Abstract for presentation – 14th International Symposium on Mutation in the Genome: detection, genome sequencing & interpretation (Variant Detection 2017), 5-7 June 2017, Spain.
Germline mutations in childhood cancer patients suspected of genetic predisposition to cancer – a retrospective analysis
Dianne E Sylvester 1, Yuyan Chen 1, Robyn Jamieson 2, Luciano Dalla Pozza 3, and Jennifer A Byrne 1.
Purpose: The proportion of childhood cancer patients with predisposing constitutive genetic mutation(s) is not clearly defined. In many treating centres the majority of childhood cancer patients are not offered germline testing even if a hereditary component is suspected. This is partly due to the cost and time-consuming nature of gene-targeted diagnostic tests. With the growing availability of massively parallel sequencing technologies, it is now possible to offer families a single sequencing test for a panel of cancer predisposition genes. We studied a retrospectively identified childhood cancer patient cohort using whole exome sequencing to identify pathogenic germline mutations, whilst also considering novel variants which may predispose to disease.
Methodology: The inclusion criteria were childhood cancer patients diagnosed at the Children’s Hospital at Westmead (1997-2015) suspected of genetic predisposition to cancer for whom frozen blood samples were available for study, specifically siblings developing cancer, patients developing multiple cancers, and/or childhood cancer in association with either a genetic syndrome and/or significant family history of malignancy. DNA was extracted from frozen blood samples and underwent whole exome sequencing using Agilent SureSelect targeted enrichment and sequencing on an Illumina HiSeq2000 (Macrogen, Korea).
Results: The data (approximately 90,000 variants per exome) were annotated with ANNOVAR  and filtered for very rare (less than 0.1% Exome Aggregation Consortium population) exonic variants in genes associated with cancer predisposition, somatic mutations in cancer and/or DNA repair (n=1047 genes). Each patient had a mean of 20 variants (range 7-62) that met the criteria. Variants were interpreted for pathogenicity using the American College of Medical Genetics and Genomics guidelines. To date, 10/39 (26%) patients carried a pathogenic/likely pathogenic germline mutation in a known cancer predisposition gene.
Conclusion: In this study of retrospectively identified childhood cancer patients suspected of genetic predisposition, over a quarter carried germline mutation(s) either known or very likely to predispose to cancer. As also previously observed [2,3], the landscape of germline mutations in childhood cancer patients is more extensive than traditionally assumed. Further to this, with additional investigations, some variants of uncertain significance may also be shown to contribute to cancer predisposition in childhood.
Progress Review Management System
Monday, 6 March 2017
Section 1 08/09/2016 Family Name SYLVESTER
Given Names DIANNE ELIZABETH
Phone(s) 0403761124 Use the following link to update contact details. MY UNI.
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Degree Doctor of Philosophy (Medicine)
Attendance Full Time
Earliest completion date 2018-06-30
Latest completion date 2019-12-31
Department Paediatrics and Child Health
Faculty Medicine (Sydney Medical School)
Research Supervisor JENNIFER ANNE BYRNE
Auxiliary Supervisors ROBYN VICKI JAMIESON Postgraduate Coordinator (or equivalent) NICHOLAS JAMES WOOD
To be completed by students who are holders of scholarships administered by the University of Sydney
2.1 Are you a No
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(Full-time is 30 hours or more per week. Part-time is less than 30 hours per week)
I have spent a lot of time reading and researching the topic, and now feel as though I have an in-depth knowledge of my thesis topic. I have written a literature review and have begun writing my methods section. I have also attended many research training seminars (statistics, writing, presenting, Endnote) organised by the postgraduate teams at Westmead. I have done oral presentations at the Children’s Cancer Research Unit seminar series and also the Discipline of child and adolescent health postgraduate conference.
Progress seemed slow in regards to the human ethics approval process and site specific governance, followed by approval from the Sydney Children’s Tumour Bank Network for accessing biological specimens. I finally had some samples available at the end of June and have had results for analysis late August. Overall I feel as though my project is coming together and I am excited to continue this journey.
Attended the Kids Cancer Alliance conference here in Sydney on the topic of my thesis (cancer predisposition), an amazing opportunity to hear and learn from experts.
The human ethics approval and the approval for the biological samples required for the project took quite a significant amount of time. The application for the first required approval was November 2015. The samples were obtained at the end of June 2016.
The approval of this project was debated by human ethics and my supervisor was excellent in communicating an understanding of the project to the committee.
To be completed by the Research Supervisor: JENNIFER ANNE BYRNE 16/09/2016
As Dianne outlined in her report, progress during the first 6 months of 2016 was slow due to the need to obtain ethics and governance approval, and then obtain Tumour Bank approval and the actual samples for sequencing. Overall, this process required about 10 months, which was substantially longer than we imagined at the outset in 2015.
Dianne kept busy during this period with a lot of reading and writing. Dianne now has a really excellent understanding of her research area, which I think well exceeds that of most students in their first PhD year. This knowledge will serve her well over the rest of her candidature, and will mean that she’s in a strong position to analyse her sequencing data that are now coming thick and fast.
Dianne is very engaged and focussed. She learns quickly and enjoys putting what she learns to immediate use. Her enthusiasm for her project is infectious and appreciated by all members of the team.
Dianne has provided me with a draft of her literature review, and although I’ve started reading this, I have not yet been able to complete my review (due to continuing grant and other submission deadlines). Dianne writes confidently, and the main aspect that she’ll need to work on is the ordering of text and ideas.
None at this stage
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Has made decent progress, but very slow start with ethics delays and slow recruitment of prospective study. Have data from retrospective study to start analyzing. Need to consider ways of fixing this – either including a fellow in the ethics application, or requesting to be able to recruit patients/families herself (as a non-clinician).
Literature review drafted, but not finalized – might be good to even consider a publication outcome from this.
Does the panel consider the candidate’s Progress Plan for the next calendar year to be feasible?
To be completed by the candidate
DIANNE ELIZABETH SYLVESTER [SID: 450652512]
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supervisory arrangements satisfactory