Dissecting the Genetic Architecture of Familial Melanoma Lauren Gabriel Aoude Bachelor of Engineering (Mechanical) Bachelor of Arts (European Studies)

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Dissecting the Genetic Architecture of Familial Melanoma Lauren Gabriel Aoude Bachelor of Engineering (Mechanical) Bachelor of Arts (European Studies) Dissecting the genetic architecture of familial melanoma Lauren Gabriel Aoude Bachelor of Engineering (Mechanical) Bachelor of Arts (European Studies) A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2014 School of Medicine / QIMR Berghofer Medical Research Institute ii Abstract Cutaneous malignant melanoma (CMM) is a disease that has had a significant impact on the lives of Australians, affecting 1 in 17 people. Around 10% of those diagnosed have a family history of melanoma and in the majority of these cases there is underlying predisposition that makes them more susceptible to melanoma development. Known high-risk loci (CDKN2A, CDK4) account for approximately half of these families. There remains, therefore, a large gap in knowledge regarding the causes of susceptibility to CMM. Uveal malignant melanoma (UMM) is a rare type of melanoma that forms in the uveal tract of the eye. Unlike cutaneous melanoma, ultraviolet radiation does not contribute to the formation of UMM. To date, only one gene has been identified that contributes to risk of uveal melanoma: BAP1. The main objective of this thesis was to discover the underlying germline mutations that contribute to increased risk in high-density CMM and UMM families lacking mutations in any of the known melanoma risk loci. The key techniques that were used to achieve this were whole-genome and exome sequencing of multiple cases from these families. By targeting novel variants that segregated with disease in families, truncating mutations leading to CMM development were found in POT1, ACD and TERF2IP (Chapters 4 and 5). This technique was also used to discover truncating germline BAP1 mutations in a UMM family from Denmark (Chapter 7). A second method of gene discovery that was used was the candidate gene approach. This first involved a literature search to discover likely candidates for melanoma susceptibility. The protein-coding regions of the chosen genes were then Sanger sequenced to identify novel variants in probands from melanoma families. This method was used to interrogate the role of PALB2, SOX10 and MITF in CMM predisposition (Chapter 3). The contribution of known melanoma predisposition genes CDKN2A, CDK4 and BAP1 to a population-based CMM sample from Queensland was also assessed. This was achieved through a combination of targeted pull-down of the selected genes using the Ion Torrent Personal Genome Machine, and also single nucleotide polymorphism analysis using Sequenom mass spectrometry. Chapters 2 and 6 of this thesis detail the contribution of these genes to CMM and UMM predisposition in population-based samples from Australia. Overall this project has made a major contribution to the field of familial melanoma genetics. We described germline mutations in members of the shelterin complex (POT1, ACD and TERF2IP) in CMM, which accounts for 9% of families lacking mutations in previously known risk loci iii CDKN2A, and CDK4. In combination with a previous finding of mutations in TERT, the work that is presented in this thesis has contributed to the discovery of a new pathway related to melanoma predisposition and thus represents a significant advance in the field. Additionally, we have estimated the contribution of known risk genes CDKN2A and BAP1 to susceptibility in a population-based sample of Queensland melanoma cases (N=1,109). We showed that CDKN2A accounts for around 1.31% of Queensland melanoma families and BAP1 accounts for around 0.63%. Additionally, we showed CDK4 mutations are extremely rare, not being found in 1,550 melanoma families from Queensland. In summary, next-generation sequencing techniques have been an invaluable tool in melanoma predisposition gene discovery. We have identified several new genes that contribute to melanoma susceptibility when mutated in the familial setting. By discovering and characterising these genes, better surveillance and treatment strategies may be available in the future for individuals with familial melanoma. iv Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my research higher degree candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the General Award Rules of The University of Queensland, immediately made available for research and study in accordance with the Copyright Act 1968. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis. v Publications during candidature Lauren G. Aoude, Michael Gartside, Peter Johansson, Jane M. Palmer, Judith Symmons, Nicholas G. Martin, Grant W. Montgomery, Nicholas K. Hayward. Prevalence of germline BAP1, CDKN2A and CDK4 mutations in an Australian population-based sample of cutaneous melanoma cases. Twin Research and Human Genetics (manuscript submitted 02/10/2014). Lauren G. Aoude, Karin A. W. Wadt and Nicholas K. Hayward. Genetics of Familial Melanoma: 20 years after CDKN2A. Pigment Cell & Melanoma Research (manuscript submitted 30/09/2014). Karin A. W. Wadt, Lauren G. Aoude, Lisa Golmard, Thomas v. O. Hansen, Xavier Sastre-Garau, Nicholas K. Hayward, Anne-Marie Gerdes. Germline RAD51B truncating mutation in a family with cutaneous melanoma. BMC Cancer (manuscript submitted 11/06/2014). Lauren G. Aoude*, Antonia L. Pritchard*, Carla Daniela Robles-Espinoza*, Karin Wadt*, Mark Harland*, Jiyeon Choi, Michael Gartside, Víctor Quesada, Peter Johansson, Jane M. Palmer, Andrew J. Ramsay, Xijun Zhang, Kristine Jones, Judith Symmons, Elizabeth A. Holland, Helen Schmid, Vanessa Bonazzi, Susan Woods, Ken Dutton-Regester, Mitchell S. Stark, Helen Snowden, Remco van Doorn, Grant W. Montgomery, Nicholas G. Martin, Thomas M. Keane, Carlos López- Otín, Anne-Marie Gerdes, Håkan Olsson, Christian Ingvar, Åke Borg, Nelleke A. Gruis, Jeffrey M. Trent, Göran Jönsson, D. Timothy Bishop, Graham J. Mann, Julia A. Newton-Bishop, Kevin M. Brown, David J. Adams, Nicholas K. Hayward. Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. Journal of the National Cancer Institute (in press). Karin A. W. Wadt*, Lauren G. Aoude*, Peter Johansson, Annalisa Gatt, Antonia Pritchard, Oana Crainic, Morten Tolstrup Andersen, Jens F Kiilgaard, Steffen Heegaard, Lone Sunde, Birgitte Federspiel, John Thompson, Stan McCarthy, Steven Kao, Anne-Marie Gerdes, Hensin Tsao, Göran Jönsson, Klaus Busam, Ruta Gupta, Jeffrey M. Trent, Kevin M. Brown, Richard Scolyer, Nicholas K. Hayward. A recurrent germline BAP1 mutation in melanoma families from two continents and extension of the BAP1 tumour predisposition spectrum to include basal cell carcinoma. Clinical Genetics. 2014 Sep; doi:10.1111/cge.12501 Lauren G. Aoude, Mai Xu, Zhen Zhen Zhao, Michael Kovacs, Jane M. Palmer, Peter Johansson, Judith Symmons, Jeffrey M. Trent, Nicholas G. Martin, Grant W. Montgomery, Kevin M. Brown and Nicholas K. Hayward. Assessment of PALB2 as a candidate melanoma susceptibility gene. PLOS One. 2014 June; 9(6):e100683. vi Carla Daniela Robles-Espinoza*, Mark Harland*, Andrew J. Ramsay*, Lauren G. Aoude*, Víctor Quesada, Zhihao Ding, Antonia L. Pritchard, Jessamy C. Tiffen, Mia Petljak, Jane M. Palmer, Judith Symmons, Peter Johansson, Mitchell S. Stark, Michael G. Gartside, Helen Snowden, Grant W. Montgomery, Nicholas G. Martin, Jimmy Z. Liu, Jiyeon Choi, Matthew Makowski, Kevin M. Brown, Thomas M. Keane, Carlos López-Otín, Nelleke A. Gruis, Nicholas K. Hayward, D. Timothy Bishop, Julia A. Newton-Bishop, David J. Adams. POT1 loss-of-function variants predispose to familial melanoma. Nature Genetics. 2014 May; 46(5):478-81. Ken Dutton-Regester, Hojabr Kakavand, Lauren G. Aoude, Mitchell S. Stark, Michael G. Gartside, Peter Johansson, Linda O’Connor, Cathy Lanagan, Varsha Tembe, Gulietta M. Pupo, Lauren E. Haydu, Christopher W. Schmidt, Graham J. Mann, John F. Thompson, Richard A. Scolyer, Nicholas K. Hayward. Melanomas of unknown primary have a mutation profile consistent with cutaneous sun-exposed melanoma. Pigment Cell & Melanoma Research. 2013 Nov; 26(6):852-60. Julia C. Cronin, Dawn E. Watkins-Chow, Art Incao, Joanne H. Hasskamp, Nicola Schönewolf, Lauren G. Aoude, Nicholas K. Hayward, Boris C. Bastian, Reinhard Dummer, Stacie K. Loftus, William J. Pavan. SOX10 ablation arrests cell cycle, induces senescence, and suppresses melanomagenesis. Cancer Research. 2013 Sep; 73(18):5709-18. Lauren G. Aoude, Karin Wadt, Anders Bojesen, Dorthe Crüger, Åke Borg, Jeffrey M. Trent, Kevin M. Brown, Anne-Marie Gerdes, Göran Jönsson, Nicholas
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