Sir Peter MacCallum Department of Oncology - Research Publications
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ItemA quantitative model to predict pathogenicity of missense variants in the TP53 gene(WILEY, 2019-06)Germline pathogenic variants in the TP53 gene cause Li-Fraumeni syndrome, a condition that predisposes individuals to a wide range of cancer types. Identification of individuals carrying a TP53 pathogenic variant is linked to clinical management decisions, such as the avoidance of radiotherapy and use of high-intensity screening programs. The aim of this study was to develop an evidence-based quantitative model that integrates independent in silico data (Align-GVGD and BayesDel) and somatic to germline ratio (SGR), to assign pathogenicity to every possible missense variant in the TP53 gene. To do this, a likelihood ratio for pathogenicity (LR) was derived from each component calibrated using reference sets of assumed pathogenic and benign missense variants. A posterior probability of pathogenicity was generated by combining LRs, and algorithm outputs were validated using different approaches. A total of 730 TP53 missense variants could be assigned to a clinically interpretable class. The outputs of the model correlated well with existing clinical information, functional data, and ClinVar classifications. In conclusion, these quantitative outputs provide the basis for individualized assessment of cancer risk useful for clinical interpretation. In addition, we propose the value of the novel SGR approach for use within the ACMG/AMP guidelines for variant classification.
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ItemAn analysis of a multiple biomarker panel to better predict prostate cancer metastasis after radical prostatectomy(WILEY, 2019-03-01)A plethora of individual candidate biomarkers for predicting biochemical relapse in localized prostate cancer (PCa) have been proposed. Combined biomarkers may improve prognostication, and ensuring validation against more clinically relevant endpoints are required. The Australian PCa Research Centre NSW has contributed to numerous studies of molecular biomarkers associated with biochemical relapse. In the current study, these biomarkers were re-analyzed for biochemical relapse, metastatic relapse and PCa death with extended follow-up. Biomarkers of significance were then used to develop a combined prognostic model for clinical outcomes and validated in a large independent cohort. The discovery cohort (n = 324) was based on 12 biomarkers with a median follow-up of 16 years. Seven biomarkers were significantly associated with biochemical relapse. Three biomarkers were associated with metastases: AZGP1, Ki67 and PML. Only AZGP1 was associated with PCa death. In their individual and combinational forms, AZGP1 and Ki67 as a dual BM signature was the most robust predictor of metastatic relapse (AUC 0.762). The AZPG1 and Ki67 signature was validated in an independent cohort of 347 PCa patients. The dual BM signature of AZGP1 and Ki67 predicted metastasis in the univariable (HR 7.2, 95% CI, 1.6-32; p = 0.01) and multivariable analysis (HR 5.4, 95% CI, 1.2-25; p = 0.03). The dual biomarker signature marginally improved risk prediction compared to AZGP1 alone (AUC 0.758 versus 0.738, p < 0.001). Our findings indicate that biochemical relapse is not an adequate surrogate for metastasis or PCa death. The dual biomarker signature of AZGP1 and Ki67 offers a small benefit in predicting metastasis over AZGP1 alone.
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ItemIdentification of cancer sex-disparity in the functional integrity of p53 and its X chromosome network(NATURE PUBLISHING GROUP, 2019-11-26)The disproportionately high prevalence of male cancer is poorly understood. We tested for sex-disparity in the functional integrity of the major tumor suppressor p53 in sporadic cancers. Our bioinformatics analyses expose three novel levels of p53 impact on sex-disparity in 12 non-reproductive cancer types. First, TP53 mutation is more frequent in these cancers among US males than females, with poorest survival correlating with its mutation. Second, numerous X-linked genes are associated with p53, including vital genomic regulators. Males are at unique risk from alterations of their single copies of these genes. High expression of X-linked negative regulators of p53 in wild-type TP53 cancers corresponds with reduced survival. Third, females exhibit an exceptional incidence of non-expressed mutations among p53-associated X-linked genes. Our data indicate that poor survival in males is contributed by high frequencies of TP53 mutations and an inability to shield against deregulated X-linked genes that engage in p53 networks.
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ItemE6AP Promotes a Metastatic Phenotype in Prostate Cancer(CELL PRESS, 2019-12-20)Although primary prostate cancer is largely curable, progression to metastatic disease is associated with very poor prognosis. E6AP is an E3 ubiquitin ligase and a transcriptional co-factor involved in normal prostate development. E6AP drives prostate cancer when overexpressed. Our study exposed a role for E6AP in the promotion of metastatic phenotype in prostate cells. We revealed that elevated levels of E6AP in primary prostate cancer correlate with regional metastasis and demonstrated that E6AP promotes acquisition of mesenchymal features, migration potential, and ability for anchorage-independent growth. We identified the metastasis suppressor NDRG1 as a target of E6AP and showed it is key in E6AP induction of mesenchymal phenotype. We showed that treatment of prostate cancer cells with pharmacological agents upregulated NDRG1 expression suppressed E6AP-induced cell migration. We propose that the E6AP-NDRG1 axis is an attractive therapeutic target for the treatment of E6AP-driven metastatic prostate cancer.
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ItemThe long and the short of it: the MDM4 tail so far(OXFORD UNIV PRESS, 2019-03)The mouse double minute 4 (MDM4) is emerging from the shadow of its more famous relative MDM2 and is starting to steal the limelight, largely due to its therapeutic possibilities. MDM4 is a vital regulator of the tumor suppressor p53. It restricts p53 transcriptional activity and also, at least in development, facilitates MDM2's E3 ligase activity toward p53. These functions of MDM4 are critical for normal cell function and a proper response to stress. Their importance for proper cell maintenance and proliferation identifies them as a risk for deregulation associated with the uncontrolled growth of cancer. MDM4 tails are vital for its function, where its N-terminus transactivation domain engages p53 and its C-terminus RING domain binds to MDM2. In this review, we highlight recently identified cellular functions of MDM4 and survey emerging therapies directed to correcting its dysregulation in disease.
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ItemRegulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma(NATL ACAD SCIENCES, 2019-09-03)Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.