their entire BRCA1 gene coding region was sequenced by direct PCR-sequencing. A novel point mutation in exon-16, with unknown significance, was observed among the breast cancer patients and control subjects. This A/G mutation caused the substitution of Glutamine 1612 with Glycine, with an allele frequency of 38.6 and 52.8% in patients and controls, respectively. In addition, a point mutation in exon-15 and eight other polymorphic alterations were detected which have been reported previously. Three of these polymorphic sites were placed in the intronic part of the gene. To understand the significance of the contribution of the BRCA1 gene in the breast cancer among Iranian, further investigations are needed.     

Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families

About 40% of French Canadian breast and/or ovarian cancer families harbor germline BRCA1 or BRCA1 mutations where common mutations account for about 84% of all mutations identified in cancer families. Within a series of BRCA1 and BRCA2 mutation-negative families, a germline TP53 13398 G>A (Arg213Gln) mutation was identified, which was selected for mutation analysis in this gene because of a family history consistent with Li–Fraumeni syndrome (LFS). Given the founder effects in this population, the 13398 G>A mutation was screened in series of 52 BRCA1 and BRCA2 mutation-negative cancer families, and a mutation-positive family was identified. However, pedigree inspection and expansion of mutation-positive families with the same mutation revealed that they were closely related to each other. To further characterize the contribution of TP53 in cancer families, mutation analysis was performed in the remaining BRCA1 and BRCA2 mutation-negative cancer families. Thirty sequence variants were identified, the majority of which occur in intronic sequences and are not predicted to affect the functionality of TP53. However, the 14538 G>A (Arg290His) mutation was identified in a family which did not exhibit features consistent with LFS or Li–Fraumeni-like (LFL) syndrome. Neither of the TP53 mutations was detected in 381 French Canadian women with breast cancer diagnosed before 50 years of age not selected for family history of cancer. In all, germline TP53 mutations were identified in two of 52 (3.8%) cancer families, suggesting that TP53 is not a major contributor to BRCA1 and BRCA2 mutation-negative breast and/or ovarian cancer families of French Canadian descent.     

Germline BRCA2 mutations in men with breast cancer.

Breast cancer in men is rare and is clearly due in some cases to an inherited predisposition. A total of 28 male breast cancer patients were tested for BRCA2 mutations; two frameshifts and one putative missense mutation were identified. One of the frameshifts was detected in the same position as a mutation estimated to be responsible for 40% of all male breast cancer cases in Iceland.     

Germline mutations in BRCA1 and BRCA2 in breast-ovarian families from a breast cancer risk evaluation clinic.

PURPOSE: Data from the Breast Cancer Linkage Consortium suggest that the proportion of familial breast and ovarian cancers linked to BRCA1 or BRCA2 may be as high as 98% depending on the characteristics of the families, suggesting that mutations in BRCA1 or BRCA2 may entirely account for hereditary breast and ovarian cancer families. We sought to determine what proportion of families with both breast and ovarian cancers seen in a breast cancer risk evaluation clinic are accounted for by coding region germline mutations in BRCA1 and BRCA2 as compared to a linkage study group. We also evaluated what clinical parameters were predictive of mutation status. PATIENTS AND METHODS: Affected women from 100 families with at least one case of breast cancer and at least one case of ovarian cancer in the same lineage were screened for germline mutations in the entire coding regions of BRCA1 and BRCA2 by conformation-sensitive gel electrophoresis, a polymerase chain reaction-based heteroduplex analysis, or direct sequencing. RESULTS: Unequivocal deleterious mutations were found in 55% (55 of 100) of the families studied. Mutations in BRCA1 and BRCA2 accounted for 80% and 20% of the mutations overall, respectively. Using multivariate analysis, the strongest predictors of detecting a mutation in BRCA1 or BRCA2 in this study group were the presence of a single family member with both breast and ovarian cancer (P <.0009; odds ratio [OR], 5.68; 95% confidence interval [CI], 2.04 to 15.76) and a young average age at breast cancer diagnosis in the family (P <.0016; OR, 1.69; 95% CI, 1.23 to 2.38). CONCLUSION: These results suggest that at least half of breast/ovarian families evaluated in a high-risk cancer evaluation clinic may have germline mutations in BRCA1 or BRCA2. Whether the remaining families have mutations in noncoding regions in BRCA1, mutations in other, as-yet-unidentified, low-penetrance susceptibility genes, or represent chance clustering remains to be determined.     

Germline BRCA1 mutations increase prostate cancer risk

Background:

Prostate cancer (PrCa) is one of the most common cancers affecting men but its aetiology is poorly understood. Family history of PrCa, particularly at a young age, is a strong risk factor. There have been previous reports of increased PrCa risk in male BRCA1 mutation carriers in female breast cancer families, but there is a controversy as to whether this risk is substantiated. We sought to evaluate the role of germline BRCA1 mutations in PrCa predisposition by performing a candidate gene study in a large UK population sample set.

Methods:

We screened 913 cases aged 36–86 years for germline BRCA1 mutation, with the study enriched for cases with an early age of onset. We analysed the entire coding region of the BRCA1 gene using Sanger sequencing. Multiplex ligation-dependent probe amplification was also used to assess the frequency of large rearrangements in 460 cases.

Results:

We identified 4 deleterious mutations and 45 unclassified variants (UV). The frequency of deleterious BRCA1 mutation in this study is 0.45% three of the mutation carriers were affected at age ⩽65 years and one developed PrCa at 69 years. Using previously estimated population carrier frequencies, deleterious BRCA1 mutations confer a relative risk of PrCa of ∼3.75-fold, (95% confidence interval 1.02–9.6) translating to a 8.6% cumulative risk by age 65.

Conclusion

This study shows evidence for an increased risk of PrCa in men who harbour germline mutations in BRCA1. This could have a significant impact on possible screening strategies and targeted treatments.     

Germline mutations in NF1 and BRCA1 in a family with neurofibromatosis type 1 and early-onset breast cancer

Neurofibromatosis type 1 (NF1) is a common dominant autosomal disorder caused by mutations in the NF1 gene. The main manifestations of NF1 are café-au-lait spots, neurofibromas, intertriginous freckling, Lisch nodules, and malignancy, including peripheral nerve sheath tumors, central nervous system gliomas, and a variety of other tumors not so clearly defined. The association between NF1 and breast cancer or other gynecologic malignancies seems uncommon and has been scarcely referred in the literature. We describe a family with two females affected by both NF1 and early-onset breast cancer, and a male with NF1. We evaluated whether the concomitance of both disorders could be attributed to a NF1 mutation and its supposed increased risk of breast cancer or to the concurrence of two NF1 and BRCA1/2 germline mutations. Mutation analyses identified a frameshift mutation in BRCA1 and a nonsense mutation in NF1. Our findings stress the importance of considering all phenotypic features in families with both NF1 and breast tumors. To offer a specific risk assessment and management of both conditions, NF1 and BRCA1/2 cancer predisposing genes should be analyzed.     

Germline mutations of BRCA1 in two Korean hereditary breast/ovarian cancer families

Testing for cancer susceptibility gene, in particular mutations in the BRCA1 gene in association with hereditary breast/ovarian cancer has been extensively studied. We investigated germline mutations in the BRCA1 gene from two Korean hereditary breast/ovarian cancer families using direct DNA sequencing. Blood samples of the thirteen family members were studied. We found three missense mutations; 3232 Aright curved arrow G, 2731 Cright curved arrow T, 3667 Aright curved arrow G. These mutations were involved in the altered coding of amino acids. According to the BIC database, clinical significance of these mutations is regarded as favor polymorphisms. Therefore, these genetic variations are not believed to be involved in the development of the disease, but may be associated with breast/ovarian cancers in another yet undefined way. For further clinical significance of these variations, additional study such as a case-controlled haplotyping study is needed.     

219例中国汉族遗传性乳腺癌患者BRCA1和BRCA2突变的研究

  目的  分析中国新疆多民族地区的高风险遗传性乳腺癌BRCA1/2基因突变位点情况。  方法  以2009年1月到2010年12月新疆医科大学附属肿瘤医院收治的来自新疆地区的68例符合高风险遗传性乳腺癌标准的患者为研究对象,其中HBC 12例,HBOC 4例,E-BC 25例,BI-BC 10例,TNB 17例。通过外周静脉血提取基因组DNA,对BRCA1/2基因的全部编码序列进行扩增。用高效液相色谱分析（DHPLC）进行突变分析预筛,结果经DNA测序验证。  结果  BRCA1/2致病性突变在新疆地区高风险遗传性乳腺癌的突变率为8.8%（6/68）。其中BRCA1的突变率为4.4%（3/68）,BRCA2的突变率为4.4%（3/68）。不同民族之间BRCA1/2突变率无统计学差异。  结论  中国新疆多民族地区的高风险遗传性乳腺癌患者部分病例具有与内地汉族人群不同的BRCA基因突变谱。BRCA1 2073delA,BRCA2 6873del CTCC及BRCA2 9481del A可能是新疆遗传性乳腺癌特有的突变位点。     

Germline BRCA1 and HMLH1 mutations in a family with male and female breast carcinoma

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease, predisposing to the development of colorectal cancer and other tumor types such as endometrial, small bowel, stomach, ovary and urinary tract carcinoma, while most investigators find no association between HNPCC and cancer of the breast. We have identified hMLH1 mutations in 2 Amsterdam-criteria HNPCC families where both male and female gene carriers were affected with breast cancer. To investigate whether these breast cancers were caused by other genetic factors, we analyzed the 2 breast cancer susceptibility genes BRCA1 and BRCA2. In one family we did not find any mutation in the breast cancer genes, while in the other, a BRCA1 mutation segregated in the breast cancer cases. Hereditary breast cancer, and in particular BRCA1 tumors, display discrete histo-pathological and immunohistological characteristics. The tumor from a woman with both hMLH1 mutations and a BRCA1 mutation exhibited typical BRCA1 histology, e.g., grade 3 invasive ductal carcinoma with dense lymphocytic infiltration, and immunohistology, estrogen receptor (ER) negative, progesterone receptor (PgR) negative, strongly p53 positive, c-erbB-2 negative and highly Ki67 positive (>50% stained cells). The histology of the breast tumor from the man with both one hMLH1 mutation and a BRCA1 mutation was a grade 2 invasive ductal carcinoma without any special BRCA1 features. Immunohistology was also different. This might merely reflect a true difference in male breast tumor progression vs. female. We cannot exclude that the combined effect of BRCA1 and hMLH1 dysfunction has a bearing on tumor progression.     

Basal-like breast cancer and the BRCA1 phenotype

Breast cancers arising in germline carriers of BRCA1 mutations have a characteristic phenotype that has been shown in many studies to differentiate BRCA1 tumours from sporadic tumours. Recently, it has become clear that the characteristic phenotype of BRCA1 tumours is due to expression of the basal-like phenotype. We review these phenotypes, the evidence for BRCA1 pathway dysfunction in sporadic basal-like cancers, and discuss the clinical significance of the basal-like phenotype for cancer genetics and treatment.     

家族性乳腺癌家系成员乳腺癌易感基因突变的研究

目的研究河北省地区家族性乳腺癌家系中的患者及健康一级亲属乳腺癌易感基因1（BRCAl）和乳腺癌易感基因2（BRCA2）突变位点及携带情况。方法研究对象为2002年6月至2008年5月河北医科大学第四医院接诊的乳腺癌患者及其亲属,分别来自12个独立的汉族家族性乳腺癌家系,该家系中有2个及2个以上一级或二级亲属乳腺癌患病史,研究病例包括13例患者及46例健康一级亲属,共59例样本。由外周血提取基因组DNA,采用聚合酶链反应一单链构象多态性分析（PCR—SSCP）和基因测序技术对国内外报告中常见的4个BRCAl／BRCA2突变热点区域（BRCAl：外显子2、11、20;BRCA2外显子11）进行检测。结果发现1个BRCAl突变位点（4193insA）和1个BRCA2突变位点（5329insT）,全部为移码突变;发现4个变异位点（BRCAl：4165T〉A、287G〉C,BRCA2：6251G〉T、5416C〉A）,4193insA、5329insT、287G〉C携带者的家系中均有3例乳腺癌患者。结论BRCAl（4193insA）、BRCA2（5329insT）以及BRCAl：4165T〉A、287G〉C和BRCA2：6251G〉T、5416C〉A可能是河北省家族性乳腺癌相关性突变位点,其携带者家系中乳腺癌发病率明显升高,建议对其一级亲属密切随访或尽早进行手术或药物干预。     

家族性乳腺癌患者及家系成员乳腺癌易感基因携带情况调查

目的 乳腺癌易感基因1(breast cancer susceptibility gene 1,BRCA1)和BRCA2基因已经证实与家族性乳腺癌密切相关.本研究旨在分析中国汉族家族性乳腺癌患者及家系成员BRCA1和BRCA2突变特征及携带情况.方法 收集2013 12-02-2015-06-08军事医学科学院附属医院确诊的中国汉族家族性乳腺癌患者55例及家系成员48名,共计103例样本.柚取外周静脉血提取DNA,应用聚合酶链反应(polymerase chain reaction,PCR) DNA直接测序方法检测BRCA1和BRCA2基因全编码外显子序列.结果 55例家族性乳腺癌患者中发现5个BRCA基因致病性突变位点,1个突变位点乳腺癌信息库中见报道(BRCA1:4730insG),4个为新发现突变位点(BRCA1:1937insC,4538insAG;BRCA2:1382delA,2820delA).家族性乳腺癌患者BRCA1/2突变率为9.09％(BRCA1,5.45％;BRCA2,3.64％),其中三阴性乳腺癌患者突变率为22.22％(x2 =1.99,P=0.20),早发性乳腺癌患者(≤35岁)突变率为20.00％,x2=0.79,P=0.39.48例家系成员检测到3个新发现突变位点(BRCA1:1370insA,3459insA;BRCA2:6502insT),总突变率为6.25％.结论 中国汉族家族性乳腺癌患者BRCA基因突变率显著低于国外,应重点关注有家族史的三阴性乳腺癌患者和早发性乳腺癌患者;家系成员中发现BRCA基因致病性突变,家系成员突变率和发病风险有待进一步研究,应引起重视.     

Germline mutations of TP53 and BRCA2 genes in breast cancer/sarcoma families

The genetic aetiology of familial aggregations of breast cancer and sarcomas has been elucidated only in part. In this study, 23 unrelated individuals from families with one case of sarcoma and at least one case of breast cancer were screened for mutations in the TP53, BRCA1 and BRCA2 genes. Families were classified according to their conformity to the criteria defining the Li-Fraumeni syndrome (LFS), Li-Fraumeni-like (LFL) syndrome and hereditary breast/ovarian cancer (HBOC). Germline TP53 mutations were identified in three instances (13%), including one LFS and two LFL families, while none of the non-LFS/non-LFL families had a TP53 mutation. Three cases (13%), including one with a TP53 mutation, carried BRCA2 mutations. Of these, two were observed in LFL/HBOC families and the other one in a non-LFS/non-LFL/HBOC family, while none of the non-HBOC families tested positive. These findings suggest that the screening of BRCA2, in addition to TP53, may be appropriate for the molecular characterisation of breast cancer/sarcoma families, with practical implications for counselling and clinical management.     

Germline BRCA1 mutation analysis in Indian breast/ovarian cancer families

Most of the predisposition to hereditary breast and ovarian cancer has been attributed to inherited defects in two tumor suppressor genes BRCA1 and BRCA2. To explore the contribution of BRCA1 mutations to hereditary breast cancer among Indian women, we examined the coding sequence of the BRCA1 gene in 14 breast cancer patients with a positive family history of breast and/or ovarian cancer. Mutation analysis was carried out using conformation sensitive gel electrophoresis (CSGE) followed by sequencing. Three mutations (21%) in the BRCA1 gene were identified. Two of them are novel mutations of which one is a missense mutation in exon 7 near the RING finger domain, while the other is a one base pair deletion in exon 11 which results in protein truncation. The third mutation, 185 delAG, has been previously described in Ashkenazi Jewish families. To our knowledge this is the first report of a study of germline BRCA1 mutation analysis in familial breast cancer in India. Our data from 14 different families suggests a lower prevalence but definite involvement of germline mutations in the BRCA1 gene among Indian women with breast cancer and a family history of breast cancer.     

Non-founder BRCA1 mutations in Russian breast cancer patients

A few founder BRCA1 mutations (5382insC, 4154delA, 185delAG) account for up to 15% of high-risk (young-onset or familial or bilateral) breast cancer (BC) cases in Russia. The impact of non-founder BRCA1 mutations in this country is less studied; in particular, there are no reports analyzing gross rearrangements of this gene in the Russian patient series. We selected for the study 95 founder mutation negative high-risk BC cases. Combination of high-resolution melting (HRM) and sequencing revealed six presumably BC-associated alleles (2080delA, 4808C > G, 5214C > T, 5236G > A, 5460G > T, 5622C > T) and one variant of an unknown significance (4885G > A). The pathogenic role of the 5236G > A mutation leading to G1706E substitution was further confirmed by the loss of heterozygosity analysis of the corresponding tumor tissue. Multiplex ligation-dependent probe amplification (MLPA) revealed two additional BRCA1 heterozygotes, which carried BRCA1 deletions involving exons 1–2 and 3–7, respectively. Based on the results of this investigation and the review of prior Russian studies, three BRCA1 mutations (2080delA, 3819del5, 3875del4) were considered with respect to their possible founder effect and tested in the additional series of 210 high-risk BC patients; two BRCA heterozygotes (2080delA and 3819del5) were revealed. We conclude that the non-founder mutations constitute the minority of BRCA1 defects in Russia.     

BRCA1 and BRCA2 germline mutations in 85 Iranian breast cancer patients

Breast cancer is the most common cancer in Iranian women (Mousavi et al in Asian Pac J Cancer Prev 9(2):275–278, 2008). Genetic predisposition accounts for 15% of all breast cancers and germline mutations in breast cancer susceptibility genes, BRCA1 and BRCA2 are responsible for a substantial proportion of high-risk breast and breast/ovarian cancer families (Collaborative Group on Hormonal Factors in Breast Cancer in Lancet 350:1047–1059, 1997; Lee et al in Int Nurs Rev 55:355–359, 2008; Hulka and Stark in Lancet 346:883–887, 1995; Kelsey in Epidemiol Rev 15:256–263, 1993; Tischer et al in J Biol Chem 266:11947–11954, 1991; Newman et al in: Proc Natl Acad Sci USA 85:3044–3048, 1988). Therefore, the aim of this study was to investigate mutations of BRCA1/2 in high risk Iranian families. We screened 85 patients who met our minimal criteria. The entire coding sequences and each intron/exon boundaries of BRCA1/2 genes were screened by direct sequencing. In the present study, we could detect the novel following mutations: p.Glu1735 p.Gly1140Ser, p.Ile26Val, p.Leu1418X, p.Glu23Gln, p.Leu3X, p.Asn1403His, p.Lys581X, p.Pro938Arg, p.Thr77Arg, p.Arg7Cys, p.Ser177Thr, IVS7+83(TT), IVS8−70(-CATT), IVS2+9(-GC), IVS1−20(-GA), IVS1−8(-AG), IVS2+24(AG), IVS5−8 (A–G), IVS2(35–39)TTcctatGAT in BRCA1 and p.Glu1391Gly, 1994_1995 (Ins A), IVS6-70−T>G in BRCA2. In agreement with findings in other populations, we found that family history is a good predictor of being a mutation carrier. Five pathogenic BRCA1 mutations and one pathogenic BRCA2 mutation were detected in 85 index cases.