https://alccrf.lions.org.au/wp-content/uploads/2018/05/SylvesterD_Progress_Report_Scholarship.pdfAbstract 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.


  1. Children’s Cancer Research Unit, Kids Research Institute, Discipline of Child & Adolescent Health, University of Sydney, Westmead, NSW,
  2. Eye and Developmental Genetics Research, Children’s Medical Research Institute, Discipline of Child & Adolescent Health and Discipline of Genetic Medicine, University of Sydney, Westmead, NSW, Australia.
  3. The Cancer Centre for Children, The Children’s Hospital at Westmead, NSW,


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 [1] 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.


  1. Wang K, Li M, Hakonarson H. ANNOVAR: Functional annotation of genetic variants from next- generation sequencing Nucleic Acids Research. doi:10.1093/nar/gkq603
  2. Zhang, J., et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med. doi:10.1056/NEJMc1600338
  3. Parsons, et al. Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid JAMA Oncol. doi:10.1001/jamaoncol.2015.5699


Progress Review Management System

Monday, 6 March 2017

12:15 PM



Higher Degree by Research Progress Review System 2016

Section 1 08/09/2016 Family Name SYLVESTER


SID                450652512/1



Phone(s)     0403761124 Use the following link to update contact details. MY UNI.


Email         dsyl2323

@uni.sydne y.edu.au

Attention: The University sends important information to your official student email address and deems all mail sent to this address to have been delivered. It is therefore important that you access this email regularly or redirect incoming email to your preferred email address, as the official student email address cannot be changed.



Degree                                                    Doctor of Philosophy (Medicine)

Attendance                                             Full Time

Commenced                                          2015-07-01

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

Section 2

To be completed by students who are holders of scholarships administered by the University of Sydney

2.1                                                                                                   Are you a                  No

scholarship holder?

If you require an extension to your scholarship and/or your candidature you must request this using Sydney Student.

 Section 3

Upload any additional documents required. As different faculties or departments require different documents, please see our guide at guide

  • Progression plan: pdf

Extra Documents (PDF only):


  • How many hours per week are devoted to your candidature? 35

(Full-time is 30 hours or more per week. Part-time is less than 30 hours per week)

  • a) How often do you communicate with your Supervisor? Daily
    1. What method(s) do you use to contact your Supervisor? In person Email
  • With reference to your progress, milestones to date, and research methodology, briefly describe your own sense of your achievements during the past year, including written work, publications or peer-reviewed presentations in any

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.

  • What opportunities do you have for association and discussions with experts in your field?

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.

  • a) Detail any personal, technical, or other problems that have interfered with the progress of your

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.

  1. Please indicate steps you, and if applicable, your supervisor have taken to help overcome these

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.

  • Have you undertaken employment this year?

Section 4

To be completed by the Research Supervisor: JENNIFER ANNE BYRNE 16/09/2016

  • has the candidate:
    1. diligently applied herself/himself to the project? Yes
    2. shown initiative consistent with the requirements of the research Yes
  1. made satisfactory progress over the year? Meets/E xceeds
  • a) How often do you communicate with your student? Daily
  1. b) What method(s) do you use to contact your student? In person


  • Have any difficulties interfered with progress? Detail of any personal, technical, and/or other problems encountered by the

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.

  • Please indicate steps you have taken to help overcome the problems detailed in 3

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.

  • Other comments on the candidate’s work and rate of progress

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.

  • Are there any significant achievements not mentioned in section 3 that you would like to mention?

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.

  • a) Has the candidate’s research topic changed significantly since the last review No
  1. b) if Yes provide details
  • Please describe any factors that might impact on the completion date

None at this stage


Section 5 Candidate Interview BAREND JACOBUS MARAIS 13/10/2016 Interview  Instructions

Annual progress candidate interviews are now mandatory for all postgraduate research candidates.

The procedures, including duration, timeline and administration of the Candidate Interview are up to the Discipline/School to determine.  However, the following guidelines are strongly recommended:

  1. The Postgraduate Coordinator need not necessarily chair the interview or be a part of the The panel (including the Chair) may be any academic member of staff within the Faculty.
  2. The supervisor will not be the chair of the panel or a panel
  3. The supervisor will only be present for part of the
  4. The candidate will have the opportunity to speak freely and openly about any aspect of his/her candidature in the absence of his/her
  5. Feedback should be provided to the candidate at the time of


  1. Feedback should be provided to the candidate at the time of
  2. Any outcomes from the interview should be dealt with by the supervisory team and the Postgraduate Co-ordinator, where
  3. Date of Interview: 12/10/2016


(dd/mm/yyyy HH:mm)

  1. Panel Chair: BAREND


  1. Panel Members: MARIA ELOISE CRAIG Marian Fernandez Denise Margaret Yuille
  2. Comments by Reviewers:

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?


  • Detail all variations to the Progress Plan required by the panel None
  • Describe actions to be taken regarding the Progress Plan and who is responsible for them
  • N/A
  • N/A
  • N/A
  • Does the student have adequate support and resources? Yes
  • Are the current supervisory arrangements satisfactory? Yes



Section 6

To be completed by the candidate

  • Have you read the comments made by your supervisor and the panel regarding your progress?
  • Acknowledging that this progress review comprises a formal part of your academic record, if you have additional comments on any aspect of your review,



Section 7 To be completed by the PGC: NICHOLAS JAMES WOOD 07/11/2016


Please note: If the Postgraduate Coordinator is also the Research Supervisor, this section must be completed by the Head of Department/School or Associate Dean.

  • Interview outcome

Meets/Exceeds Comment:

APR satisfactory

  • Required variation to

progress Plan


  • N/A


  • N/A
  • N/A
  • Are the current

supervisory arrangements satisfactory


  • N/A
  • N/A