Inherited TP53 Variants and Risk of Prostate Cancer.

Adult Genetic Predisposition to Disease Germ-Line Mutation Humans Li-Fraumeni Syndrome / epidemiology Male Middle Aged Prostatic Neoplasms / epidemiology Retrospective Studies Tumor Suppressor Protein p53 / genetics
Attenuated Genetic testing Germline Hypomorphic mutation Inherited cancer syndrome Li-Fraumeni syndrome Pathogenic variant Prostate cancer Screening TP53

Journal

European urology
ISSN: 1873-7560
Titre abrégé: Eur Urol
Pays: Switzerland
ID NLM: 7512719

Informations de publication

Date de publication:
Mar 2022
Historique:
received: 09 05 2021
revised: 22 09 2021
accepted: 28 10 2021
pubmed: 6 12 2021
medline: 19 4 2022
entrez: 5 12 2021
Statut: ppublish

Résumé

Inherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53. To determine whether gTP53 predisposes to prostate cancer. This multi-institutional retrospective study characterizes prostate cancer incidence in a cohort of LFS males and gTP53 prevalence in a prostate cancer cohort. We evaluated the spectrum of gTP53 variants and clinical features associated with prostate cancer. We identified 31 prostate cancer cases among 163 adult LFS males, including 26 of 54 aged ≥50 yr. Among 117 LFS males without prostate cancer at the time of genetic testing, six were diagnosed with prostate cancer over a median (interquartile range [IQR]) of 3.0 (1.3-7.2) yr of follow-up, a 25-fold increased risk (95% confidence interval [CI] 9.2-55; p < 0.0001). We identified gTP53 in 38 of 6850 males (0.6%) in the prostate cancer cohort, a relative risk 9.1-fold higher than that of population controls (95% CI 6.2-14; p < 0.0001; gnomAD). We observed hotspots at the sites of attenuated variants not associated with classic LFS. Two-thirds of available gTP53 prostate tumors had somatic inactivation of the second TP53 allele. Among gTP53 prostate cancer cases in this study, the median age at diagnosis was 56 (IQR: 51-62) yr, 44% had Gleason ≥8 tumors, and 29% had advanced disease at diagnosis. Complementary analyses of prostate cancer incidence in LFS males and gTP53 prevalence in prostate cancer cohorts suggest that gTP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 considered in germline prostate cancer susceptibility testing. Inherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer.

Sections du résumé

BACKGROUND BACKGROUND
Inherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53.
OBJECTIVE OBJECTIVE
To determine whether gTP53 predisposes to prostate cancer.
DESIGN, SETTING, AND PARTICIPANTS METHODS
This multi-institutional retrospective study characterizes prostate cancer incidence in a cohort of LFS males and gTP53 prevalence in a prostate cancer cohort.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS METHODS
We evaluated the spectrum of gTP53 variants and clinical features associated with prostate cancer.
RESULTS AND LIMITATIONS CONCLUSIONS
We identified 31 prostate cancer cases among 163 adult LFS males, including 26 of 54 aged ≥50 yr. Among 117 LFS males without prostate cancer at the time of genetic testing, six were diagnosed with prostate cancer over a median (interquartile range [IQR]) of 3.0 (1.3-7.2) yr of follow-up, a 25-fold increased risk (95% confidence interval [CI] 9.2-55; p < 0.0001). We identified gTP53 in 38 of 6850 males (0.6%) in the prostate cancer cohort, a relative risk 9.1-fold higher than that of population controls (95% CI 6.2-14; p < 0.0001; gnomAD). We observed hotspots at the sites of attenuated variants not associated with classic LFS. Two-thirds of available gTP53 prostate tumors had somatic inactivation of the second TP53 allele. Among gTP53 prostate cancer cases in this study, the median age at diagnosis was 56 (IQR: 51-62) yr, 44% had Gleason ≥8 tumors, and 29% had advanced disease at diagnosis.
CONCLUSIONS CONCLUSIONS
Complementary analyses of prostate cancer incidence in LFS males and gTP53 prevalence in prostate cancer cohorts suggest that gTP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 considered in germline prostate cancer susceptibility testing.
PATIENT SUMMARY RESULTS
Inherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer.

Identifiants

DOI: 10.1016/j.eururo.2021.10.036 PMID: 34863587 PMC: PMC8891030
pubmed: 34863587
pii: S0302-2838(21)02139-4
doi: 10.1016/j.eururo.2021.10.036
pmc: PMC8891030
mid: NIHMS1756199
pii:
doi:

Substances chimiques

TP53 protein, human 0
Tumor Suppressor Protein p53 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

243-250

Subventions

Organisme : NCI NIH HHS
ID : P30 CA015704
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA097186
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA242218
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016520
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA221836
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA215312
Pays : United States

Commentaires et corrections

Type : CommentIn
Type : CommentIn

Informations de copyright

Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.

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Auteurs

Kara N Maxwell (KN)

Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia PA, 19104.

Heather H Cheng (HH)

Division of Oncology, Department of Medicine, University of Washington, Seattle, WA, USA; Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Jacquelyn Powers (J)

Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Roman Gulati (R)

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Elisa M Ledet (EM)

Tulane Cancer Center, Tulane Medical School, New Orleans, LA, USA.

Casey Morrison (C)

Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Anh Le (A)

Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Ryan Hausler (R)

Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT 84148.

Jill Stopfer (J)

Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.

Sophie Hyman (S)

Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.

Wendy Kohlmann (W)

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Anne Naumer (A)

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Jennie Vagher (J)

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Samantha E Greenberg (SE)

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Lorraine Naylor (L)

Seattle Cancer Care Alliance, Seattle, WA, USA.

Mercy Laurino (M)

Seattle Cancer Care Alliance, Seattle, WA, USA.

Eric Q Konnick (EQ)

Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.

Brian H Shirts (BH)

Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.

Saud H AlDubayan (SH)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Eliezer M Van Allen (EM)

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Bastien Nguyen (B)

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Joseph Vijai (J)

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Wassim Abida (W)

Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Maria I Carlo (MI)

Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Marianne Dubard-Gault (M)

Seattle Cancer Care Alliance, Seattle, WA, USA; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.

Daniel J Lee (DJ)

Department of Surgery, Division of Urology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia PA, 19104.

Luke D Maese (LD)

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.

Diana Mandelker (D)

Diagnostic Molecular Genetics Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Bruce Montgomery (B)

Division of Oncology, Department of Medicine, University of Washington, Seattle, WA, USA; Fred Hutchinson Cancer Research Center, Seattle, WA, USA; VA Puget Sound Health Care System, Seattle, WA 98108.

Michael J Morris (MJ)

Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Piper Nicolosi (P)

Invitae Corporation, San Francisco, CA, USA.

Robert L Nussbaum (RL)

Invitae Corporation, San Francisco, CA, USA.

Lauren E Schwartz (LE)

Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Zsofia Stadler (Z)

Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Judy E Garber (JE)

Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.

Kenneth Offit (K)

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Joshua D Schiffman (JD)

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA; PEEL Therapeutics, Inc., Salt Lake City, UT, USA.

Peter S Nelson (PS)

Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Seattle Cancer Care Alliance, Seattle, WA, USA.

Oliver Sartor (O)

Tulane Cancer Center, Tulane Medical School, New Orleans, LA, USA.

Michael F Walsh (MF)

Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Colin C Pritchard (CC)

Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA. Electronic address: cpritch@uw.edu.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Inherited TP53 Variants and Risk of Prostate Cancer.
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Inherited TP53 Variants and Risk of Prostate Cancer.
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation germinale › Inherited TP53 Variants and Risk of Prostate Cancer.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Inherited TP53 Variants and Risk of Prostate Cancer.
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Troubles dus à un défaut de réparation de l'ADN › Syndrome de Li-Fraumeni › Inherited TP53 Variants and Risk of Prostate Cancer.
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Inherited TP53 Variants and Risk of Prostate Cancer.
questionsmedicales.fr › Maladies urogénitales › Tumeurs de l'appareil urogénital › Tumeurs de l'appareil génital mâle › Tumeurs de la prostate › Inherited TP53 Variants and Risk of Prostate Cancer.
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études rétrospectives › Inherited TP53 Variants and Risk of Prostate Cancer.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Phosphoprotéines › Protéine p53 suppresseur de tumeur › Inherited TP53 Variants and Risk of Prostate Cancer.