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Lars O Baumbusch,
Aslaug Helland,
Yun Wang,
Knut Liestøl,
Marci E Schaner,
Ruth Holm,
Dariush Etemadmoghadam,
Kathryn Alsop,
Pat Brown,
Gillian Mitchell, Sian Fereday,
Anna Defazio,
David D L Bowtell,
Gunnar B Kristensen,
Ole Christian Lingjærde,
Anne-Lise Børresen-Dale
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ABSTRACT: Genomic instability and copy number alterations in cancer are generally associated with poor prognosis; however, recent studies have suggested that extreme levels of genomic aberrations may be beneficial for the survival outcome for patients with specific tumour types. We investigated the extent of genomic instability in predominantly high-grade serous ovarian cancers (SOC) using two independent datasets, generated in Norway (n = 74) and Australia (n = 70), respectively. Genomic instability was quantified by the Total Aberration Index (TAI), a measure of the abundance and genomic size of copy number changes in a tumour. In the Norwegian cohort, patients with TAI above the median revealed significantly prolonged overall survival (p<0.001) and progression-free survival (p<0.05). In the Australian cohort, patients with above median TAI showed prolonged overall survival (p<0.05) and moderately, but not significantly, prolonged progression-free survival. Results were confirmed by univariate and multivariate Cox regression analyses with TAI as a continuous variable. Our results provide further evidence supporting an association between high level of genomic instability and prolonged survival of high-grade SOC patients, possibly as disturbed genome integrity may lead to increased sensitivity to chemotherapeutic agents.
PLoS ONE 01/2013; 8(1):e54356. · 4.09 Impact Factor
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Roel G W Verhaak,
Pablo Tamayo,
Ji-Yeon Yang,
Diana Hubbard,
Hailei Zhang,
Chad J Creighton, Sian Fereday,
Michael Lawrence,
Scott L Carter,
Craig H Mermel, [......],
Anna Defazio,
Michael J Birrer,
Joe W Gray,
John N Weinstein,
David D Bowtell,
Ronny Drapkin,
Jill P Mesirov,
Gad Getz,
Douglas A Levine,
Matthew Meyerson
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ABSTRACT: Because of the high risk of recurrence in high-grade serous ovarian carcinoma (HGS-OvCa), the development of outcome predictors could be valuable for patient stratification. Using the catalog of The Cancer Genome Atlas (TCGA), we developed subtype and survival gene expression signatures, which, when combined, provide a prognostic model of HGS-OvCa classification, named "Classification of Ovarian Cancer" (CLOVAR). We validated CLOVAR on an independent dataset consisting of 879 HGS-OvCa expression profiles. The worst outcome group, accounting for 23% of all cases, was associated with a median survival of 23 months and a platinum resistance rate of 63%, versus a median survival of 46 months and platinum resistance rate of 23% in other cases. Associating the outcome prediction model with BRCA1/BRCA2 mutation status, residual disease after surgery, and disease stage further optimized outcome classification. Ovarian cancer is a disease in urgent need of more effective therapies. The spectrum of outcomes observed here and their association with CLOVAR signatures suggests variations in underlying tumor biology. Prospective validation of the CLOVAR model in the context of additional prognostic variables may provide a rationale for optimal combination of patient and treatment regimens.
The Journal of clinical investigation 12/2012; · 15.39 Impact Factor
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Prue A Cowin,
Joshy George, Sian Fereday,
Elizabeth Loehrer,
Peter Van Loo,
Carleen Cullinane,
Dariush Etemadmoghadam,
Sarah Ftouni,
Laura Galletta,
Michael S Anglesio, [......],
Elizabeth L Christie,
Richard B Pearson,
Paul R Harnett,
Viola Heinzelmann-Schwarz,
Michael Friedlander,
Orla McNally,
Michael Quinn,
Peter Campbell,
Anna deFazio,
David D L Bowtell
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ABSTRACT: High-grade serous cancer (HGSC), the most common subtype of ovarian cancer, often becomes resistant to chemotherapy, leading to poor patient outcomes. Intratumoral heterogeneity occurs in nearly all solid cancers, including ovarian cancer, contributing to the development of resistance mechanisms. In this study, we examined the spatial and temporal genomic variation in HGSC using high-resolution single-nucleotide polymorphism arrays. Multiple metastatic lesions from individual patients were analyzed along with 22 paired pretreatment and posttreatment samples. We documented regions of differential DNA copy number between multiple tumor biopsies that correlated with altered expression of genes involved in cell polarity and adhesion. In the paired primary and relapse cohort, we observed a greater degree of genomic change in tumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy. Notably, deletion or downregulation of the lipid transporter LRP1B emerged as a significant correlate of acquired resistance in our analysis. Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin. Together, our findings underscore the large degree of variation in DNA copy number in spatially and temporally separated tumors in HGSC patients, and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients.
Cancer Research 08/2012; 72(16):4060-73. · 7.86 Impact Factor
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Kathryn Alsop, Sian Fereday,
Cliff Meldrum,
Anna deFazio,
Catherine Emmanuel,
Joshy George,
Alexander Dobrovic,
Michael J Birrer,
Penelope M Webb,
Colin Stewart,
Michael Friedlander,
Stephen Fox,
David Bowtell,
Gillian Mitchell
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ABSTRACT: The frequency of BRCA1 and BRCA2 germ-line mutations in women with ovarian cancer is unclear; reports vary from 3% to 27%. The impact of germ-line mutation on response requires further investigation to understand its impact on treatment planning and clinical trial design.
Women with nonmucinous ovarian carcinoma (n = 1,001) enrolled onto a population-based, case-control study were screened for point mutations and large deletions in both genes. Survival outcomes and responses to multiple lines of chemotherapy were assessed.
Germ-line mutations were found in 14.1% of patients overall, including 16.6% of serous cancer patients (high-grade serous, 22.6%); 44% had no reported family history of breast or ovarian cancer. Patients carrying germ-line mutations had improved rates of progression-free and overall survival. In the relapse setting, patients carrying mutations more frequently responded to both platin- and nonplatin-based regimens than mutation-negative patients, even in patients with early relapse after primary treatment. Mutation-negative patients who responded to multiple cycles of platin-based treatment were more likely to carry somatic BRCA1/2 mutations.
BRCA mutation status has a major influence on survival in ovarian cancer patients and should be an additional stratification factor in clinical trials. Treatment outcomes in BRCA1/2 carriers challenge conventional definitions of platin resistance, and mutation status may be able to contribute to decision making and systemic therapy selection in the relapse setting. Our data, together with the advent of poly(ADP-ribose) polymerase inhibitor trials, supports the recommendation that germ-line BRCA1/2 testing should be offered to all women diagnosed with nonmucinous, ovarian carcinoma, regardless of family history.
Journal of Clinical Oncology 06/2012; 30(21):2654-63. · 18.37 Impact Factor
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ABSTRACT: To determine if time to diagnosis is associated with stage of disease at diagnosis or survival among women with symptomatic ovarian cancer.
A representative sample of Australian women (n = 1,463) with ovarian cancer diagnosed between 2002 and 2005 who participated in a population-based case-control study were interviewed regarding the events leading to their diagnosis and were observed for mortality for 5 years.
Of the 1,318 women (90%) who presented to a medical practitioner with symptoms, 55% presented within 1 month, 70% in less than 2 months, and 92% within 6 months of symptom onset. There were no significant differences in the time from symptom onset to first medical practitioner consultation (P = .19) or symptom onset to diagnosis (P = .64) among women with borderline, early (International Federation of Gynecology and Obstetrics [FIGO] stages I to II) or late (FIGO stages III to IV) disease. There was also no association between time to diagnosis and survival; adjusted hazard ratio for long delay (> 12 months from symptom onset to diagnosis) versus short delay (≤ 1 month) was 0.94 (95% CI, 0.68 to 1.30). Women who had asymptomatic cancers diagnosed incidentally (n = 145) were younger and were more likely to have borderline or stage I disease compared with women who had symptomatic ovarian cancer.
The results of this study suggest that, once ovarian cancer is symptomatic, reducing the time to diagnosis would not greatly alter stage of disease at diagnosis or survival.
Journal of Clinical Oncology 06/2011; 29(16):2253-8. · 18.37 Impact Factor
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Kimberly C Wiegand,
Sohrab P Shah,
Osama M Al-Agha,
Yongjun Zhao,
Kane Tse,
Thomas Zeng,
Janine Senz,
Melissa K McConechy,
Michael S Anglesio,
Steve E Kalloger, [......],
Arusha Oloumi,
Niki Boyd,
Samuel A Aparicio,
Ie-Ming Shih,
Anne-Marie Mes-Masson,
David D Bowtell,
Martin Hirst,
Blake Gilks,
Marco A Marra,
David G Huntsman
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ABSTRACT: Ovarian clear-cell and endometrioid carcinomas may arise from endometriosis, but the molecular events involved in this transformation have not been described.
We sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWI–SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas.
ARID1A mutations were seen in 55 of 119 ovarian clear-cell carcinomas (46%), 10 of 33 endometrioid carcinomas (30%), and none of the 76 high-grade serous ovarian carcinomas. Seventeen carcinomas had two somatic mutations each. Loss of the BAF250a protein correlated strongly with the ovarian clear-cell carcinoma and endometrioid carcinoma subtypes and the presence of ARID1A mutations. In two patients, ARID1A mutations and loss of BAF250a expression were evident in the tumor and contiguous atypical endometriosis but not in distant endometriotic lesions.
These data implicate ARID1A as a tumor-suppressor gene frequently disrupted in ovarian clear-cell and endometrioid carcinomas. Since ARID1A mutation and loss of BAF250a can be seen in the preneoplastic lesions, we speculate that this is an early event in the transformation of endometriosis into cancer. (Funded by the British Columbia Cancer Foundation and the Vancouver General Hospital–University of British Columbia Hospital Foundation.).
New England Journal of Medicine 10/2010; 363(16):1532-43. · 53.30 Impact Factor
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Ahmed Ashour Ahmed,
Dariush Etemadmoghadam,
Jillian Temple,
Andy G Lynch,
Mohamed Riad Australian Ovarian Cancer Study Group,
Raghwa Sharma,
Colin Stewart, Sian Fereday,
Carlos Caldas,
Anna deFazio,
David Bowtell,
James D Brenton
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ABSTRACT: Numerous studies have tested the association between TP53 mutations in ovarian cancer and prognosis but these have been consistently confounded by limitations in study design, methodology, and/or heterogeneity in the sample cohort. High-grade serous (HGS) carcinoma is the most clinically important histological subtype of ovarian cancer. As these tumours may arise from the ovary, Fallopian tube or peritoneum, they are collectively referred to as high-grade pelvic serous carcinoma (HGPSC). To identify the true prevalence of TP53 mutations in HGPSC, we sequenced exons 2–11 and intron–exon boundaries in tumour DNA from 145 patients. HGPSC cases were defined as having histological grade 2 or 3 and FIGO stage III or IV. Surprisingly, pathogenic TP53 mutations were identified in 96.7% (n = 119/123) of HGPSC cases. Molecular and pathological review of mutation-negative cases showed evidence of p53 dysfunction associated with copy number gain of MDM2 or MDM4, or indicated the exclusion of samples as being low-grade serous tumours or carcinoma of uncertain primary site. Overall, p53 dysfunction rate approached 100% of confirmed HGPSCs. No association between TP53 mutation and progression-free or overall survival was found. From this first comprehensive mapping of TP53 mutation rate in a homogeneous group of HGPSC patients, we conclude that mutant TP53 is a driver mutation in the pathogenesis of HGPSC cancers. Because TP53 mutation is almost invariably present in HGPSC, it is not of substantial prognostic or predictive significance. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology 04/2010; 221(1):49 - 56. · 6.32 Impact Factor
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Ahmed Ashour Ahmed,
Dariush Etemadmoghadam,
Jillian Temple,
Andy G Lynch,
Mohamed Riad,
Raghwa Sharma,
Colin Stewart, Sian Fereday,
Carlos Caldas,
Anna Defazio,
David Bowtell,
James D Brenton
[show abstract]
[hide abstract]
ABSTRACT: Numerous studies have tested the association between TP53 mutations in ovarian cancer and prognosis but these have been consistently confounded by limitations in study design, methodology, and/or heterogeneity in the sample cohort. High-grade serous (HGS) carcinoma is the most clinically important histological subtype of ovarian cancer. As these tumours may arise from the ovary, Fallopian tube or peritoneum, they are collectively referred to as high-grade pelvic serous carcinoma (HGPSC). To identify the true prevalence of TP53 mutations in HGPSC, we sequenced exons 2-11 and intron-exon boundaries in tumour DNA from 145 patients. HGPSC cases were defined as having histological grade 2 or 3 and FIGO stage III or IV. Surprisingly, pathogenic TP53 mutations were identified in 96.7% (n = 119/123) of HGPSC cases. Molecular and pathological review of mutation-negative cases showed evidence of p53 dysfunction associated with copy number gain of MDM2 or MDM4, or indicated the exclusion of samples as being low-grade serous tumours or carcinoma of uncertain primary site. Overall, p53 dysfunction rate approached 100% of confirmed HGPSCs. No association between TP53 mutation and progression-free or overall survival was found. From this first comprehensive mapping of TP53 mutation rate in a homogeneous group of HGPSC patients, we conclude that mutant TP53 is a driver mutation in the pathogenesis of HGPSC cancers. Because TP53 mutation is almost invariably present in HGPSC, it is not of substantial prognostic or predictive significance.
The Journal of Pathology 02/2010; 221(1):49-56. · 6.32 Impact Factor
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Dariush Etemadmoghadam,
Anna deFazio,
Rameen Beroukhim,
Craig Mermel,
Joshy George,
Gad Getz,
Richard Tothill,
Aikou Okamoto,
Maria B Raeder,
Paul Harnett, [......],
Yoke-Eng Chiew,
Nadia Traficante, Sian Fereday,
Daryl Johnson,
Stephen Fox,
William Sellers,
Mitsuyoshi Urashima,
Helga B Salvesen,
Matthew Meyerson,
David Bowtell
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ABSTRACT: A significant number of women with serous ovarian cancer are intrinsically refractory to platinum-based treatment. We analyzed somatic DNA copy number variation and gene expression data to identify key mechanisms associated with primary resistance in advanced-stage serous cancers.
Genome-wide copy number variation was measured in 118 ovarian tumors using high-resolution oligonucleotide microarrays. A well-defined subset of 85 advanced-stage serous tumors was then used to relate copy number variation to primary resistance to treatment. The discovery-based approach was complemented by quantitative-PCR copy number analysis of 12 candidate genes as independent validation of previously reported associations with clinical outcome. Likely copy number variation targets and tumor molecular subtypes were further characterized by gene expression profiling.
Amplification of 19q12, containing cyclin E (CCNE1), and 20q11.22-q13.12, mapping immediately adjacent to the steroid receptor coactivator NCOA3, was significantly associated with poor response to primary treatment. Other genes previously associated with copy number variation and clinical outcome in ovarian cancer were not associated with primary treatment resistance. Chemoresistant tumors with high CCNE1 copy number and protein expression were associated with increased cellular proliferation but so too was a subset of treatment-responsive patients, suggesting a cell-cycle independent role for CCNE1 in modulating chemoresponse. Patients with a poor clinical outcome without CCNE1 amplification overexpressed genes involved in extracellular matrix deposition.
We have identified two distinct mechanisms of primary treatment failure in serous ovarian cancer, involving CCNE1 amplification and enhanced extracellular matrix deposition. CCNE1 copy number is validated as a dominant marker of patient outcome in ovarian cancer.
Clinical Cancer Research 03/2009; 15(4):1417-27. · 7.74 Impact Factor
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Michael S Anglesio,
Jeremy M Arnold,
Joshy George,
Anna V Tinker,
Richard Tothill,
Nic Waddell,
Lisa Simms,
Bianca Locandro, Sian Fereday,
Nadia Traficante,
Peter Russell,
Raghwa Sharma,
Michael J Birrer,
Anna deFazio,
Georgia Chenevix-Trench,
David D L Bowtell
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ABSTRACT: Approximately, 10% to 15% of serous ovarian tumors fall into the category designated as tumors of low malignant potential (LMP). Like their invasive counterparts, LMP tumors may be associated with extraovarian disease, for example, in the peritoneal cavity and regional lymph nodes. However, unlike typical invasive carcinomas, patients generally have a favorable prognosis. The mutational profile also differs markedly from that seen in most serous carcinomas. Typically, LMP tumors are associated with KRAS and BRAF mutations. Interrogation of expression profiles in serous LMP tumors suggested overall redundancy of RAS-MAPK pathway mutations and a distinct mechanism of oncogenesis compared with high-grade ovarian carcinomas. Our findings indicate that activating mutation of the RAS-MAPK pathway in serous LMP may be present in >70% of cases compared with approximately 12.5% in serous ovarian carcinomas. In addition to mutations of KRAS (18%) and BRAF (48%) mutations, ERBB2 mutations (6%), but not EGFR, are prevalent among serous LMP tumors. Based on the expression profile signature observed throughout our serous LMP cohort, we propose that RAS-MAPK pathway activation is a requirement of serous LMP tumor development and that other activators of this pathway are yet to be defined. Importantly, as few nonsurgical options exist for treatment of recurrent LMP tumors, therapeutic targeting of this pathway may prove beneficial, especially in younger patients where maintaining fertility is important.
Molecular Cancer Research 11/2008; 6(11):1678-90. · 4.29 Impact Factor
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Sharon E Johnatty,
Jonathan Beesley,
Jim Paul, Sian Fereday,
Amanda B Spurdle,
Penelope M Webb,
Karen Byth,
Sharon Marsh,
Howard McLeod,
Paul R Harnett,
Robert Brown,
Anna DeFazio,
Georgia Chenevix-Trench
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ABSTRACT: The human ABCB1 gene encodes P-glycoprotein, which transports a broad range of anticancer drugs, including paclitaxel. Although the functional consequences of ABCB1 polymorphisms have been the subject of numerous studies, few have assessed the association with clinical outcome.
We assessed the association between the 2677G>T/A, 3435C>T, and 1236C>T ABCB1 polymorphisms and progression-free and overall survival in 309 patients from the Australian Ovarian Cancer Study treated with paclitaxel/carboplatin and subsequently tested significant observations in an independent validation set.
Women who carried the minor T/A alleles at the 2677G>T/A polymorphism were significantly less likely to relapse following treatment compared with homozygote GG carriers (P(Log-rank)=0.001) in the Australian Ovarian Cancer Study cohort. Subgroup analyses showed that this effect was limited to cases with residual disease <or=1 cm (P(Log-rank)=0.0004), not for those with residual disease >1 cm (P(Log-rank)=0.3). This effect was not confirmed in an independent validation set of carboplatin/paclitaxel-treated patients (n=278) using a higher residual disease cut point (<or=2 cm). However, analysis of the unrestricted data set expanded to include docetaxel-treated patients (n=914) did support an effect of the 2677T/A allele in patients with no macroscopic residual disease (hazard ratio, 0.70; 95% confidence interval, 0.46-1.04; P(one-sided)=0.039).
Our findings indicate that there is an effect of the 2677G>T/A polymorphism on progression-free survival in ovarian cancer patients who are treated with a taxane/carboplatin, which is dependent on the extent of residual disease, with a better prognosis for patients with the 2677T/A allele and minimal residual disease.
Clinical Cancer Research 09/2008; 14(17):5594-601. · 7.74 Impact Factor
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Richard W Tothill,
Anna V Tinker,
Joshy George,
Robert Brown,
Stephen B Fox,
Stephen Lade,
Daryl S Johnson,
Melanie K Trivett,
Dariush Etemadmoghadam,
Bianca Locandro,
Nadia Traficante, Sian Fereday,
Jillian A Hung,
Yoke-Eng Chiew,
Izhak Haviv,
Dorota Gertig,
Anna DeFazio,
David D L Bowtell
[show abstract]
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ABSTRACT: The study aim to identify novel molecular subtypes of ovarian cancer by gene expression profiling with linkage to clinical and pathologic features.
Microarray gene expression profiling was done on 285 serous and endometrioid tumors of the ovary, peritoneum, and fallopian tube. K-means clustering was applied to identify robust molecular subtypes. Statistical analysis identified differentially expressed genes, pathways, and gene ontologies. Laser capture microdissection, pathology review, and immunohistochemistry validated the array-based findings. Patient survival within k-means groups was evaluated using Cox proportional hazards models. Class prediction validated k-means groups in an independent dataset. A semisupervised survival analysis of the array data was used to compare against unsupervised clustering results.
Optimal clustering of array data identified six molecular subtypes. Two subtypes represented predominantly serous low malignant potential and low-grade endometrioid subtypes, respectively. The remaining four subtypes represented higher grade and advanced stage cancers of serous and endometrioid morphology. A novel subtype of high-grade serous cancers reflected a mesenchymal cell type, characterized by overexpression of N-cadherin and P-cadherin and low expression of differentiation markers, including CA125 and MUC1. A poor prognosis subtype was defined by a reactive stroma gene expression signature, correlating with extensive desmoplasia in such samples. A similar poor prognosis signature could be found using a semisupervised analysis. Each subtype displayed distinct levels and patterns of immune cell infiltration. Class prediction identified similar subtypes in an independent ovarian dataset with similar prognostic trends.
Gene expression profiling identified molecular subtypes of ovarian cancer of biological and clinical importance.
Clinical Cancer Research 09/2008; 14(16):5198-208. · 7.74 Impact Factor
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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 Canc Family Stud,
K Cunningham Fdn Consortium Res Fa
