Sir Peter MacCallum Department of Oncology - Research Publications
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ItemReply to the Baader-Meinhof phenomenon in ductal carcinoma in situ of the breast(WILEY-BLACKWELL, 2016-09)
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ItemThe prognostic significance of lysosomal protective protein (cathepsin A) in breast ductal carcinoma in situ(WILEY, 2019-06)AIMS: Cathepsin A (CTSA) is a key regulatory enzyme for galactoside metabolism. Additionally, it has a distinct proteolytic activity and plays a role in tumour progression. CTSA is differentially expressed at the mRNA level between breast ductal carcinoma in situ (DCIS) and invasive breast carcinoma (IBC). In this study, we aimed to characterise CTSA protein expression in DCIS and evaluate its prognostic significance. METHODS AND RESULTS: A large cohort of DCIS [n = 776 for pure DCIS and n = 239 for DCIS associated with IBC (DCIS/IBC)] prepared as a tissue microarray was immunohistochemically stained for CTSA. High CTSA expression was observed in 48% of pure DCIS. High expression was associated with features of poor DCIS prognosis, including younger age at diagnosis (<50 years), higher nuclear grade, hormone receptor negativity, HER2 positivity, high proliferative index and high hypoxia inducible factor 1 alpha expression. High CTSA expression was associated with shorter recurrence-free interval (RFI) (P = 0.0001). In multivariate survival analysis for patients treated with breast conserving surgery, CTSA was an independent predictor of shorter RFI (P = 0.015). DCIS associated with IBC showed higher CTSA expression than pure DCIS (P = 0.04). In the DCIS/IBC cohort, CTSA expression was higher in the invasive component than the DCIS component (P < 0.0001). CONCLUSION: CTSA is not only associated with aggressive behaviour and poor outcome in DCIS but also a potential marker to predict co-existing invasion in DCIS.
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ItemMolecular comparison of interval and screen-detected breast cancers(WILEY, 2019-06)
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ItemMolecular analysis of PALB2-associated breast cancers(WILEY, 2018-05)
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ItemInvasion in breast lesions: the role of the epithelial-stroma barrier(WILEY, 2018-06)Despite the significant biological, behavioural and management differences between ductal carcinoma in situ (DCIS) and invasive carcinoma of the breast, they share many morphological and molecular similarities. Differentiation of these two different lesions in breast pathological diagnosis is based typically on the presence of an intact barrier between the malignant epithelial cells and stroma; namely, the myoepithelial cell (MEC) layer and surrounding basement membrane (BM). Despite being robust diagnostic criteria, the identification of MECs and BM to differentiate in-situ from invasive carcinoma is not always straightforward. The MEC layer around DCIS may be interrupted and/or show an altered immunoprofile. MECs may be absent in some benign locally infiltrative lesions such as microglandular adenosis and infiltrating epitheliosis, and occasionally in non-infiltrative conditions such as apocrine lesions, and in these contexts this does not denote malignancy or invasive disease with metastatic potential. MECs may also be absent around some malignant lesions such as some forms of papillary carcinoma, yet these behave in an indolent fashion akin to some DCIS. In Paget's disease, malignant mammary epithelial cells extend anteriorly from the ducts to infiltrate the epidermis of the nipple but do not typically infiltrate through the BM into the dermis. Conversely, BM-like material can be seen around invasive carcinoma cells and around metastatic tumour cell deposits. Here, we review the role of MECs and BM in breast pathology and highlight potential clinical implications. We advise caution in interpretation of MEC features in breast pathology and mindfulness of the substantive evidence base in the literature associated with behaviour and clinical outcome of lesions classified as benign on conventional morphological examination before changing classification to an invasive lesion on the sole basis of MEC characteristics.
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ItemDuctal Carcinoma In Situ Biology, Biomarkers, and Diagnosis(FRONTIERS MEDIA SA, 2017-10-23)Ductal carcinoma in situ (DCIS) is an often-diagnosed breast disease and a known, non-obligate, precursor to invasive breast carcinoma. In this review, we explore the clinical and pathological features of DCIS, fundamental elements of DCIS biology including gene expression and genetic events, the relationship of DCIS with recurrence and invasive breast cancer, and the interaction of DCIS with the microenvironment. We also survey how these various elements are being used to solve the clinical conundrum of how to optimally treat a disease that has potential to progress, and yet is also likely over-treated in a significant proportion of cases.
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ItemLRH-1 expression patterns in breast cancer tissues are associated with tumour aggressiveness(IMPACT JOURNALS LLC, 2017-10-13)The significance and regulation of liver receptor homologue 1 (LRH-1, NR5A2), a tumour-promoting transcription factor in breast cancer cell lines, is unknown in clinical breast cancers. This study aims to determine LRH-1/NR5A2 expression in breast cancers and relationship with DNA methylation and tumour characteristics. In The Cancer Genome Atlas breast cancer cohort NR5A2 expression was positively associated with intragenic CpG island methylation (1.4-fold expression for fully methylated versus not fully methylated, p=0.01) and inversely associated with promoter CpG island methylation (0.6-fold expression for fully methylated versus not fully methylated, p=0.036). LRH-1 immunohistochemistry of 329 invasive carcinomas and ductal carcinoma in situ (DCIS) was performed. Densely punctate/coarsely granular nuclear reactivity was significantly associated with high tumour grade (p<0.005, p=0.033 in invasive carcinomas and DCIS respectively), negative estrogen receptor status (p=0.008, p=0.038 in overall cohort and invasive carcinomas, respectively), negative progesterone receptor status (p=0.003, p=0.013 in overall cohort and invasive carcinomas, respectively), HER2 amplification (overall cohort p=0.034) and non-luminal intrinsic subtype (p=0.018, p=0.038 in overall cohort and invasive carcinomas, respectively). These significant associations of LRH-1 protein expression with tumour phenotype suggest that LRH-1 is an important indicator of tumour biology in breast cancers and may be useful in risk stratification.
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ItemAnalysis of the Mitogen-activated protein kinase kinase 4 (MAP2K4) tumor suppressor gene in ovarian cancer(BMC, 2011-05-17)BACKGROUND: MAP2K4 is a putative tumor and metastasis suppressor gene frequently found to be deleted in various cancer types. We aimed to conduct a comprehensive analysis of this gene to assess its involvement in ovarian cancer. METHODS: We screened for mutations in MAP2K4 using High Resolution Melt analysis of 149 primary ovarian tumors and methylation at the promoter using Methylation-Specific Single-Stranded Conformation Polymorphism analysis of 39 tumors. We also considered the clinical impact of changes in MAP2K4 using publicly available expression and copy number array data. Finally, we used siRNA to measure the effect of reducing MAP2K4 expression in cell lines. RESULTS: In addition to 4 previously detected homozygous deletions, we identified a homozygous 16 bp truncating deletion and a heterozygous 4 bp deletion, each in one ovarian tumor. No promoter methylation was detected. The frequency of MAP2K4 homozygous inactivation was 5.6% overall, and 9.8% in high-grade serous cases. Hemizygous deletion of MAP2K4 was observed in 38% of samples. There were significant correlations of copy number and expression in three microarray data sets. There was a significant correlation between MAP2K4 expression and overall survival in one expression array data set, but this was not confirmed in an independent set. Treatment of JAM and HOSE6.3 cell lines with MAP2K4 siRNA showed some reduction in proliferation. CONCLUSIONS: MAP2K4 is targeted by genetic inactivation in ovarian cancer and restricted to high grade serous and endometrioid carcinomas in our cohort.
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ItemMicroRNA Genes and Their Target 3′-Untranslated Regions Are Infrequently Somatically Mutated in Ovarian Cancers(PUBLIC LIBRARY SCIENCE, 2012-04-20)MicroRNAs are key regulators of gene expression and have been shown to have altered expression in a variety of cancer types, including epithelial ovarian cancer. MiRNA function is most often achieved through binding to the 3'-untranslated region of the target protein coding gene. Mutation screening using massively-parallel sequencing of 712 miRNA genes in 86 ovarian cancer cases identified only 5 mutated miRNA genes, each in a different case. One mutation was located in the mature miRNA, and three mutations were predicted to alter the secondary structure of the miRNA transcript. Screening of the 3'-untranslated region of 18 candidate cancer genes identified one mutation in each of AKT2, EGFR, ERRB2 and CTNNB1. The functional effect of these mutations is unclear, as expression data available for AKT2 and EGFR showed no increase in gene transcript. Mutations in miRNA genes and 3'-untranslated regions are thus uncommon in ovarian cancer.