Protocol for a comprehensive prospective cohort study of trio-based whole-genome sequencing for underlying cancer predisposition in paediatric and adolescent patients newly diagnosed with cancer: the PREDICT study

Noemi Auxiliadora Fuentes Bolanos; Bhavna Padhye; Macabe Daley; Jacqueline Hunter; Kate Hetherington; Meera Warby; Eliza Courtney; Judy Kirk; Sarah Josephi-Taylor; Yuyan Chen; Frank Alvaro; Kristine Barlow-Stewart; Marie Wong-Erasmus; Paulette Barahona; Pamela Ajuyah; Ann-Kristin Altekoester; Vanessa J Tyrrell; Loretta M S Lau; Claire Wakefield; Dianne Sylvester; Katherine Tucker; Mark Pinese; Luciano Dalla Pozza; Tracey A O'Brien

doi:10.1136/bmjopen-2022-070082

Protocol for a comprehensive prospective cohort study of trio-based whole-genome sequencing for underlying cancer predisposition in paediatric and adolescent patients newly diagnosed with cancer: the PREDICT study

BMJ Open. 2023 May 30;13(5):e070082. doi: 10.1136/bmjopen-2022-070082.

Authors

Noemi Auxiliadora Fuentes Bolanos^#^{1

2}, Bhavna Padhye^#^{3

4}, Macabe Daley^#², Jacqueline Hunter^{5

6}, Kate Hetherington^{6

7}, Meera Warby^{2

8}, Eliza Courtney^{1

2}, Judy Kirk^{9

10}, Sarah Josephi-Taylor^{11

12}, Yuyan Chen⁴, Frank Alvaro¹³, Kristine Barlow-Stewart^{2

5}, Marie Wong-Erasmus^{2

6}, Paulette Barahona^{2

6}, Pamela Ajuyah^{2

6}, Ann-Kristin Altekoester^{2

6}, Vanessa J Tyrrell², Loretta M S Lau^{1

2}, Claire Wakefield^{5

6}, Dianne Sylvester⁴, Katherine Tucker^{1

8}, Mark Pinese^#^{2

6}, Luciano Dalla Pozza^#¹⁴, Tracey A O'Brien^#¹

Affiliations

¹ Kids Cancer Centre, Sydney Children's Hospitals Network Randwick, Randwick, New South Wales, Australia.
² Children's Cancer Institute, Lowy Cancer Centre, UNSW, Randwick, New South Wales, Australia.
³ Cancer Centre for Children, The Children's Hospital at Westmead, Westmead, New South Wales, Australia bhavna.padhye@health.nsw.gov.au.
⁴ Kids Research, Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
⁵ Behavioural Sciences Unit, Kids Cancer Centre, Randwick, New South Wales, Australia.
⁶ School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia.
⁷ Behavioural Sciences Unit, Sydney Children's Hospital Randwick, Randwick, New South Wales, Australia.
⁸ Hereditary Cancer Centre, Prince of Wales Hospital Nelune Comprehensive Cancer Centre - NCCC, Randwick, New South Wales, Australia.
⁹ Familial Cancer Service, Westmead Hospital, Westmead, New South Wales, Australia.
¹⁰ Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
¹¹ Department of Clinical Genetics, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹² Discipline of Genomic Medicine, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
¹³ Paediatric Oncology Service, John Hunter Children's Hospital, Hunter Region Mail Centre, New South Wales, Australia.
¹⁴ Cancer Centre for Children, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.

^# Contributed equally.

Abstract

Introduction: Identifying an underlying germline cancer predisposition (CP) in a child with cancer has potentially significant implications for both the child and biological relatives. Cohort studies indicate that 10%-15% of paediatric cancer patients carry germline pathogenic or likely pathogenic variants in cancer predisposition genes, but many of these patients do not meet current clinical criteria for genetic testing. This suggests broad tumour agnostic germline testing may benefit paediatric cancer patients. However, the utility and psychosocial impact of this approach remain unknown. We hypothesise that an approach involving trio whole-genome germline sequencing (trio WGS) will identify children and families with an underlying CP in a timely fashion, that the trio design will streamline cancer risk counselling to at-risk relatives if CP was inherited, and that trio testing will not have a negative psychosocial impact on families.

Method and analysis: To test this, we present the Cancer PREDisposition In Childhood by Trio sequencing study (PREDICT). This study will assess the clinical utility of trio WGS to identify CP in unselected patients with cancer 21 years or younger in New South Wales, Australia. PREDICT will perform analysis of biological parents to determine heritability and will examine the psychosocial impact of this trio sequencing approach. PREDICT also includes a broad genomics research programme to identify new candidate genes associated with childhood cancer risk.

Ethics and dissemination: By evaluating the feasibility, utility and psychosocial impact of trio WGS to identify CP in paediatric cancer, PREDICT will inform how such comprehensive testing can be incorporated into a standard of care at diagnosis for all childhood cancer patients.

Trial registration number: NCT04903782.

Keywords: cancer genetics; molecular aspects; molecular biology; paediatric clinical genetics & dysmorphology; paediatric oncology; protocols & guidelines.

Publication types

Clinical Study
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Child
Cohort Studies
Disease Susceptibility
Genetic Predisposition to Disease
Humans
Neoplasms* / diagnosis
Neoplasms* / genetics
Prospective Studies
Whole Genome Sequencing / methods

Associated data

ClinicalTrials.gov/NCT04903782