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Dive into the research topics where Jennifer A. Leary is active.

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Featured researches published by Jennifer A. Leary.


Breast Cancer Research | 2006

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 Butow; Christine L. Clarke; Edward Edkins; Gerda M Evans; Sian Fereday; Eric Haan; Michael Gattas; Graham G. Giles; Jack Goldblatt; John L. Hopper; Judy Kirk; Jennifer A. Leary; Geoffery Lindeman; Eveline Niedermayr; Kelly-Anne Phillips; Sandra Picken; Gulietta M. Pupo; Christobel Saunders; Clare L. Scott; Amanda B. Spurdle; Graeme Suthers; Katherine L. Tucker; Georgia Chenevix-Trench

IntroductionThe Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) is a multidisciplinary, collaborative framework for the investigation of familial breast cancer. Based in Australia, the primary aim of kConFab is to facilitate high-quality research by amassing a large and comprehensive resource of epidemiological and clinical data with biospecimens from individuals at high risk of breast and/or ovarian cancer, and from their close relatives.MethodsEpidemiological, 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.ResultsOf kConFabs 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. kConFabs fresh tissue bank includes 253 specimens of breast or ovarian tissue – both normal and malignant – including 126 from carriers of BRCA1 or BRCA2 mutations.ConclusionThese 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.


Journal of Medical Genetics | 2005

Large genomic rearrangements of both BRCA2 and BRCA1 are a feature of the inherited breast/ovarian cancer phenotype in selected families

A M Woodward; T A Davis; A G S Silva; Judy Kirk; Jennifer A. Leary

Introduction: A strong family history of breast and/or ovarian cancer can often be explained by small insertions, deletions, or substitutions in BRCA1 or BRCA2 and large genomic rearrangements in BRCA1. However, there is little evidence that genomic rearrangements are a major factor in BRCA2 associated breast cancer and the frequencies of rearrangements in BRCA1 in large clinic based populations are unknown. Objective: To investigate the frequency of large genomic rearrangements in BRCA1 and BRCA2 in a large clinic based population at high risk of developing breast and/or ovarian cancer. Methods: Multiplex ligation dependent probe amplification was used to comprehensively screen BRCA1 and/or BRCA2 in 312 index cases. Results: Three novel deletions detected in BRCA2 were found exclusively in families with at least one case of male breast cancer. Novel rearrangements in BRCA1 were detected mostly in families with both breast and ovarian cancer. Families with these mutations were significantly younger at average age of cancer diagnosis. Conclusion: Screening for large genomic rearrangements in both BRCA1 and BRCA2 is strongly supported by this study, in particular in multiple case breast/ovarian families with a young age of onset (BRCA1) and families containing at least one case of male breast cancer (BRCA2).


Genes, Chromosomes and Cancer | 2004

Germ-line mutations in BRCA1 or BRCA2 in the normal breast are associated with altered expression of estrogen-responsive proteins and the predominance of progesterone receptor A.

Patricia A. Mote; Jennifer A. Leary; Kelly A. Avery; Kerstin Sandelin; Georgia Chenevix-Trench; Judy Kirk; Christine L. Clarke; kConFab Investigators

The breast cancer susceptibility genes BRCA1 and BRCA2 are responsible for a large proportion of familial breast and ovarian cancer, yet little is known of how disruptions in the functions of the proteins these genes encode increased cancer risk preferentially in hormone‐dependent tissue. There is no information on whether a germ‐line mutation in BRCA1 or BRCA2 causes disruptions in hormone‐signaling pathways in the normal breast. In this study markers of hormone responsiveness were measured in prophylactically removed normal breast tissue (n = 31) in women bearing a germ‐line pathogenic mutation in one of the BRCA genes. The estrogen receptor (ER) and proteins associated with ER action in hormone‐sensitive tissues, namely, PS2 and the progesterone receptor (PR), were detected immunohistochemically. ER expression was not different in BRCA mutation carriers than in noncarriers, but there was a reduction in PS2 expression. PR expression was also reduced, and there was a striking lack of expression of the PRB isoform, which resulted in cases with PRA‐only expression in BRCA1 and BRCA2 mutation carriers. The alterations in PS2 and PR expression were similar in the BRCA1 and BRCA2 carriers, demonstrating that although these proteins are structurally and functionally distinct, there is overlap in their interaction with hormone‐signaling pathways. This study provides evidence for altered cell function arising from loss of function of one BRCA allele in the normal breast, leading to PS2 loss, preferential PRB loss, and expression of PRA alone. In breast cancer development, PRA overexpression becomes evident in premalignant lesions and is associated with features of poor prognosis in invasive disease and altered cell function in vitro. The results of this study suggest that heterozygosity for a germ‐line mutation in BRCA1 or BRCA2 results in development of PRA predominance. This is likely to lead to changes in progesterone signaling in hormone‐dependent tissues, which may be a factor in the increased risk of cancer in these tissues in women with germ‐line BRCA1 or BRCA2 mutations.


British Journal of Cancer | 2006

Evaluation of models to predict BRCA germline mutations

H H Kang; Rachel Williams; Jennifer A. Leary; Clare Ringland; Judy Kirk; Robyn L. Ward

The selection of candidates for BRCA germline mutation testing is an important clinical issue yet it remains a significant challenge. A number of risk prediction models have been developed to assist in pretest counselling. We have evaluated the performance and the inter-rater reliability of four of these models (BRCAPRO, Manchester, Penn and the Myriad-Frank). The four risk assessment models were applied to 380 pedigrees of families who had undergone BRCA1/2 mutation analysis. Sensitivity, specificity, positive and negative predictive values, likelihood ratios and area under the receiver operator characteristic (ROC) curve were calculated for each model. Using a greater than 10% probability threshold, the likelihood that a BRCA test result was positive in a mutation carrier compared to the likelihood that the same result would be expected in an individual without a BRCA mutation was 2.10 (95% confidence interval (CI) 1.66–2.67) for Penn, 1.74 (95% CI 1.48–2.04) for Myriad, 1.35 (95% CI 1.19–1.53) for Manchester and 1.68 (95% CI 1.39–2.03) for BRCAPRO. Application of these models, therefore, did not rule in BRCA mutation carrier status. Similar trends were observed for separate BRCA1/2 performance measures except BRCA2 assessment in the Penn model where the positive likelihood ratio was 5.93. The area under the ROC curve for each model was close to 0.75. In conclusion, the four models had very little impact on the pre-test probability of disease; there were significant clinical barriers to using some models and risk estimates varied between experts. Use of models for predicting BRCA mutation status is not currently justified for populations such as that evaluated in the current study.


Genes, Chromosomes and Cancer | 1997

Analysis of loss of heterozygosity and KRAS2 mutations in ovarian neoplasms: Clinicopathological correlations

Georgia Chenevix-Trench; Judith Kerr; Terry Hurst; Yang-Chia Shih; David M. Purdie; Lee Bergman; Michael Friedlander; Barbara Sanderson; Anna Zournazi; Tania Coombs; Jennifer A. Leary; Eric Crawford; Andrew N. Shelling; Inez Cooke; Trivadi S. Ganesan; Jeffrey Searle; Chan Choi; J. Carl Barrett; Soo Keat Khoo; Bruce G. Ward

The molecular events that give rise to ovarian epithelial neoplasms are not well understood. In particular, it is not known whether adenocarcinomas arise from benign or low malignant potential (LMP) precursors. We have examined a large series of benign (25) and LMP (31) ovarian tumors for loss of heterozygosity (LOH) at multiple loci on 17 chromosomes. LOH was observed in benign tumors on chromosomes 6 (14%) and 9 (5%) and on the X chromosome (33%) only. LOH on these chromosomes was also detected in a small number of LMP neoplasms, suggesting that these may derive sometimes from benign precursors. In addition, we examined LOH in 93 adenocarcinomas. Analysis of associations between LOH events showed that LOH on chromosomes 5 and 17 (P = 0.0002) and on chromosomes 17 and 18 (P = 0.00007) were associated significantly with each other, which suggests that these may represent cooperative, progressive events. No novel significant associations were identified between LOH events and stage, grade, or histology, which would indicate the existence of genetic heterogeneity in ovarian neoplasms. KRAS2 mutations were detected more often in LMP neoplasms than in malignant tumors (P = 0.004) and were detected more often in Stage I/II malignant tumors than in Stage III/IV malignant tumors (P = 0.033), suggesting that LMP tumors with KRAS2 mutations are unlikely to progress to frank malignancy. Univariate (but not multivariate) survival analysis showed that LOH of chromosomes 11 (P = 0.039) and 17 (P = 0.04) was associated with a significantly worse prognosis. Replication of these novel findings is necessary, and the identification, isolation, and characterization of the critical genes affected by LOH will determine their importance in the pathogenesis of ovarian malignancies. Genes Chromosom. Cancer 18:75–83, 1997.


Human Genetics | 2003

Average age-specific cumulative risk of breast cancer according to type and site of germline mutations in BRCA1 and BRCA2 estimated from multiple-case breast cancer families attending Australian family cancer clinics

Clare L. Scott; Mark A. Jenkins; Melissa C. Southey; Tracey A. Davis; Jennifer A. Leary; Douglas F. Easton; Kelly-Anne Phillips; John L. Hopper

If the risk of disease is not the same for all germline mutations in a given gene, or if there are other familial modifiers of risk in carriers, then family-history-based estimates of average risk for detected mutations in that gene will depend on how carriers are sampled. Risk may also depend on the site or type of mutation. We studied 51 families with strong histories of breast cancer who attended Australian family cancer clinics and in which a germline mutation in BRCA1 or BRCA2 had been identified (28 and 23 families, respectively). Breast cancer risk in carriers was estimated under maximum likelihood theory, using information from all family members including those not tested, with adjustment for ascertainment by conditioning on genotype of the proband and family phenotype. The average cumulative risk of breast cancer for mutations in either BRCA1 or BRCA2 was 27% (95% confidence interval 16–43%) to age 50 and 64% (44–83%) to age 70. When grouped, the incidence in carriers was on average 17 (10–30) times that in non-carriers, independent of gene or mutation type (hazard ratios: 11 (4–29) for BRCA1, 23 (12–43) for BRCA2 (P for difference = 0.23); 13 (6–29) for protein-truncating mutations, 30 (9–104) for missense mutations and 30 (10–90) for splice-site mutations). For missense mutations, this was equivalent to a cumulative risk to age 70 of 83% (40–100%) and was due in part, but not totally, to the missense mutations 300 T>G in BRCA1 and 4486 G>T in BRCA2, which were individually found to be associated with high risk (P<0.001). Mutations in the central region of BRCA1 may be associated with a lower risk. The issue of the pathogenicity of specific variants may be addressed analytically providing there are one or more suitably informative families with that mutation.


Cancer Letters | 1996

MDR1 and multidrug resistance-associated protein (MRP) gene expression in epithelial ovarian tumors

Maria Kavallaris; Jennifer A. Leary; Julie A. Barrett; Michael Friedlander

Clinical drug resistance poses a major problem in the successful treatment of ovarian cancer. Two genes, MDR1 and MRP, have been found to play a role in the multidrug resistance phenotype of a number of human tumors. Using a sensitive semiquantitative PCR assay we examined 53 primary untreated ovarian tumors for expression of both MDR1 and MRP genes. Approximately one-third of the tumors expressed MDR1 while all the tumors expressed varying levels of the MRP gene.


British Journal of Cancer | 1990

Demonstration of somatic rearrangements and genomic heterogeneity in human ovarian cancer by DNA fingerprinting

E. M. Boltz; P. Harnett; Jennifer A. Leary; R. Houghton; R. F. Kefford; M. L. Friedlander

A detailed study was performed in 14 patients with epithelial ovarian tumours using the satellite probes 33.15, 228S and 216S to investigate the nature of somatic changes and frequency with which clonal changes could be demonstrated during metastasis and progression. Somatic changes were evident in approximately 70% of ovarian tumours, the most common being a deletion or reduction in intensity of a band suggesting loss of heterozygosity. Additional changes that were observed included increased intensification of single bands and the appearance of novel DNA fragments. Somatic alterations were seen following digestion of DNA with methylation resistant restriction endonucleases indicating that methylation differences alone could not account for all of the somatic changes. Using DNA fingerprint analysis ovarian tumours were shown to be heterogeneous with different DNA patterns observed in different sites in five of eight patients. Generally, within an individual patient the primary and metastases appeared to share a DNA fingerprint pattern with minor variations occurring in different sites suggesting that different populations have derived from a common stem line. This study clearly demonstrates that DNA fingerprint analysis is a sensitive method to detect somatic changes in tumour DNA and for investigating the development of clonal heterogeneity in ovarian tumours.


Pathology | 1991

In-situ hybridization using biotinylated DNA probes to human papillomavirus in adenocarcinoma-in-situ and endocervical glandular dysplasia of the uterine cervix

Jennifer A. Leary; Richard Jaworski; Roger Houghton

&NA; In‐situ hybridization using biotinylated probes to human papillomavirus (HPV) DNA was performed on formalin fixed paraffin embedded tissue in 30 patients with histologically confirmed adenocarcinoma‐in‐situ (AIS). Thirteen of the 30 cases contained areas of endocervical glandular dysplasia (EGD) admixed with AIS. Twenty one patients showed positive staining of the AIS nuclei for HPV DNA. Ten cases (33%) were positive for HPV 16 DNA and 11 cases (37%) were positive for HPV 18 DNA. No case showed synchronous expression of HPV 16 and 18 DNA. All cases of AIS were negative for HPV 6b and 11 DNA. Four cases of EGD were positive for HPV 18 DNA and 2 cases were positive for HPV 16 DNA. Four of 6 cases of intestinal dysplasia/AIS were positive for HPV 18 DNA. Associated squamous abnormalities (HPV ± CIN ± SCC) were noted in 15 cases. Of these, 7 showed positive staining for HPV DNA in the squamous lesion. Moreover, 5 of these were positive in both the AIS and squamous lesion. In‐situ hybridization using biotinylated DNA probes is a sensitive and safe technique readily adaptable to routine histopathology.


Biotechnic & Histochemistry | 1998

Immunohistochemical Detection of Progesterone Receptors in Archival Breast Cancer

Patricia A. Mote; Jennifer A. Leary; Christine L. Clarke

The progesterone receptor (PR) is an important marker of response to endocrine agents in breast cancer. Immunohistochemical demonstration of PR in formalin fixed tissue has previously proved difficult, and heat pretreatment is considered necessary to retrieve the antigen. There are few data on the effectiveness of autoclaving in unmasking PR, however, and it is not known whether all PR epitopes are equally unmasked. The objectives of this study were to compare the efficacy of autoclaving and microwaving to retrieve PR antigen in archival breast tumors, to determine whether there is an epitope-dependent variability in the pretreatment required, and to examine different slide types and adhesives to reduce the problem of section loss frequently associated with these procedures. Paraffin embedded sections were cut at 2 or 4 microm, mounted onto various slide types with or without the addition of adhesive, and heat pretreated prior to immunoperoxidase staining. Whereas PR immunoreactivity was clearly demonstrated in tissue after both autoclaving and microwaving, autoclaving produced a significantly stronger staining intensity under the conditions used in this study. The duration of autoclaving required to reveal PR fully differed for different epitopes examined. In the absence of heat pretreatment, PR was not detected. Section retention was improved by the use of adhesives and by cutting tissue at 2 microm. Maximum retention was obtained using positively charged slides coated with Mayer albumen adhesive. We conclude that for maximal tissue preservation autoclave pretreatment is the preferred method of PR antigen retrieval from archival breast tumors, that there is epitope-dependent variability in pretreatment required, and that section loss during this procedure can be minimized by choice of slide type, the use of adhesive, and by cutting sections at 2 microm.

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Georgia Chenevix-Trench

QIMR Berghofer Medical Research Institute

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Amanda B. Spurdle

QIMR Berghofer Medical Research Institute

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Clare L. Scott

Walter and Eliza Hall Institute of Medical Research

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Heather Thorne

Peter MacCallum Cancer Centre

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Judith Kerr

QIMR Berghofer Medical Research Institute

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