Centre for Cancer Research - Research Publications

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Author: Grimmond, Sean × Author: Hofmann, Oliver × End date: 2019 ×

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    Lost in translation: returning germline genetic results in genome-scale cancer research
    Johns, AL ; Mckay, SH ; Humphris, JL ; Pinese, M ; Chantrill, LA ; Mead, RS ; Tucker, K ; Andrews, L ; Goodwin, A ; Leonard, C ; High, HA ; Nones, K ; Patch, A-M ; Merrett, ND ; Pavlakis, N ; Kassahn, KS ; Samra, JS ; Miller, DK ; Chang, DK ; Pajic, M ; Pearson, JV ; Grimmond, SM ; Waddell, N ; Zeps, N ; Gill, AJ ; Biankin, AV (BMC, 2017-04-28)
    BACKGROUND: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies. METHODS: We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy. RESULTS: A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR. CONCLUSION: Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low.
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    CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan
    Vennin, C ; Melenec, P ; Rouet, R ; Nobis, M ; Cazet, AS ; Murphy, KJ ; Herrmann, D ; Reed, DA ; Lucas, MC ; Warren, SC ; Elgundi, Z ; Pinese, M ; Kalna, G ; Roden, D ; Samuel, M ; Zaratzian, A ; Grey, ST ; Da Silva, A ; Leung, W ; Mathivanan, S ; Wang, Y ; Braithwaite, AW ; Christ, D ; Benda, A ; Parkin, A ; Phillips, PA ; Whitelock, JM ; Gill, AJ ; Sansom, OJ ; Croucher, DR ; Parker, BL ; Pajic, M ; Morton, JP ; Cox, TR ; Timpson, P ; Johns, AL ; Chantrill, LA ; Chou, A ; Steinmann, A ; Arshi, M ; Dwarte, T ; Froio, D ; Pereira, B ; Ritchie, S ; Chambers, CR ; Metcalf, X ; Waddell, N ; Pearson, J ; Patch, A-M ; Nones, K ; Newell, F ; Mukhopadhyay, P ; Addala, V ; Kazakoff, S ; Holmes, O ; Leonard, C ; Wood, S ; Grimmond, SM ; Hofmann, O ; Christ, A ; Bruxner, T ; Samra, JS ; Pavlakis, N ; High, HA ; Asghari, R ; Merrett, ND ; Pavey, D ; Das, A ; Cosman, PH ; Ismail, K ; O'Connnor, C ; Stoita, A ; Williams, D ; Spigellman, A ; Lam, VW ; McLeod, D ; Kirk, J ; Kench, JG ; Grimison, P ; Cooper, CL ; Sandroussi, C ; Goodwin, A ; Mead, RS ; Tucker, K ; Andrews, L ; Texler, M ; Forest, C ; Epari, KP ; Ballal, M ; Fletcher, DR ; Mukhedkar, S ; Zeps, N ; Beilin, M ; Feeney, K ; Nguyen, NQ ; Ruszkiewicz, AR ; Worthley, C ; Chen, J ; Brooke-Smith, ME ; Papangelis, V ; Clouston, AD ; Barbour, AP ; O'Rourke, TJ ; Fawcett, JW ; Slater, K ; Hatzifotis, M ; Hodgkinson, P ; Nikfarjam, M ; Eshleman, JR ; Hruban, RH ; Wolfgang, CL ; Lawlor, RT ; Beghelli, S ; Corbo, V ; Scardoni, M ; Bassi, C ; Biankin, A ; Dixon, J ; Jamieson, NB ; Chang, DK (NATURE PORTFOLIO, 2019-08-12)
    Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer.