Rare germline variants in childhood cancer patients suspected of genetic predisposition to cancer

Dianne E Sylvester; Yuyan Chen; Natalie Grima; Federica Saletta; Bhavna Padhye; Bruce Bennetts; Dale Wright; Michael Krivanek; Nicole Graf; Li Zhou; Daniel Catchpoole; Judy Kirk; Olivier Latchoumanin; Liang Qiao; Mandy Ballinger; David Thomas; Robyn Jamieson; Luciano Dalla-Pozza; Jennifer A Byrne

doi:10.1002/gcc.23006

Rare germline variants in childhood cancer patients suspected of genetic predisposition to cancer

Genes Chromosomes Cancer. 2022 Feb;61(2):81-93. doi: 10.1002/gcc.23006. Epub 2021 Oct 30.

Authors

Dianne E Sylvester^{1

2}, Yuyan Chen^{1

2}, Natalie Grima^{1

2}, Federica Saletta^{1

2}, Bhavna Padhye³, Bruce Bennetts⁴, Dale Wright⁴, Michael Krivanek⁵, Nicole Graf⁵, Li Zhou⁶, Daniel Catchpoole⁶, Judy Kirk⁷, Olivier Latchoumanin⁸, Liang Qiao⁸, Mandy Ballinger⁹, David Thomas⁹, Robyn Jamieson^{2

10}, Luciano Dalla-Pozza³, Jennifer A Byrne^{1

2

11}

Affiliations

¹ Molecular Oncology Laboratory, Children's Cancer Research Unit, Kids Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
² Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
³ The Cancer Centre for Children, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
⁴ Sydney Genome Diagnostics, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
⁵ Histopathology Department, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
⁶ Sydney Children's Tumour Bank Network, Children's Cancer Research Unit, Kids Research, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
⁷ Familial Cancer Service, Westmead Hospital, Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia.
⁸ Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney & Westmead Hospital, Westmead, New South Wales, Australia.
⁹ The Kinghorn Cancer Centre & Genomic Cancer Medicine, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
¹⁰ Eye and Developmental Genetics Research Group, The Children's Hospital at Westmead and Children's Medical Research Institute, and Disciplines of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
¹¹ NSW Health Statewide Biobank, NSW Health Pathology, Camperdown, New South Wales, Australia.

PMID: 34687117
DOI: 10.1002/gcc.23006

Abstract

Identification of cancer-predisposing germline variants in childhood cancer patients is important for therapeutic decisions, disease surveillance and risk assessment for patients, and potentially, also for family members. We investigated the spectrum and prevalence of pathogenic germline variants in selected childhood cancer patients with features suggestive of genetic predisposition to cancer. Germline DNA was subjected to exome sequencing to filter variants in 1048 genes of interest including 176 known cancer predisposition genes (CPGs). An enrichment burden analysis compared rare deleterious germline CPG variants in the patient cohort with those in a healthy aged control population. A subset of predicted deleterious variants in novel candidate CPGs was investigated further by examining matched tumor samples, and the functional impact of AXIN1 variants was analyzed in cultured cells. Twenty-two pathogenic/likely pathogenic (P/LP) germline variants detected in 13 CPGs were identified in 19 of 76 patients (25.0%). Unclear association with the diagnosed cancer types was observed in 11 of 19 patients carrying P/LP CPG variants. The burden of rare deleterious germline variants in autosomal dominant CPGs was significantly higher in study patients versus healthy aged controls. A novel AXIN1 frameshift variant (Ser321fs) may impact the regulation of β-catenin levels. Selection of childhood cancer patients for germline testing based on features suggestive of an underlying genetic predisposition could help to identify carriers of clinically relevant germline CPG variants, and streamline the integration of germline genomic testing in the pediatric oncology clinic.

Keywords: cancer predisposition; genomics; germline variants; pediatric oncology.

Publication types

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

MeSH terms

Adolescent
Aged
Child
Child, Preschool
Cohort Studies
Exome Sequencing
Genetic Predisposition to Disease* / epidemiology
Genetic Predisposition to Disease* / genetics
Germ-Line Mutation / genetics*
Humans
Infant
Infant, Newborn
Neoplasms* / epidemiology
Neoplasms* / genetics