The Hunt For the Source of Mutations in Cancer

Free Public Lecture

The Hunt For the Source of Mutations in Cancer

Ian Potter Auditorium
Kenneth Myer Building

Royal Parade, Parkville

Booking not required

A Story of Discovery and Innovation at the Coalface.

R Douglas Wright Lecture 2016

Dr. Robyn A. Lindley is an Honorary Senior Fellow in the Department of Pathology, Faculty of Medicine, Dentistry & Health Sciences at the University of Melbourne. She is also an inventor, and Chief Scientific Officer (CSO) and Director of GMDx Co Pty Ltd. Robyn has morphed into an internationally recognized immunogeneticist who has been publishing on the molecular mechanisms of evolution and somatic hypermutation (SHM) in the immune system for almost two decades. SMH is the cellular mechanism responsible for antibody diversity.

This journey began in 1996 when she joined with ANU Immunologists Edward J Steele and Robert V Blanden as co-authors of Lamarck’s Signature, a best-selling science book that laid out the scientific evidence for antibody diversity and the evolution of immune recognition via reverse transcription-coupled feedback loops. This was followed by a breakthrough paper in 2006 with ANU’s Edward J Steele and Georg F Weiller, that provided the first data-driven evidence for the reverse transcription-based mechanism in antibody producing cells. This was a crucial step for understanding the processes involved in the accumulation of unwanted genetic mutations in somatic cells that may ultimately give rise to cancer. In 2010, she published the highly regarded The Soma, that was a synthesis of evolutionary genetic mechanisms. In the same year, with Edward J Steele, it was shown that the diagnostic strand-biased mutation patterns are the same for mouse antibody genes, and for all human cancers analyzed (in part or in toto). The overwhelming conclusion was that all cancers displayed a similar form of dysregulated error prone somatic hypermutation that is normally tightly edited in normal hypermutating B cells in the immune system.

This research prompted some key questions: “What are the root causes of cancer in humans? and, “How can these be identified?” In mid-2012, Robyn Lindley began to answer these questions by interrogating several public mutation databases. Using her skills in recognizing patterns amongst complex series of numbers she shook off the pre-existing dogma that ‘mutations occur randomly’. She discovered that most mutations in the genes of cancer cells occur in a highly non-random fashion, and that the patterns observed are associated with proteins called deaminases that result in a high level of mutagenesis in cancer cells. Most mutations were found to occur at specific sites, codon-context motif signatures. The processes involved are referred to as Targeted Somatic Mutation (TSM). Realizing the diagnostic and prognostic potential of these findings, she began filing patent applications in late 2012. The first scientific paper describing TSM processes was published in Cancer Genetics in May 2013.Recently in 2016, she published a paper showing that some changes in TSM signatures arising in an individual can be used to predict progression or recurrence in ovarian cancer.

With difficulties funding research, and scientific discoveries that break the rules of long-standing scientific dogma, the journey has not been easy. Yet, in this era of rapid and relatively cheap genome-wide sequencing, Robyn Lindley’s discoveries give straight forward biological meaning to cancer mutation signatures. She will tell this unfolding scientific story of the discovery of the underlying rules governing TSM and the path to funding clinical applications in a way all those interested will understand.

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