共查询到20条相似文献,搜索用时 190 毫秒
1.
Konstantopoulou I Rampias T Ladopoulou A Koutsodontis G Armaou S Anagnostopoulos T Nikolopoulos G Kamakari S Nounesis G Stylianakis A Karanikiotis C Razis E Gogas H Keramopoulos A Gaki V Markopoulos C Skarlos D Pandis N Bei T Arzimanoglou I Fountzilas G Yannoukakos D 《Breast cancer research and treatment》2008,107(3):431-441
127 Greek breast/ovarian cancer families were screened for germline BRCA1/2 mutations by dHPLC followed by direct sequencing. Our results indicated 16 and 5 breast/ovarian cancer families bearing deleterious
mutations in the BRCA1 and BRCA2 genes, respectively. Two novel BRCA2 germline mutations (G4X and 3783del10) are reported here for the first time. Subsequent compilation of our present findings
with previously reported mutation data reveals that in a total of 287 Greek breast/ovarian cancer families, 46 and 13 carry
a deleterious mutation in BRCA1 and BRCA2, respectively. It should be noted that two BRCA1 mutations, 5382insC and G1738R, both located in exon 20, account for 46% of the families found to carry a mutation. Based
on our mutation analysis results, we propose here a hierarchical, cost-effective BRCA1/2 mutation screening protocol for individuals of Greek ethnic origin. The suggested protocol can impact on the clinical management
of breast-ovarian cancer families on a national healthcare system level.
Irene Konstantopoulou and Theodore Rampias equally contributed to this work. 相似文献
2.
Peixoto A Salgueiro N Santos C Varzim G Rocha P Soares MJ Pereira D Rodrigues H Bento MJ Fráguas A Moura G Regateiro F Castedo S Teixeira MR 《Familial cancer》2006,5(4):379-387
We present the first characterisation of the mutational spectrum of the entire coding sequences and exon–intron boundaries of the BRCA1 and BRCA2 genes as well as large BRCA1 rearrangements in Portuguese families with inherited predisposition to breast/ovarian cancer. Of the 100 probands studied, pathogenic mutations were identified in 22 (24.7%) of 89 breast and/or ovarian cancer families with more than one affected member (15 in BRCA1 and seven in BRCA2), but in none of the 11 patients without family history of cancer. One (6.7%) of the BRCA1 mutations is a large deletion involving exons 11–15. Seven pathogenic point mutations are novel: 2088C>T, 2156delinsCC, and 4255_4256delCT in BRCA1 and 4608_4609delTT, 5036delA, 5583_5584insT, and 8923C>T in BRCA2. The novel 2156delinsCC was identified in three probands from different families and probably represents a founder mutation in our population. We also found a previously reported 3450_3453del4 mutation in three unrelated patients. In addition to the 22 pathogenic mutations, we identified 19 missense mutations of uncertain pathogenic significance, three of them (5241G>C in BRCA1 and IVS6+13C>T and 3731T>C in BRCA2) previously undescribed. The percentage of cases with truncating mutations in BRCA1 and BRCA2 was higher in breast/ovarian cancer (37.0%, mostly BRCA1) and male breast cancer (40%, all BRCA2) families than in families with only female breast cancer (17.5%). Interestingly, we found evidence for genetic anticipation regarding age at diagnosis of both breast and ovarian cancer in those families presenting affected members in more than one generation. These findings should be taken into consideration while planning screening and prophylactic measures in families with inherited predisposition to breast and ovarian cancer. 相似文献
3.
Lindor NM Lindor RA Apicella C Dowty JG Ashley A Hunt K Mincey BA Wilson M Smith MC Hopper JL 《Familial cancer》2007,6(4):473-482
Context Models have been developed to predict the probability that a person carries a detectable germline mutation in the BRCA1 or BRCA2 genes. Their relative performance in a clinical setting is unclear.
Objective To compare the performance characteristics of four BRCA1/BRCA2 gene mutation prediction models: LAMBDA, based on a checklist and scores developed from data on Ashkenazi Jewish (AJ) women;
BRCAPRO, a Bayesian computer program; modified Couch tables based on regression analyses; and Myriad II tables collated by
Myriad Genetics Laboratories.
Design and setting Family cancer history data were analyzed from 200 probands from the Mayo Clinic Familial Cancer Program, in a multispecialty
tertiary care group practice. All probands had clinical testing for BRCA1 and BRCA2 mutations conducted in a single laboratory.
Main outcomes measures For each model, performance was assessed by the area under the receiver operator characteristic curve (ROC) and by tests of
accuracy and dispersion. Cases “missed” by one or more models (model predicted less than 10% probability of mutation when
a mutation was actually found) were compared across models.
Results All models gave similar areas under the ROC curve of 0.71 to 0.76. All models except LAMBDA substantially under-predicted
the numbers of carriers. All models were too dispersed.
Conclusions In terms of ranking, all prediction models performed reasonably well with similar performance characteristics. Model predictions
were widely discrepant for some families. Review of cancer family histories by an experienced clinician continues to be vital
to ensure that critical elements are not missed and that the most appropriate risk prediction figures are provided. 相似文献
4.
High Incidence of 4153delA <Emphasis Type="Italic">BRCA1</Emphasis> Gene Mutations in Lithuanian Breast- and Breast-ovarian Cancer Families 总被引:1,自引:1,他引:0
Summary BRCA1 and BRCA2 gene mutations confer a high lifetime risk to breast and ovarian cancers. We have screened cancer patients from 13 families
with at least three breast and/or ovarian cancers from Lithuania for 5382insC, C61G and 4153delA BRCA1 gene mutations. One of three mutations was found in 9 of the 13 studied families (69%). 4153delA was the most frequently
detected and accounted for 56% of all identified mutation. 5382insC and C61G accounted for 33% and 11% of found mutations,
respectively. Significantly higher, than in other populations, incidence of 4153delA indicates that this may be founder BRCA1 mutation characteristic for Lithuanians. Our analysis shows that testing of 4153delA, 5382insC, C61G BRCA1 mutations should be extremely effective and inexpensive tool in testing Lithuanian population aimed to identify individuals
with high risk of breast and ovarian cancers. 相似文献
5.
Li WF Hu Z Rao NY Song CG Zhang B Cao MZ Su FX Wang YS He PQ Di GH Shen KW Wu J Lu JS Luo JM Liu XY Zhou J Wang L Zhao L Liu YB Yuan WT Yang L Shen ZZ Huang W Shao ZM 《Breast cancer research and treatment》2008,110(1):99-109
To have an overview of the role of BRCA1 and BRCA2 genes among Chinese high-risk breast cancer patients, we analyzed 489 such high-risk breast cancer patients from four breast
disease clinical centers in China, by using PCR-DHPLC or SSCP-DNA sequencing analysis. Allelotype analysis was done at five
short tandem repeat (STR) markers in or adjacent to BRCA1 on the recurrent mutation carriers. For those analyzed both genes, 8.7% of early-onset breast cancer cases and 12.9% of familial
breast cancer cases had a BRCA1 or BRCA2 mutation, as compared with the 26.1% of cases with both early-onset breast cancer and affected relatives. For those reporting
malignancy family history other than breast/ovarian cancer, the prevalence of BRCA1/2 mutation is about 20.5%, and it was significantly higher than the patients only with family history of breast/ovarian cancer
(P = 0.02). The family history of ovarian cancer (26.7% vs. 11.9%) and stomach cancer (23.8% vs. 11.8%) doubled the incidence
of BRCA1/2, but the difference did not reach the statistical significance. Two recurrent mutations in BRCA1, 1100delAT and 5589del8, were identified. The recurrent mutations account for 34.8% BRCA1 mutations in our series. Similar allelotypes were detected in most STR status for those harboring the same mutations. The
BRCA1 associated tumors were more likely to exhibit a high tumor grade, negative C-erbB-2/neu status and triple negative (ER, PgR
and C-erbB-2/neu negative) status (P < 0.05). We recommended the BRCA1 and BRCA2 genetic analysis could be done for high-risk breast cancer patient in Chinese population, especially for those with both
early-onset breast cancer and affected relatives. There may be some degree of shared ancestry for the two recurrent BRCA1 mutations in Chinese.
Wen-Feng Li and Zhen Hu have contributed equally to this work. 相似文献
6.
BRCA1 and BRCA2 mutations in ovarian cancer patients from China: ethnic‐related mutations in BRCA1 associated with an increased risk of ovarian cancer
下载免费PDF全文
![点击此处可从《International journal of cancer. Journal international du cancer》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Tingyan Shi Pan Wang Caixia Xie Sheng Yin Di Shi Congchong Wei Wenbin Tang Rong Jiang Xi Cheng Qingyi Wei Qing Wang Rongyu Zang 《International journal of cancer. Journal international du cancer》2017,140(9):2051-2059
BRCA1/2 are cancer predisposition genes involved in hereditary breast and ovarian cancer (HBOC). Mutation carriers display an increased sensitivity to inhibitors of poly(ADP‐ribose) polymerase (PARP). Despite a number of small‐size hospital‐based studies being previously reported, there is not yet, to our knowledge, precise data of BRCA1/2 mutations among Chinese ovarian cancer patients. We performed a multicenter cohort study including 916 unselected consecutive epithelial ovarian cancer (EOC) patients from eastern China to screen for BRCA1/2 mutations using the next‐generation sequencing approach. A total of 153 EOC patients were found to carry pathogenic germline mutations in BRCA1/2, accounting for an overall mutation incidence of 16.7% with the predominance in BRCA1 (13.1%) compared with BRCA2 (3.9%). We identified 53 novel pathogenic mutations, among which the c.283_286delCTTG and the c.4573C > T of BRCA1 were both found in two unrelated patients. More importantly, the most common mutation found in this study, c.5470_5477del8 was most likely to be Chinese population‐related without an apparent founder origin. This hot‐spot mutation was presumably associated with an increased risk of ovarian cancer. Taken together, germline BRCA1/2 mutations were common in Chinese EOC patients with distinct mutational spectrum compared to Western populations. Our study contributes to the current understanding of BRCA1/2 mutation prevalence worldwide. We recommend BRCA1/2 genetic testing to all Chinese women diagnosed with EOC to identify HBOC families, to provide genetic counseling and clinical management for at‐risk relatives. Mutation carriers may also benefit from PARP‐targeted therapies. 相似文献
7.
Purpose. There is increasing evidence that BRCA1 and BRCA2 associated tumors may differ from sporadic cancers. The purpose of this report is to review the current state of knowledge of BRCA1 and BRCA2, the biology of associated tumors, and possible risk reduction strategies in women with these deleterious mutations.
Design and methods. We conducted an extensive literature search of all published articles (including Medline) on preclinical data on the function of BRCA1 and BRCA2, associated tumor pathology, and the clinical management for both unaffected carriers and affected patients.
Results. BRCA1 and BRCA2 are likely to act as tumor suppressor genes, and together with RAD51 operate in a common DNA damage response pathway implicated in double-strand repair. Breast cancers associated with BRCA1 are frequently of a higher grade, steroid hormone receptor negative, and appear to have a higher proportion of atypical or typical medullary subtype. Conversely, BRCA2 associated breast cancers do not differ significantly from sporadic cancers. No special tumor phenotype has been ascribed to BRCA1 or BRCA2 associated ovarian cancers. Guidelines for risk reduction strategies for the high risk unaffected carrier have been recommended by expert panels in the USA and Europe. Lifestyle changes, multi-modality screening, chemoprevention, and prophylactic oophorectomy and mastectomy, with their possible benefits and attendant risks are described. Finally, locoregional and systemic treatment in breast and ovarian cancers associated with these mutations, and differences between these and sporadic cancers are discussed.
Conclusions. Although the incidence of breast or ovarian cancers that can be attributed to BRCA1 or BRCA2 mutations account for less than 5% of all cancers, these cancers may differ from sporadic cases in terms of tumor biology and phenotype. These differences may impact directly on clinical management of breast and ovarian cancer patients, and their relatives. Further recommendations of these patients are constantly changing as new information emerges on the clinical behavior of these cancers. 相似文献
8.
Aretini P D'Andrea E Pasini B Viel A Mariani Costantini R Cortesi L Ricevuto E Agata S Bisegna R Boiocchi M Caligo MA Chieco-Bianchi L Cipollini G Crucianelli R D'Amico C Federico M Ghimenti C De Giacomi C De Nicolo A Della Puppa L Ferrari S Ficorella C Iandolo D Manoukian S Marchetti P Marroni F Menin C Montagna M Ottini L Pensotti V Pierotti M Radice P Santarosa M Silingardi V Turchetti D Bevilacqua G Presciuttini S 《Breast cancer research and treatment》2003,81(1):71-79
Mutations in BRCA1 and BRCA2 show different expressivity with respect to cancer risk, and allelic heterogeneity may be present in both genes. We collected 179 pedigrees with identified germline mutation (104 BRCA1 and 75 BRCA2), ascertained in six collaborating centers of the Italian Consortium for Hereditary Breast and Ovarian Cancer. Significant heterogeneity was detected for several variables, and a logistic regression model including age of diagnosis in the proband, presence of ovarian cancer in the family, presence of prostate or pancreatic cancer in the family, and presence of male breast cancer in the family proved to be effective in predicting the presence of a mutation in a gene rather than the other. Excess of familial aggregation of both breast and ovarian cancer was observed in both genes. Proportion of ovarian cancer was increased in the 5' portion of BRCA1, and presence of prostate or pancreatic cancer in a family was correlated with presence of ovarian cancer in BRCA2. 相似文献
9.
Stadler ZK Salo-Mullen E Patil SM Pietanza MC Vijai J Saloustros E Hansen NA Kauff ND Kurtz RC Kelsen DP Offit K Robson ME 《Cancer》2012,118(2):493-499
BACKGROUND:
Germline mutations in the BRCA2 cancer susceptibility gene are associated with an increased risk of pancreatic cancer (PC). Breast‐pancreas cancer families with BRCA1 mutations have also been observed. The influence of a family history (FH) of PC on BRCA mutation prevalence in patients with breast cancer (BC) is unknown.METHODS:
A clinical database review (2000‐2009) identified 211 Ashkenazi Jewish (AJ) BC probands who 1) underwent BRCA1/2 mutation analysis by full gene sequencing or directed testing for Ashkenazi founder mutations (BRCA1: 185delAG and 5382insC; BRCA2: 6174delT) and 2) had a FH of PC in a first‐, second‐, or third‐degree relative. For each proband, the pretest probability of identifying a BRCA1/2 mutation was estimated using the Myriad II model. The observed‐to‐expected (O:E) mutation prevalence was calculated for the entire group.RESULTS:
Of the 211 AJ BC probands with a FH of PC, 30 (14.2%) harbored a BRCA mutation. Fourteen (47%) of the mutations were in BRCA1 and 16 (53%) were in BRCA2. Patients diagnosed with BC at age ≤ 50 years were found to have a higher BRCA1/2 mutation prevalence than probands with BC who were diagnosed at age > 50 years (21.1% vs 6.9%; P = .003). In patients with a first‐, second‐, or third‐degree relative with PC, mutation prevalences were 15.4%, 15.3%, and 8.6%, respectively (P = .58). In the overall group, the observed BRCA1/2 mutation prevalence was 14.2% versus an expected prevalence of 11.8% (O:E ratio, 1.21; P = .15).CONCLUSIONS:
BRCA1 and BRCA2 mutations are observed with nearly equal distribution in AJ breast‐pancreas cancer families, suggesting that both genes are associated with PC risk. In this population, a FH of PC was found to have a limited effect on mutation prevalence. Cancer 2011;. © 2011 American Cancer Society. 相似文献10.
Rafnar T Benediktsdottir KR Eldon BJ Gestsson T Saemundsson H Olafsson K Salvarsdottir A Steingrimsson E Thorlacius S 《European journal of cancer (Oxford, England : 1990)》2004,40(18):208-2793
A single founder mutation in each of the BRCA genes has been identified in Iceland. The frequency of the BRCA1 G5193A and BRCA2 999del5 mutations in all ovarian cancer patients diagnosed over the period 1991–2000 was determined. Mutation status was correlated with family history, tumour morphology and age at diagnosis. Samples from 86% of cases (179 carcinomas and 74 borderline tumours) were available. In the carcinomas, BRCA1 and BRCA2 mutations were present in 1.2% and 6% of cases, respectively. No BRCA mutations were found in the borderline tumours. Odds Ratio (OR) of developing ovarian cancer was 20.65 for BRCA2 carriers. Family history of breast/ovarian cancer was present for 70% of BRCA2 carriers and approximately 14% for non-carriers with carcinoma. In conclusion, BRCA2 999del5 is present in 6% of ovarian cancer cases in Iceland and is associated with a 20-fold increase in the risk of the disease. The BRCA1 G5193A mutation is too rare to contribute significantly to ovarian cancer in Iceland. 相似文献
11.
Balmaña J Díez O Campos B Majewski M Sanz J Alonso C Baiget M Garber JE 《Breast cancer research and treatment》2005,92(3):273-277
Summary Background. There has been controversy regarding whether BRCA1 germline mutations favor female births or whether the sex imbalances observed are attributable to ascertainment bias. Our aims were to compare the sex ratios among offspring of BRCA1-positive, BRCA2-positive, and BRCA-negative families undergoing genetic testing in clinical programs, and to determine whether ascertainment bias is responsible for the observed preponderance of female offspring.Patients and methods. A total of 145 breast and/or ovarian cancer families with mutations in BRCA1 (n = 83) or BRCA2 (n = 62), and 90 families without identifiable mutation were collected for the study from familial cancer clinics in Barcelona, Spain, and Boston, US. Sex ratio was analyzed among all births in the families and offspring of all (tested and obligate) carriers. In order to minimize the effect of family history of cancer, the analysis was also performed among offspring of the most recent generation of mutation-positive carriers who did not have affected children and compared with a control group comprised of the offspring of the most recent adult generation of non-carriers from families with a known mutation.Results. There was a statistically higher proportion of female births in all groups (BRCA1 59% (95% CI = 57–61%), BRCA2 58% (56–61%), and BRCA-negative 59% (56–61%), respectively). The female preponderance persisted in analyses limited to offspring of BRCA1 and BRCA2 carriers (61% (57–65%), and 62% (58–66%), respectively), with no differences between the two mutation groups. In contrast, the excess of female offspring disappeared when ascertainment or recall biases were minimized, 44% (37–52%), and 39% (26–53%) for BRCA1; 51% (44–58%), and 46% (33–60%) for BRCA2.Conclusions. Our findings suggest that there is no asymmetry in birth outcomes among BRCA1 or BRCA2 mutations carriers. Rather ascertainment bias in families participating in genetic testing, or in the family history information they provide is likely to account for excess of female offspring previously reported. 相似文献
12.
Hansen Tv Jønson L Albrechtsen A Andersen MK Ejlertsen B Nielsen FC 《Breast cancer research and treatment》2009,115(2):315-323
BRCA1 and BRCA2 germ-line mutations predispose to breast and ovarian cancer. Large genomic rearrangements of BRCA1 account for 0–36% of all disease causing mutations in various populations, while large genomic rearrangements in BRCA2 are more rare. We examined 642 East Danish breast and/or ovarian cancer patients in whom a deleterious mutation in BRCA1 and BRCA2 was not detected by sequencing using the multiplex ligation-dependent probe amplification (MLPA) assay. We identified 15
patients with 7 different genomic rearrangements, including a BRCA1 exon 5–7 deletion with a novel breakpoint, a BRCA1 exon 13 duplication, a BRCA1 exon 17–19 deletion, a BRCA1 exon 3–16 deletion, and a BRCA2 exon 20 deletion with a novel breakpoint as well as two novel BRCA1 exon 17–18 and BRCA1 exon 19 deletions. The large rearrangements in BRCA1 and BRCA2 accounted for 9.2% (15/163) of all BRCA1 and BRCA2 mutations in East Denmark. Nine patients had the exon 3–16 deletion in BRCA1. By SNP analysis we find that the patients share a 5 Mb fragment of chromosome 17, including BRCA1, indicating that the exon 3–16 deletion represents a Danish founder mutation.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
13.
Kathryn P. Pennington MD Tom Walsh PhD Ming Lee PhD Christopher Pennil MS Akiva P. Novetsky MD Kathy J. Agnew BS Anne Thornton MS Rochelle Garcia MD David Mutch MD Mary‐Claire King PhD Paul Goodfellow PhD Elizabeth M. Swisher MD 《Cancer》2013,119(2):332-338
BACKGROUND:
Uterine serous carcinoma (USC) is not recognized as part of any defined hereditary cancer syndrome, and its association with hereditary breast and ovarian carcinoma and Lynch syndrome are uncertain.METHODS:
Using targeted capture and massively parallel genomic sequencing, 151 subjects with USC were assessed for germline mutations in 30 tumor suppressor genes, including BRCA1 (breast cancer 1, early onset), BRCA2, the DNA mismatch repair genes (MLH1 [mutL homolog 1], MSH2 [mutS homolog 2], MSH6, PMS2 [postmeiotic segregation increased 2]), TP53 (tumor protein p53), and 10 other genes in the Fanconi anemia–BRCA pathway. Ten cases with < 10% serous histology were also assessed.RESULTS:
Seven subjects (4.6%) carried germline loss‐of‐function mutations: 3 subjects (2.0%) with mutations in BRCA1, 2 subjects (1.3%) with mutations in TP53, and 2 subjects (1.3%) with mutations in CHEK2 (checkpoint kinase 2). One subject with < 10% serous histology had an MSH6 mutation. Subjects with MSH6 and TP53 mutations had neither personal nor family histories suggestive of Lynch or Li‐Fraumeni syndromes. Of the 22 women with USC and a personal history of breast carcinoma, the frequency of BRCA1 mutations was 9%, compared to 0.9% in 119 women with no such history.CONCLUSIONS:
Approximately 5% of women with USC have germline mutations in 3 different tumor suppressor genes: BRCA1, CHEK2, and TP53. Mutations in DNA mismatch repair genes that cause Lynch syndrome are rare in USC. The germline BRCA1 mutation rate in USC subjects of 2% is higher than expected in a nonfounder population, suggesting that USC is associated with hereditary breast and ovarian carcinoma in a small proportion of cases. Women with USC and breast cancer should be offered genetic testing for BRCA1 and BRCA2 mutations. Cancer 2013. © 2012 American Cancer Society. 相似文献14.
Ottini L Rizzolo P Zanna I Falchetti M Masala G Ceccarelli K Vezzosi V Gulino A Giannini G Bianchi S Sera F Palli D 《Breast cancer research and treatment》2009,116(3):577-586
Background Male breast cancer (MBC) is a rare and scarcely investigated disease. The strongest genetic risk factor for MBC is represented
by inherited BRCA2 mutations, whereas the association between MBC and BRCA1 mutations is less clear. MBC appears to be biologically similar to breast cancer in females, however the phenotypic characteristics
of BRCA1/2-related MBCs are not yet well elucidated. Objective To investigate the genetic and phenotypic characteristics of MBC in a large and well-characterized population-based series
of 108 MBCs from Tuscany (Central Italy) and to evaluate associations between BRCA1/BRCA2 mutation status and clinical-pathological features including breast/ovarian cancer first-degree family history, tumor histology
and grade, proliferative activity, estrogen/progesterone receptors (ER/PR) and epidermal growth factor receptor 2 (HER2) expression.
Results
BRCA1/BRCA2 mutations were identified in ten MBCs, in particular, two cases (1.9%) carried BRCA1 and eight cases (7.4%) carried BRCA2 mutations. The same BRCA1 mutation (3347delAG) was detected in two unrelated MBC cases. Three novel BRCA2 pathogenic mutations were found. Statistically significant associations emerged between BRCA2-related tumors and absence of PR expression (P = 0.008), HER2 over-expression (P = 0.002) and high tumor grade (P = 0.005). Conclusions Here, we (i) reported that in our population about 9% of MBC cases are accounted for by BRCA1/BRCA2 mutations; (ii) enlarged the BRCA2 mutational spectrum and (iii) characterized a specific phenotype associated with BRCA2-related MBCs suggestive of aggressive behavior. Overall, our results may have important implications on clinical management
for this rare disease. 相似文献
15.
Novel germline mutations in breast cancer susceptibility genes BRCA1, BRCA2 and p53 gene in breast cancer patients from India 总被引:1,自引:0,他引:1
Hedau S Jain N Husain SA Mandal AK Ray G Shahid M Kant R Gupta V Shukla NK Deo SS Das BC 《Breast cancer research and treatment》2004,88(2):177-186
Mutations in breast cancer susceptibility genes, BRCA1 and BRCA2 account for more than 80% of hereditary breast and ovarian cancers. p53 tumor suppressor gene that controls cellular growth and differentiation is also known to be mutated in more than 50% of human cancers including breast cancer. We have carried out a study on BRCA1 and BRCA2 along with p53 gene mutations in both sporadic as well as familial breast cancer patients from India where breast cancer is fast emerging as a major cancer among premenopausal urban women. We examined 124 untreated primary breast cancer patients comprising 100 sporadic and 24 familial cases including 56 age-matched healthy controls for the presence of BRCA1, BRCA2 and the p53 gene mutations using PCR-SSCP and direct nucleotide sequencing. Certain frequently mutated exons such as 2, 5, 11, 13 and 20 of BRCA1, exons 2, 9, 11 (for 6174delT), 18 and 20 of BRCA2 and 4–9 exons of p53 gene were analyzed in sporadic breast cancer while all 22 coding exons of BRCA1 including its flanking intronic regions along with above mentioned exons of BRCA2 and p53 gene were analyzed in familial breast cancer patients. We identified six patients (25%) with BRCA1 mutation of which three were found to be of novel type one in exon 16 (4956insG) and two in exon 7 (Lys110Thr) (Ser114Pro) out of 24 familial breast cancer patients studied from two different geographic regions/populations of India. Two sisters from a single family (12.5%) out of eight families from Goa with Portuguese colonial origin showed presence of founder Ashkenazi Jewish BRCA1 mutation (185delAG) along with (IVS7 561–34T>C; IVS18 527166G>A). While from New Delhi, four (25%) of 16 breast cancer families showed BRCA1 mutations; a frame shift protein truncating (4956insG), a transition nonsense (Gln1395Stop) and two amino acid substitutions (Lys110Thr) and (Ser114Pro). Only one (4%) p53 mutation (Val97Ile) in its exon 4 along with BRCA1 mutation (4956insG) could be detected. No major sequence variation in BRCA2 gene was observed except for G203A at 5 UTR of exon 2, a common population polymorphism in two Goan patients who also showed silent nucleotide change for amino acid serine at codon 1436 of BRCA1 gene. None of the 100 sporadic breast cancer patients revealed any protein truncating or deleterious BRCA1 or BRCA2 gene mutation. Interestingly, three (3%) p53 mutations in its exon 5 were detected in sporadic breast cancer patients. Although three novel BRCA1 mutations including a founder Ashkenazi Jewish BRCA1 mutation were recorded in Indian women with familial breast cancer, the overall prevalence of BRCA gene mutations in Indian women with a family history of breast cancer appears to be low. 相似文献
16.
Over the last four decades, Henry Lynch has collected pedigrees and samples from high risk breast and/or ovarian cancer families,
generating a unique resource for the study of breast cancer susceptibility. These families have made a major contribution
to increasing our knowledge in the cancer genetic susceptibility field, allowing the discovery of a genetic association between
breast and ovarian cancer predisposition, contributing to the mapping of the BRCA1 and BRCA2 genes, advancing the idea of the existence of other breast cancer susceptibility genes, allowing the evaluation of BRCA-associated cancer risks and psychosocial aspects of BRCA testing and so on. Ten years after the cloning of BRCA1 and BRCA2, we report the current status of these families and compare the observed BRCA1/2 mutation detection rate with the estimations obtained by linkage analysis of the Breast Cancer Linkage Consortium families. 相似文献
17.
Choi DH Cho DY Lee MH Park HS Ahn SH Son BH Haffty BG 《Breast cancer research and treatment》2008,112(3):569-573
The germline CHEK2 1100delC mutation is a low penetrance breast cancer susceptibility allele, frequently observed in patient with family history
of breast cancer and/or young age and the frequency varied according to race or ethnicity. In this study, we evaluated the
significance of CHEK2 1100delC in predisposition to breast cancer by assessing its frequency in a material of 493 Korean breast cancer patients
who had been screened for BRCA1 and BRCA2 mutations (42 patients had deleterious mutation of BRCA1/2). Mutation detection of CHEK2 1100delC was based upon analysis of primer extension products generated for previously amplified genomic DNA using a chip
based MALDI-TOP mass spectrometry platform. After overall measurement automatically, assays which had bad peaks were checked
again manually. None of the 493 Korean patients with breast cancer who were candidate for BRCA1 and BRCA2 test carried the 1100delC mutation observed in Caucasians with limited frequency. In the previous studies, we observed higher
or comparable prevalence of BRCA1 and BRCA2 mutations in Korean patients with breast cancer compared to Caucasian breast cancer population. In the present study, we
evaluated the role of a CHEK2 1100delC as a susceptibility mutation of breast cancer in the Korean population. However, our results suggest that this mutation
is absent or may be very infrequent in Korean patients with breast cancer who have high risk of BRCA1 and BRCA2 mutation, making its screening irrelevant from the practical point view. 相似文献
18.
Palanca Suela S Esteban Cardeñosa E Barragán González E Oltra Soler S de Juan Jiménez I Chirivella González I Segura Huerta A Guillén Ponce C Martínez de Dueñas E Bolufer Gilabert P;Group for Assessment of Hereditary Cancer of Valencia Community 《Breast cancer research and treatment》2008,112(1):63-67
Background Alterations in BRCA1 gene are responsible for the majority of hereditary breast and/or ovarian cancers. However, the frequency of detected germline
mutations is lower than expected by linkage analysis. Standard PCR-based screening methods are mainly used for detecting mutations,
but the large genomic rearrangements are commonly overlooked. The purpose of this study was to confirm and characterize a
novel deletion identified in BRCA1 gene which has not yet been reported to date. Methods Multiplex ligation-dependent probe amplification was used to analyze BRCA1 rearrangements in 255 unrelated index patients with familial breast and/or ovarian cancer negative for BRCA1/BRCA2 mutations studied in Program of Genetic Counselling on Cancer of Valencia Community (Spain). The breakpoints of detected
novel rearrangement were characterized by sequencing. Results and discussion Five different rearrangements in the BRCA1 gene were identified in five unrelated index patients out of the 225 (2%). We found four large genomic rearrangements already
described consisting in a 1A/1B and 2 deletion; deletion of exons 5–7; deletion of exons 8–13; exon 20 deletion. Additionally,
we found the novel g.8097_22733del14637 deletion that encompasses exons 3–5. This deletion affects the RING domain of the
BRCA1 protein and it is suggestive of having a negative impact on its function. Conclusion The new mutation here reported broadens the mutational spectrum of large rearrangements. Furthermore, the five large rearrangements
found in patients non-carriers of BRCA1/BRCA2 mutations reinforce the need of studying BRCA1 large genomic rearrangements in genetic counselling programs. 相似文献
19.
Bayraktar S Elsayegh N Gutierrez Barrera AM Lin H Kuerer H Tasbas T Muse KI Ready K Litton J Meric-Bernstam F Hortobagyi GN Albarracin CT Arun B 《Cancer》2012,118(6):1515-1522
BACKGROUND:
It is unclear whether women with ductal carcinoma in situ (DCIS), like their counterparts with invasive breast cancer, warrant genetic risk assessment and testing on the basis of high‐risk variables. The authors of this report identified predictive factors for mutations in the breast cancer‐susceptibility genes BRCA1 and BRCA2 in women who were diagnosed with DCIS.METHODS:
One hundred eighteen women with DCIS who were referred for genetic counseling and underwent genetic testing for BRCA1/BRCA2 mutations between 2003 and 2010 were included in the study. Logistic regression models were fit to determine the associations between potential predictive factors and BRCA status.RESULTS:
Of 118 high‐risk women with DCIS, 27% (n = 32) tested positive for BRCA1/BRCA2 mutations. Of those, 10% (n = 12) and 17% (n = 20) had BRCA1 and BRCA2 mutations, respectively. Age, race, and tumor characteristics did not differ between BRCA noncarriers and carriers. In a multivariate logistic model, ≥2 relatives with ovarian cancer (OC) (odds ratio [OR], 8.81; 95% confidence interval [CI], 1.38‐56.29; P = .034), and a score ≥10% according to the BRCAPRO mathematical model for calculating the probability that a particular family member carries a germline BRCA mutation (OR, 6.37; 95% CI, 2.23‐18.22; P = .0005) remained as independent significant predictors for a BRCA mutation. Fifty‐seven percent of mutation carriers but only 25% of noncarriers underwent prophylactic mastectomy(P = .0037). This difference remained significant for patients aged ≤40 years (P = .025).CONCLUSIONS:
Women who had DCIS and a family history of OC or who had BRCAPRO scores ≥10% had a high rate of BRCA positivity regardless of age at diagnosis. These findings suggest that high‐risk patients with DCIS are appropriate candidates for genetic testing for BRCA mutations in the presence of predictive factors even if they do not have invasive breast cancer. Cancer 2011;. © 2011 American Cancer Society. 相似文献20.
Stacey A. South MD Heidi Vance MS Carolyn Farrell MS CNP Richard A. DiCioccio PhD Cathy Fahey BS M. Steven Piver MD Kerry J. Rodabaugh MD 《Cancer》2009,115(2):324-333