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

Sylvester, DE; Chen, Y; Grima, N; Saletta, F; Padhye, B; Bennetts, B; Wright, D; Krivanek, M; Graf, N; Zhou, L; Catchpoole, D; Kirk, J; Latchoumanin, O; Qiao, L; Ballinger, M; Thomas, D; Jamieson, R; Dalla-Pozza, L; Byrne, JA

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

Sylvester, DE Chen, Y Grima, N Saletta, F Padhye, B Bennetts, B Wright, D Krivanek, M Graf, N Zhou, L Catchpoole, D

Kirk, J Latchoumanin, O Qiao, L Ballinger, M Thomas, D Jamieson, R Dalla-Pozza, L Byrne, JA

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Publisher:: Wiley
Publication Type:: Journal Article
Citation:: Genes Chromosomes Cancer, 2022, 61, (2), pp. 81-93
Issue Date:: 2022-02

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Field	Value	Language
dc.contributor.author	Sylvester, DE
dc.contributor.author	Chen, Y
dc.contributor.author	Grima, N
dc.contributor.author	Saletta, F
dc.contributor.author	Padhye, B
dc.contributor.author	Bennetts, B
dc.contributor.author	Wright, D
dc.contributor.author	Krivanek, M
dc.contributor.author	Graf, N
dc.contributor.author	Zhou, L
dc.contributor.author	Catchpoole, D https://orcid.org/0000-0001-5836-1413
dc.contributor.author	Kirk, J
dc.contributor.author	Latchoumanin, O
dc.contributor.author	Qiao, L
dc.contributor.author	Ballinger, M
dc.contributor.author	Thomas, D
dc.contributor.author	Jamieson, R
dc.contributor.author	Dalla-Pozza, L
dc.contributor.author	Byrne, JA
dc.date.accessioned	2023-04-05T01:41:26Z
dc.date.available	2021-10-13
dc.date.available	2023-04-05T01:41:26Z
dc.date.issued	2022-02
dc.identifier.citation	Genes Chromosomes Cancer, 2022, 61, (2), pp. 81-93
dc.identifier.issn	1045-2257
dc.identifier.issn	1098-2264
dc.identifier.uri	http://hdl.handle.net/10453/169138
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Wiley
dc.relation.ispartof	Genes Chromosomes Cancer
dc.relation.isbasedon	10.1002/gcc.23006
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.mesh	Adolescent
dc.subject.mesh	Aged
dc.subject.mesh	Child
dc.subject.mesh	Child, Preschool
dc.subject.mesh	Cohort Studies
dc.subject.mesh	Genetic Predisposition to Disease
dc.subject.mesh	Germ-Line Mutation
dc.subject.mesh	Humans
dc.subject.mesh	Infant
dc.subject.mesh	Infant, Newborn
dc.subject.mesh	Neoplasms
dc.subject.mesh	Exome Sequencing
dc.subject.mesh	Humans
dc.subject.mesh	Neoplasms
dc.subject.mesh	Genetic Predisposition to Disease
dc.subject.mesh	Cohort Studies
dc.subject.mesh	Germ-Line Mutation
dc.subject.mesh	Adolescent
dc.subject.mesh	Aged
dc.subject.mesh	Child
dc.subject.mesh	Child, Preschool
dc.subject.mesh	Infant
dc.subject.mesh	Infant, Newborn
dc.subject.mesh	Exome Sequencing
dc.subject.mesh	Adolescent
dc.subject.mesh	Aged
dc.subject.mesh	Child
dc.subject.mesh	Child, Preschool
dc.subject.mesh	Cohort Studies
dc.subject.mesh	Genetic Predisposition to Disease
dc.subject.mesh	Germ-Line Mutation
dc.subject.mesh	Humans
dc.subject.mesh	Infant
dc.subject.mesh	Infant, Newborn
dc.subject.mesh	Neoplasms
dc.subject.mesh	Exome Sequencing
dc.title	Rare germline variants in childhood cancer patients suspected of genetic predisposition to cancer.
dc.type	Journal Article
utslib.citation.volume	61
utslib.location.activity	United States
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
utslib.copyright.status	closed_access	*
dc.date.updated	2023-04-05T01:41:24Z
pubs.issue	2
pubs.publication-status	Published
pubs.volume	61
utslib.citation.issue	2

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.

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http://hdl.handle.net/10453/169138