Seminar: Dr Lucy Gately and A/Prof Bernie Pope

Understanding survivors of glioblastoma: who they are and their experiences

Dr Lucy Gately, Clinical Research Fellow
St Vincent’s Hospital, Melbourne

Glioblastoma is the most common and most aggressive primary brain tumour in adults. Even with conventional treatment, survival remains poor at 12 months. Approximately 13% of patients survive longer than two years from diagnosis and are deemed long-term survivors. Currently, little is known about who this population is and the issues they face during their survivorship. This research aims to better understand the indicators that predict for long-term survivorship so that we can identify these patients earlier in their disease course, as well as understand their experiences during survival so that we can better cater for these patients both as medical professionals and as a community.

Classifying DNA mismatch repair variant pathogenicity using protein structure and function predictions

A/Prof Bernie Pope, Lead Bioinformatician (Cancer and Clinical Genomics)
UMCCR and Department of Clinical Pathology, Melbourne Bioinformatics

The DNA mismatch repair (MMR) mechanism plays an important role in maintaining genome integrity by correcting small mutations that can arise from DNA damage or from mistakes made during replication and recombination. Loss of MMR function in a cell can lead to a rapid accumulation of somatic mutations, giving rise to a hypermutated phenotype. In humans, this mutational process can lead to cancer when key oncogenes are disrupted. Individuals who carry a pathogenic germline mutation in an MMR gene are at a substantially higher lifetime risk of many types of cancer, a condition known as Lynch syndrome. Therefore, considerable effort has been made over many years in identifying pathogenic MMR gene variants in the population.

A major challenge for this work has been the discrimination of high-risk deleterious variants from those which are benign. Addressing this challenge, the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) has established a database of expertly curated and classified MMR variants. The database contains a collection of over 2600 unique MMR gene variants associated with pathogenicity classifications. However, nearly 800 of those variants fall into the "uncertain" class, posing challenges for variant interpretation.

In this talk, A/Prof Pope will describe the group's efforts to incorporate predicted protein structural and functional features of MMR variants to develop a new computational classifier of pathogenicity. He will also demonstrate our new website, called StruMMR, for visualising and interpreting the results of the classifier. The group believes this information will provide further guidance to the interpretation of novel variants not currently classified within the InSiGHT database and assist with re-classification of variants within the "uncertain" class.