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Search Results: 1 - 10 of 5117 matches for " Australian Breast Cancer Family Study (ABCFS) and Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFaB) "
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The intronic G13964C variant in p53 is not a high-risk mutation in familial breast cancer in Australia
Anna Marsh, Amanda B Spurdle, Bruce C Turner, Sian Fereday, Heather Thorne, Gulietta M Pupo, Graham J Mann, John L Hopper, Joseph F Sambrook, Georgia Chenevix-Trench, Australian Breast Cancer Family Study (ABCFS) and Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFaB)
Breast Cancer Research , 2001, DOI: 10.1186/bcr319
Abstract: We genotyped 71 familial breast cancer patients and 143 control individuals for the G13964C variant using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis.Three (4.2%; 95% confidence interval [CI] 0–8.9%) G13964C heterozygotes were identified. The variant was also identified in 5 out of 143 (3.5%; 95% CI 0.6–6.4%) control individuals without breast cancer or a family history of breast cancer, however, which is no different to the proportion found in familial cases (P = 0.9).The present study would have had 80% power to detect an odds ratio of 4.4, and we therefore conclude that the G13946C polymorphism is not a 'high-risk' mutation for familial breast cancer.Mutations in BRCA1 and BRCA2 account for approximately 50% of breast/ovarian cancer pedigrees with more than four affected cases [1], whereas mutations in PTEN [2], CHK2 [3] and ATM [4] have been reported in a small number of breast cancer families or women with early onset breast cancer. In addition, germ line missense mutations in the p53 gene are associated with Li Fraumeni syndrome, a feature of which is early onset breast cancer [5]. The p53 gene is the most commonly mutated gene in human malignancies and has many important biological functions, including the control of cell cycle checkpoint after DNA damage. Deleterious germ line mutations in the p53 gene are found in less than 1% of all breast cancer patients, suggesting that the contribution of exonic mutations to familial breast cancer risk is small [6,7,8,9,10]. However, mutations in regulatory regions of the gene may affect p53 expression and thereby increase the risk of disease.One candidate for such a mutation is the G13964C variant in intron 6 of the p53 gene, which has been reported in 3 out of 42 patients with hereditary breast cancer (including a CC homozygote affected at age 59 years) but in none of 171 sporadic breast cancer patients (P = 0.0003) [11]. All three patients with the p53 variant had strong f
Detecting differential allelic expression using high-resolution melting curve analysis: application to the breast cancer susceptibility gene CHEK2
Tú Nguyen-Dumont, Lars P Jordheim, Jocelyne Michelon, Nathalie Forey, Sandrine McKay-Chopin, Kathleen Cuningham Foundation Consortium for Research into Familial Aspects of Breast Cancer (kConFab), Olga Sinilnikova, Florence Le Calvez-Kelm, Melissa C Southey, Sean V Tavtigian, Fabienne Lesueur
BMC Medical Genomics , 2011, DOI: 10.1186/1755-8794-4-39
Abstract: We implemented an assay based on high-resolution melting (HRM) curve analysis and developed an analysis tool for DAE assessment.We observed allelic expression imbalance in 4 of the 41 LCLs examined. All four were carriers of the truncating mutation 1100delC. We confirmed previous findings that this mutation induces non-sense mediated mRNA decay. In our series, we ruled out the possibility of a functional sequence variant located in the promoter region or in a regulatory element of CHEK2 that would lead to DAE in the transcriptional regulatory milieu of freely proliferating LCLs.Our results support that HRM is a sensitive and accurate method for DAE assessment. This approach would be of great interest for high-throughput mutation screening projects aiming to identify genes carrying functional regulatory polymorphisms.The CHEK2 gene (cell cycle checkpoint kinase 2) is a multiorgan tumour susceptibility gene involved in the maintenance of genomic stability. CHEK2 functions downstream of ATM (Ataxia-telangiectasia mutated) to phosphorylate several substrates, including TP53 (Tumour protein p53), Cdc25C (Cell division cycle 25C) and BRCA1 (Breast cancer 1, early onset), leading to cell cycle arrest, activation of DNA repair or apoptosis in response to DNA double-stranded breaks. Since CHEK2 plays a key role in the DNA damage pathway, loss of function of the protein may allow cells to evade normal cell cycle checkpoints, ultimately leading to tumour initiation or progression. The CHEK2*1100delC deletion, falling in the kinase domain of the protein, has been widely studied for its contribution to inherited breast cancer susceptibility [1]. This mutation induces a premature stop codon in exon 10, and causes the truncation of the protein at codon 381 thus abrogating its kinase activity. The frequency of CHEK2*1100delC differs between ethnic populations, and is higher in the North of Europe and low or absent in other countries [2].The CHEK2-Breast Cancer Consortium reported a
No germline mutations in the histone acetyltransferase gene EP300 in BRCA1 and BRCA2 negative families with breast cancer and gastric, pancreatic, or colorectal cancer
Ian G Campbell, David Choong, Georgia Chenevix-Trench, the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer
Breast Cancer Research , 2004, DOI: 10.1186/bcr803
Abstract: We screened the entire coding region of EP300 for mutations in the youngest affected members of 23 non-BRCA1/BRCA2 breast cancer families with at least one confirmed case of gastric, pancreatic and/or colorectal cancer. These families were ascertained in Australia through the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer.Denaturing HPLC analysis identified a heterozygous alteration at codon 211, specifically a GGC to AGC (glycine to serine) alteration, in two individuals. This conservative amino acid change was not within any known functional domains of EP300. The frequency of the Ser211 variant did not differ significanlty between a series of 352 breast cancer patients (4.0%) and 254 control individuals (2.8%; P = 0.5).The present study does not support a major role for EP300 mutations in breast and ovarian cancer families with a history of gastric, pancreatic and/or colorectal cancer.Pathogenic mutations in BRCA1 and BRCA2 account for the majority of but not all multiple-case breast cancer families that include members with ovarian cancer or male breast cancer. Among families with four or more female cases of breast cancer, almost 70% may be due to other predisposition genes [1]. Because there is a plethora of plausible breast cancer susceptibility candidates, any approach to their identification must be focused. Tumour suppressor genes that are known to be somatically inactivated in breast cancers are particularly attractive candidates and warrant close scrutiny. One such gene is EP300, which is a member of the histone acetyltransferase group of proteins. Its encoded protein, EP300, has been shown to regulate transcription through chromatin remodelling and by acting as a transcriptional coactivator [2]. It has been speculated that EP300 may play a central role in regulating responses to signals that induce growth or differentiation [3].Several lines of evidence suggest that EP300 may function as a tumour suppressor. EP300 is a
Variation in the RAD51 gene and familial breast cancer
Felicity Lose, Paul Lovelock, Georgia Chenevix-Trench, Graham J Mann, Gulietta M Pupo, Amanda B Spurdle, the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer
Breast Cancer Research , 2006, DOI: 10.1186/bcr1415
Abstract: All nine coding exons of the RAD51 gene were analysed for variation in 46 well-characterised, BRCA1/2-negative breast cancer families using denaturing high-performance liquid chromatography. Genotyping of the exon 6 p.R150Q variant was performed in an additional 66 families. Additionally, lymphoblastoid cell lines from breast cancer patients were subjected to single nucleotide primer extension analysis to assess RAD51 expression.No coding region variation was found, and all intronic variation detected was either found in unaffected controls or was unlikely to have functional consequences. Single nucleotide primer extension analysis did not reveal any allele-specific changes in RAD51 expression in all lymphoblastoid cell lines tested.Our study indicates that RAD51 is not a major familial breast cancer predisposition gene.Hereditary breast cancer accounts for around 5–10% of all breast cancer cases, while the other 90–95% is assumed to be 'sporadic', with no apparent family history. A large proportion of familial breast cancer (<40%) can be attributed to mutations in the high-risk genes BRCA1 and BRCA2 [1]. Additional breast cancer genes have been discovered, largely through disease syndromes displaying a predisposition for breast cancer. Breast cancer in families with syndromes such as Li-Fraumeni syndrome (resulting from p53 gene mutations) [2] and Cowden syndrome (the mutated PTEN gene) [3], however, are each estimated to account for less than 1% of hereditary breast cancer, and mutations in ATM (the gene mutated in ataxia telangiectasia) and CHEK2 are also predicted to account for only a small proportion of familial breast cancer [4,5]. The genetic basis of the large majority of familial breast cancer therefore remains unaccounted for.It is well known that deficiencies in DNA repair can lead to carcinogenesis. Double-stranded DNA breaks (DSBs) may be the most detrimental form of DNA damage because, if left unrepaired, the detection of broken chromosomes will lead
Correction: BCoR-L1 variation and breast cancer
Felicity Lose, Jeremy Arnold, David B Young, Carolyn J Brown, Graham J Mann, Gulietta M Pupo, The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Kum Khanna, Georgia Chenevix-Trench, Amanda B Spurdle
Breast Cancer Research , 2008, DOI: 10.1186/bcr2153
Abstract: The figures should therefore appear in the order shown in this correction.
BCoR-L1 variation and breast cancer
Felicity Lose, Jeremy Arnold, David B Young, Carolyn J Brown, Graham J Mann, Gulietta M Pupo, The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Kum Khanna, Georgia Chenevix-Trench, Amanda B Spurdle
Breast Cancer Research , 2007, DOI: 10.1186/bcr1759
Abstract: We performed mutation analysis of 38 BRCA1/2 mutation-negative breast cancer families with male breast cancer, prostate cancer, and/or haplotype sharing around BCoR-L1 to determine whether there is a role for BCoR-L1 as a high-risk breast cancer predisposition gene. In addition, we conducted quantitative real-time PCR (qRT-PCR) on lymphoblastoid cell lines (LCLs) from the index cases from these families and a number of cancer cell lines to assess the role of BCoR-L1 dysregulation in cancer and cancer families.Very little variation was detected in the coding region, and qRT-PCR analysis revealed that BCoR-L1 expression is highly variable in cancer-free subjects, high-risk breast cancer patients, and cancer cell lines. We also report the investigation of a new expression control, DIDO1 (death inducer-obliterator 1), that is superior to GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and UBC (ubiquitin C) for analysis of expression in LCLs.Our results suggest that BCoR-L1 expression does not play a large role in predisposition to familial breast cancer.Less than 40% of familial breast cancer can be attributed to mutations in the high-risk genes BRCA1 and BRCA2 despite their high penetrance [1,2]. Syndromes displaying a predisposition for breast cancer such as Li-Fraumeni syndrome (resulting from p53 gene mutations) [3], ataxia telangiectasia (ataxia telangiectasia-mutated, or ATM, gene) [4], and Cowden syndrome (phosphatase and tensin homologue, or PTEN, gene) [5] are estimated to account for no more than 10% of familial breast cancer collectively, and additional moderate-risk genes such as CHEK2 [6] and the recently reported BRIP1 (also called BACH1) [7] and PALB2 [8,9] account for an even smaller percentage. This leaves a large proportion of the genetic basis of familial breast cancer unexplained.Interestingly, BRCA2, p53, ATM, CHEK2, and BRIP1 all interact with the multifunctional tumour suppressor, BRCA1. BRCA1-interacting proteins are logical breast cancer candid
Mutation analysis of FANCD2, BRIP1/BACH1, LMO4 and SFN in familial breast cancer
Aaron G Lewis, James Flanagan, Anna Marsh, Gulietta M Pupo, Graham Mann, Amanda B Spurdle, Geoffrey J Lindeman, Jane E Visvader, Melissa A Brown, Georgia Chenevix-Trench, the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer
Breast Cancer Research , 2005, DOI: 10.1186/bcr1336
Abstract: The families used in this study were ascertained through the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab). Denaturing high performance liquid chromatography (DHPLC) analysis of the coding regions of these four genes was conducted in the youngest affected cases of 30 to 267 non-BRCA1/2 breast cancer families. In addition, a further 399 index cases were also screened for mutations in two functionally significant regions of the FANCD2 gene and 253 index cases were screened for two previously reported mutations in BACH1 (p. P47A and p. M299I).DHPLC analysis of FANCD2 identified six silent exonic variants, and a large number of intronic variants, which tagged two common haplotypes. One protein truncating variant was found in BRIP1/BACH1, as well as four missense variants, a silent change and a variant in the 3' untranslated region. No missense or splice site mutations were found in LMO4 or SFN. Analysis of the missense, silent and frameshift variants of FANCD2 and BACH1 in relatives of the index cases, and in a panel of controls, found no evidence suggestive of pathogenicity.There is no evidence that highly penetrant exonic or splice site mutations in FANCD2, BRIP1/BACH1, LMO4 or SFN contribute to familial breast cancer. Large scale association studies will be necessary to determine whether any of the polymorphisms or haplotypes identified in these genes contributes to breast cancer risk.Pathogenic mutations in BRCA1, BRCA2, TP53, PTEN, ATM and CHEK2 account for approximately a third of high-risk breast cancer families, suggesting that other breast cancer susceptibility genes exist [1-5]. Given the number of candidate breast cancer susceptibility genes, any approach to their identification needs to be focussed. Genes whose products are known to interact with BRCA1 and/or BRCA2, or are down-regulated in breast tumours, are particularly attractive candidates, and can be prioritised for investigation.FANCD2 is one of eight gene
Heterogeneity of Breast Cancer Associations with Five Susceptibility Loci by Clinical and Pathological Characteristics
Montserrat Garcia-Closas ,Per Hall,Heli Nevanlinna,Karen Pooley,Jonathan Morrison,Douglas A. Richesson,Stig E. Bojesen,B?rge G. Nordestgaard,Christen K. Axelsson,Jose I. Arias,Roger L. Milne,Gloria Ribas,Anna González-Neira,Javier Benítez,Pilar Zamora,Hiltrud Brauch,Christina Justenhoven,Ute Hamann,Yon-Dschun Ko,Thomas Bruening,Susanne Haas,Thilo D?rk,Peter Schürmann,Peter Hillemanns,Natalia Bogdanova,Michael Bremer,Johann Hinrich Karstens,Rainer Fagerholm,Kirsimari Aaltonen,Kristiina Aittom?ki,Karl von Smitten,Carl Blomqvist,Arto Mannermaa,Matti Uusitupa,Matti Eskelinen,Maria Tengstr?m,Veli-Matti Kosma,Vesa Kataja,Georgia Chenevix-Trench,Amanda B. Spurdle,Jonathan Beesley,Xiaoqing Chen,Australian Ovarian Cancer Management Group,The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer,Peter Devilee,Christi J. van Asperen,Catharina E. Jacobi,Rob A. E. M. Tollenaar,Petra E.A. Huijts,Jan G. M. Klijn,Jenny Chang-Claude,Silke Kropp,Tracy Slanger,Dieter Flesch-Janys,Elke Mutschelknauss,Ramona Salazar,Shan Wang-Gohrke,Fergus Couch,Ellen L. Goode,Janet E. Olson,Celine Vachon,Zachary S. Fredericksen,Graham G. Giles,Laura Baglietto,Gianluca Severi,John L. Hopper,Dallas R. English,Melissa C. Southey,Christopher A. Haiman,Brian E. Henderson,Laurence N. Kolonel,Loic Le Marchand,Daniel O. Stram,David J. Hunter,Susan E. Hankinson,David G. Cox,Rulla Tamimi,Peter Kraft,Mark E. Sherman,Stephen J. Chanock,Jolanta Lissowska,Louise A. Brinton,Beata Peplonska
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000054
Abstract: A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27–1.36)) than ER-negative (1.08 (1.03–1.14)) disease (P for heterogeneity = 10?13). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10?5, 10?8, 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10?4, respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09–1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83–0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.
Analysis of cancer risk and BRCA1 and BRCA2 mutation prevalence in the kConFab familial breast cancer resource
Graham J Mann, Heather Thorne, Rosemary L Balleine, Phyllis N Butow, Christine L Clarke, Edward Edkins, Gerda M Evans, Sián Fereday, Eric Haan, Michael Gattas, Graham G Giles, Jack Goldblatt, John L Hopper, Judy Kirk, Jennifer A Leary, Geoffrey Lindeman, Eveline Niedermayr, Kelly-Anne Phillips, Sandra Picken, Gulietta M Pupo, Christobel Saunders, Clare L Scott, Amanda B Spurdle, Graeme Suthers, Kathy Tucker, Georgia Chenevix-Trench, The Kathleen Cuningham Consortium for Research in Familial Breast Cancer
Breast Cancer Research , 2005, DOI: 10.1186/bcr1377
Abstract: Epidemiological, family history and lifestyle data, as well as biospecimens, are collected from multiple-case breast cancer families ascertained through family cancer clinics in Australia and New Zealand. We used the Tyrer-Cuzick algorithms to assess the prospective risk of breast cancer in women in the kConFab cohort who were unaffected with breast cancer at the time of enrolment in the study.Of kConFab's first 822 families, 518 families had multiple cases of female breast cancer alone, 239 had cases of female breast and ovarian cancer, 37 had cases of female and male breast cancer, and 14 had both ovarian cancer as well as male and female breast cancer. Data are currently held for 11,422 people and germline DNAs for 7,389. Among the 812 families with at least one germline sample collected, the mean number of germline DNA samples collected per family is nine. Of the 747 families that have undergone some form of mutation screening, 229 (31%) carry a pathogenic or splice-site mutation in BRCA1 or BRCA2. Germline DNAs and data are stored from 773 proven carriers of BRCA1 or BRCA1 mutations. kConFab's fresh tissue bank includes 253 specimens of breast or ovarian tissue – both normal and malignant – including 126 from carriers of BRCA1 or BRCA2 mutations.These kConFab resources are available to researchers anywhere in the world, who may apply to kConFab for biospecimens and data for use in ethically approved, peer-reviewed projects. A high calculated risk from the Tyrer-Cuzick algorithms correlated closely with the subsequent occurrence of breast cancer in BRCA1 and BRCA2 mutation positive families, but this was less evident in families in which no pathogenic BRCA1 or BRCA2 mutation has been detected.Ten to fifteen percent of women with breast cancer also have close relatives affected, and in many multiple-case families susceptibility to the disease appears to manifest as a dominantly inherited Mendelian trait. The BRCA1 locus on chromosome 17 co-segregates with breast
How do women at increased, but unexplained, familial risk of breast cancer perceive and manage their risk? A qualitative interview study
Louise A Keogh, Belinda J McClaren, Carmel Apicella, John L Hopper, the Australian Breast Cancer Family Study
Hereditary Cancer in Clinical Practice , 2011, DOI: 10.1186/1897-4287-9-7
Abstract: Participants were recruited from a population-based sample (the Australian Breast Cancer Family Study - ABCFS). The ABCFS includes women diagnosed with breast cancer and their relatives. For this study, women without breast cancer with at least one first- or second-degree relative diagnosed with breast cancer before age 50 were eligible unless a BRCA1 or BRCA2 mutation had been identified in their family. Data collection consisted of an audio recorded, semi-structured interview on the topic of breast cancer risk and screening decision-making. Data was analysed thematically.A total of 24 interviews were conducted, and saturation of the main themes was achieved. Women were classified into one of five groups: don't worry about cancer risk, but do screening; concerned about cancer risk, so do something; concerned about cancer risk, so why don't I do anything?; cancer inevitable; cancer unlikely.The language and framework women use to describe their risk of breast cancer must be the starting point in attempts to enhance women's understanding of risk and their prevention behaviour.It has been argued that health and risk have replaced illness and disease as the domains of interest for medicine [1,2]. 'The focus is no longer on illness, disability, and disease as matters of fate, but on health as a matter of ongoing moral self-transformation' [1, p172]. Women who have not had breast cancer, but who have a high familial risk of the disease, are a pertinent example of this phenomenon. While they may be physically well, the risk of breast cancer is likely to be a focus of their health care and practice, and there are proven interventions that decrease breast cancer incidence for women at high risk [3-5]. Genetic testing for a disease-predisposing mutation can provide a risk estimate and appropriate risk reduction options can be recommended for women from families in which a mutation is found, but for women from families in which no mutation has been identified this clarity and
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