. 2022 Mar;81(3):243-250.

doi: 10.1016/j.eururo.2021.10.036. Epub 2021 Dec 1.

Inherited TP53 Variants and Risk of Prostate Cancer

Kara N Maxwell¹, Heather H Cheng², Jacquelyn Powers³, Roman Gulati⁴, Elisa M Ledet⁵, Casey Morrison⁶, Anh Le³, Ryan Hausler⁷, Jill Stopfer⁸, Sophie Hyman⁸, Wendy Kohlmann⁹, Anne Naumer⁹, Jennie Vagher⁹, Samantha E Greenberg⁹, Lorraine Naylor¹⁰, Mercy Laurino¹⁰, Eric Q Konnick¹¹, Brian H Shirts¹², Saud H AlDubayan¹³, Eliezer M Van Allen¹³, Bastien Nguyen¹⁴, Joseph Vijai¹⁵, Wassim Abida¹⁶, Maria I Carlo¹⁶, Marianne Dubard-Gault¹⁷, Daniel J Lee¹⁸, Luke D Maese¹⁹, Diana Mandelker²⁰, Bruce Montgomery²¹, Michael J Morris¹⁶, Piper Nicolosi²², Robert L Nussbaum²², Lauren E Schwartz⁶, Zsofia Stadler¹⁶, Judy E Garber⁸, Kenneth Offit¹⁵, Joshua D Schiffman²³, Peter S Nelson²⁴, Oliver Sartor⁵, Michael F Walsh²⁵, Colin C Pritchard²⁶

Affiliations

¹ 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.
² Division of Oncology, Department of Medicine, University of Washington, Seattle, WA, USA; Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³ Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁴ Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁵ Tulane Cancer Center, Tulane Medical School, New Orleans, LA, USA.
⁶ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁷ 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.
⁸ Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.
⁹ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
¹⁰ Seattle Cancer Care Alliance, Seattle, WA, USA.
¹¹ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
¹² Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.
¹³ 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.
¹⁴ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁵ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁶ Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁷ Seattle Cancer Care Alliance, Seattle, WA, USA; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
¹⁸ 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.
¹⁹ 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.
²⁰ Diagnostic Molecular Genetics Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²¹ 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.
²² Invitae Corporation, San Francisco, CA, USA.
²³ 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.
²⁴ Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Seattle Cancer Care Alliance, Seattle, WA, USA.
²⁵ 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.
²⁶ 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.

PMID: 34863587
PMCID: PMC8891030
DOI: 10.1016/j.eururo.2021.10.036

Inherited TP53 Variants and Risk of Prostate Cancer

Kara N Maxwell et al. Eur Urol. 2022 Mar.

. 2022 Mar;81(3):243-250.

doi: 10.1016/j.eururo.2021.10.036. Epub 2021 Dec 1.

Authors

Affiliations

¹ 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.
² Division of Oncology, Department of Medicine, University of Washington, Seattle, WA, USA; Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³ Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁴ Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁵ Tulane Cancer Center, Tulane Medical School, New Orleans, LA, USA.
⁶ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁷ 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.
⁸ Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.
⁹ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
¹⁰ Seattle Cancer Care Alliance, Seattle, WA, USA.
¹¹ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
¹² Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.
¹³ 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.
¹⁴ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁵ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁶ Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁷ Seattle Cancer Care Alliance, Seattle, WA, USA; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.
¹⁸ 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.
¹⁹ 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.
²⁰ Diagnostic Molecular Genetics Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²¹ 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.
²² Invitae Corporation, San Francisco, CA, USA.
²³ 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.
²⁴ Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Seattle Cancer Care Alliance, Seattle, WA, USA.
²⁵ 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.
²⁶ 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.

PMID: 34863587
PMCID: PMC8891030
DOI: 10.1016/j.eururo.2021.10.036

Abstract

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: To determine whether gTP53 predisposes to prostate cancer.

Design, setting, and participants: 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: We evaluated the spectrum of gTP53 variants and clinical features associated with prostate cancer.

Results and limitations: 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: 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: Inherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer.

Keywords: Attenuated; Genetic testing; Germline; Hypomorphic mutation; Inherited cancer syndrome; Li-Fraumeni syndrome; Pathogenic variant; Prostate cancer; Screening; TP53.

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Figures

**Fig. 1 –**
Summary of results (graphical abstract). LFS = Li-Fraumeni syndrome; PrCa = prostate cancer; SEER = Surveillance, Epidemiology, and End Results.

**Fig. 2 –**
Distribution of *TP53* pathogenic and likely pathogenic variants. Lollipop plot depicts 67 germline P/LP variants in patients with prostate cancer. Green color represents missense variants, black represents truncating variants (frameshift, nonsense, and splice site), and black lines represent large deletion variants. Hotspots for prostate cancer were observed at sites of reduced penetrance variants at codons 158, 181, 282, 283, and 337. Classic LFS hotspot mutations (R175H, G245S, R248Q, and R282W) are indicated with red asterisks. LFS = Li-Fraumeni syndrome; P/LP = pathogenic and likely pathogenic.

See this image and copyright information in PMC

Comment in

TP53: Another Piece of the Prostate Cancer Genetics Puzzle.
Castro E. Castro E. Eur Urol. 2022 Mar;81(3):251-252. doi: 10.1016/j.eururo.2021.11.023. Epub 2021 Dec 9. Eur Urol. 2022. PMID: 34895923 No abstract available.
Re: Kara N. Maxwell, Heather H. Cheng, Jacquelyn Powers, et al. Inherited TP53 Variants and Risk of Prostate Cancer. Eur Urol 2022;81:243-50: Off-core Li-Fraumeni Syndrome Spectrum Cancers: Increasing Interest for Prostate Cancer?
Sassi H, Caron O, Rouleau E. Sassi H, et al. Eur Urol. 2022 Dec;82(6):e172-e173. doi: 10.1016/j.eururo.2022.07.038. Epub 2022 Sep 22. Eur Urol. 2022. PMID: 36153247 No abstract available.

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1. Nicolosi P, Ledet E, Yang S, et al. Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines. JAMA Oncol 2019;5:523–8. - PMC - PubMed
1. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016;375:443–53. - PMC - PubMed
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Inherited TP53 Variants and Risk of Prostate Cancer

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Inherited TP53 Variants and Risk of Prostate Cancer

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