Cancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum.

Fortuno, C; Feng, B-J; Carroll, C; Innella, G; Kohlmann, W; Lázaro, C; Brunet, J; Feliubadaló, L; Iglesias, S; Menéndez, M; Teulé, A; Ballinger, ML; Thomas, DM; Campbell, A; Field, M; Harris, M; Kirk, J; Pachter, N; Poplawski, N; Susman, R; Tucker, K; Wallis, M; Williams, R; Cops, E; Goldgar, D; kConFab Investigators,; James, PA; Spurdle, AB

Cancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum.

Fortuno, C Feng, B-J Carroll, C Innella, G Kohlmann, W Lázaro, C Brunet, J Feliubadaló, L Iglesias, S Menéndez, M Teulé, A Ballinger, ML Thomas, DM Campbell, A Field, M Harris, M Kirk, J Pachter, N Poplawski, N Susman, R Tucker, K Wallis, M Williams, R Cops, E Goldgar, D kConFab Investigators, James, PA Spurdle, AB

Permalink

Publisher:: American Society of Clinical Oncology (ASCO)
Publication Type:: Journal Article
Citation:: JCO Precis Oncol, 2024, 8, (8), pp. e2300453
Issue Date:: 2024-02

Recently Added

	Filename	Description	Size
	Cancer Risks Associated With iTP53i Pathogenic Variants Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of F.pdf	Published version	884.29 kB		View/Open

Copyright Clearance Process

Recently Added
In Progress
Open Access

This item is new to OPUS and is not currently available.

Full metadata record

Field	Value	Language
dc.contributor.author	Fortuno, C
dc.contributor.author	Feng, B-J
dc.contributor.author	Carroll, C
dc.contributor.author	Innella, G
dc.contributor.author	Kohlmann, W
dc.contributor.author	Lázaro, C
dc.contributor.author	Brunet, J
dc.contributor.author	Feliubadaló, L
dc.contributor.author	Iglesias, S
dc.contributor.author	Menéndez, M
dc.contributor.author	Teulé, A
dc.contributor.author	Ballinger, ML
dc.contributor.author	Thomas, DM
dc.contributor.author	Campbell, A
dc.contributor.author	Field, M
dc.contributor.author	Harris, M
dc.contributor.author	Kirk, J
dc.contributor.author	Pachter, N
dc.contributor.author	Poplawski, N
dc.contributor.author	Susman, R
dc.contributor.author	Tucker, K
dc.contributor.author	Wallis, M
dc.contributor.author	Williams, R
dc.contributor.author	Cops, E
dc.contributor.author	Goldgar, D
dc.contributor.author	kConFab Investigators,
dc.contributor.author	James, PA
dc.contributor.author	Spurdle, AB
dc.date.accessioned	2025-04-02T02:57:45Z
dc.date.available	2025-04-02T02:57:45Z
dc.date.issued	2024-02
dc.identifier.citation	JCO Precis Oncol, 2024, 8, (8), pp. e2300453
dc.identifier.issn	2473-4284
dc.identifier.issn	2473-4284
dc.identifier.uri	http://hdl.handle.net/10453/186447
dc.description.abstract	PURPOSE: Establishing accurate age-related penetrance figures for the broad range of cancer types that occur in individuals harboring a pathogenic germline variant in the TP53 gene is essential to determine the most effective clinical management strategies. These figures also permit optimal use of cosegregation data for classification of TP53 variants of unknown significance. Penetrance estimation can easily be affected by bias from ascertainment criteria, an issue not commonly addressed by previous studies. MATERIALS AND METHODS: We performed a maximum likelihood penetrance estimation using full pedigree data from a multicenter study of 146 TP53-positive families, incorporating adjustment for the effect of ascertainment and population-specific background cancer risks. The analysis included pedigrees from Australia, Spain, and United States, with phenotypic information for 4,028 individuals. RESULTS: Core Li-Fraumeni syndrome (LFS) cancers (breast cancer, adrenocortical carcinoma, brain cancer, osteosarcoma, and soft tissue sarcoma) had the highest hazard ratios of all cancers analyzed in this study. The analysis also detected a significantly increased lifetime risk for a range of cancers not previously formally associated with TP53 pathogenic variant status, including colorectal, gastric, lung, pancreatic, and ovarian cancers. The cumulative risk of any cancer type by age 50 years was 92.4% (95% CI, 82.2 to 98.3) for females and 59.7% (95% CI, 39.9 to 81.3) for males. Females had a 63.3% (95% CI, 35.6 to 90.1) cumulative risk of developing breast cancer by age 50 years. CONCLUSION: The results from maximum likelihood analysis confirm the known high lifetime risk for the core LFS-associated cancer types providing new risk estimates and indicate significantly increased lifetime risks for several additional cancer types. Accurate cancer risk estimates will help refine clinical recommendations for TP53 pathogenic variant carriers and improve TP53 variant classification.
dc.format	Print
dc.language	eng
dc.publisher	American Society of Clinical Oncology (ASCO)
dc.relation.ispartof	JCO Precis Oncol
dc.relation.isbasedon	10.1200/PO.23.00453
dc.rights	info:eu-repo/semantics/restrictedAccess
dc.subject.classification	3211 Oncology and carcinogenesis
dc.subject.mesh	Male
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	United States
dc.subject.mesh	Middle Aged
dc.subject.mesh	Li-Fraumeni Syndrome
dc.subject.mesh	Genes, p53
dc.subject.mesh	Pedigree
dc.subject.mesh	Tumor Suppressor Protein p53
dc.subject.mesh	Genetic Predisposition to Disease
dc.subject.mesh	Breast Neoplasms
dc.subject.mesh	Risk Factors
dc.subject.mesh	Humans
dc.subject.mesh	Breast Neoplasms
dc.subject.mesh	Li-Fraumeni Syndrome
dc.subject.mesh	Genetic Predisposition to Disease
dc.subject.mesh	Risk Factors
dc.subject.mesh	Pedigree
dc.subject.mesh	Genes, p53
dc.subject.mesh	Middle Aged
dc.subject.mesh	United States
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Tumor Suppressor Protein p53
dc.subject.mesh	Male
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	United States
dc.subject.mesh	Middle Aged
dc.subject.mesh	Li-Fraumeni Syndrome
dc.subject.mesh	Genes, p53
dc.subject.mesh	Pedigree
dc.subject.mesh	Tumor Suppressor Protein p53
dc.subject.mesh	Genetic Predisposition to Disease
dc.subject.mesh	Breast Neoplasms
dc.subject.mesh	Risk Factors
dc.title	Cancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum.
dc.type	Journal Article
utslib.citation.volume	8
utslib.location.activity	United States
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
utslib.copyright.status	recently_added	*
dc.date.updated	2025-04-02T02:57:42Z
pubs.issue	8
pubs.publication-status	Published
pubs.volume	8
utslib.citation.issue	8

Abstract:

PURPOSE: Establishing accurate age-related penetrance figures for the broad range of cancer types that occur in individuals harboring a pathogenic germline variant in the TP53 gene is essential to determine the most effective clinical management strategies. These figures also permit optimal use of cosegregation data for classification of TP53 variants of unknown significance. Penetrance estimation can easily be affected by bias from ascertainment criteria, an issue not commonly addressed by previous studies. MATERIALS AND METHODS: We performed a maximum likelihood penetrance estimation using full pedigree data from a multicenter study of 146 TP53-positive families, incorporating adjustment for the effect of ascertainment and population-specific background cancer risks. The analysis included pedigrees from Australia, Spain, and United States, with phenotypic information for 4,028 individuals. RESULTS: Core Li-Fraumeni syndrome (LFS) cancers (breast cancer, adrenocortical carcinoma, brain cancer, osteosarcoma, and soft tissue sarcoma) had the highest hazard ratios of all cancers analyzed in this study. The analysis also detected a significantly increased lifetime risk for a range of cancers not previously formally associated with TP53 pathogenic variant status, including colorectal, gastric, lung, pancreatic, and ovarian cancers. The cumulative risk of any cancer type by age 50 years was 92.4% (95% CI, 82.2 to 98.3) for females and 59.7% (95% CI, 39.9 to 81.3) for males. Females had a 63.3% (95% CI, 35.6 to 90.1) cumulative risk of developing breast cancer by age 50 years. CONCLUSION: The results from maximum likelihood analysis confirm the known high lifetime risk for the core LFS-associated cancer types providing new risk estimates and indicate significantly increased lifetime risks for several additional cancer types. Accurate cancer risk estimates will help refine clinical recommendations for TP53 pathogenic variant carriers and improve TP53 variant classification.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/186447