Inherited TP53 Variants and Risk of Prostate Cancer

被引：61

作者：

Maxwell, Kara N. ^{[1
,2
,24
]}

Cheng, Heather H. ^{[3
,4
]}

Powers, Jacquelyn ^{[1
]}

Gulati, Roman ^{[4
]}

Ledet, Elisa M. ^{[5
]}

Morrison, Casey ^{[6
]}

Le, Anh ^{[1
]}

Hausler, Ryan ^{[1
,25
]}

Stopfer, Jill ^{[7
]}

Hyman, Sophie ^{[7
]}

Kohlmann, Wendy ^{[8
]}

Naumer, Anne ^{[8
]}

Vagher, Jennie ^{[8
]}

Greenberg, Samantha E. ^{[8
]}

Naylor, Lorraine ^{[9
]}

Laurino, Mercy ^{[9
]}

Konnick, Eric Q. ^{[10
]}

Shirts, Brian H. ^{[10
,21
]}

AlDubayan, Saud H. ^{[11
,12
]}

Van Allen, Eliezer M. ^{[11
,12
]}

Nguyen, Bastien ^{[13
]}

Vijai, Joseph ^{[14
]}

Abida, Wassim ^{[15
]}

Carlo, Maria, I ^{[15
]}

Dubard-Gault, Marianne ^{[9
,23
]}

Lee, Daniel J. ^{[16
,24
]}

Maese, Luke D. ^{[8
,17
]}

Mandelker, Diana ^{[18
]}

Montgomery, Bruce ^{[3
,4
,26
]}

Morris, Michael J. ^{[15
]}

Nicolosi, Piper ^{[19
]}

Nussbaum, Robert L. ^{[19
]}

Schwartz, Lauren E. ^{[6
]}

Stadler, Zsofia ^{[15
]}

Garber, Judy E. ^{[7
]}

Offit, Kenneth ^{[14
]}

Schiffman, Joshua D. ^{[8
,17
,20
]}

Nelson, Peter S. ^{[4
,9
]}

Sartor, Oliver ^{[5
]}

Walsh, Michael F. ^{[15
,22
]}

Pritchard, Colin C. ^{[10
,21
]}

机构：

[1] Univ Penn, Perelman Sch Med, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA

[2] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA

[3] Univ Washington, Dept Med, Div Oncol, Seattle, WA 98195 USA

[4] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA

[5] Tulane Med Sch, Tulane Canc Ctr, New Orleans, LA USA

[6] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[7] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA

[8] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA

[9] Seattle Canc Care Alliance, Seattle, WA USA

[10] Univ Washington, Dept Lab Med & Pathol, 1959 NE Pacific St, Seattle, WA 98195 USA

[11] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[12] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02142 USA

[13] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

[14] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[15] Mem Sloan Kettering Canc Ctr, Div Solid Tumor Oncol, New York, NY 10021 USA

[16] Univ Penn, Perelman Sch Med, Dept Surg, Div Urol, Philadelphia, PA 19104 USA

[17] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA

[18] Mem Sloan Kettering Canc Ctr, Diagnost Mol Genet Lab, 1275 York Ave, New York, NY 10021 USA

[19] Invitae Corp, San Francisco, CA USA

[20] PEEL Therapeut Inc, Salt Lake City, UT USA

[21] Brotman Baty Inst Precis Med, Seattle, WA USA

[22] Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave, New York, NY 10021 USA

[23] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA

[24] Corporal Michael J Crescenz Vet Affairs Med Ctr, Philadelphia, PA 19104 USA

[25] George E Wahlen Dept Vet Affairs Med Ctr, Salt Lake City, UT 84148 USA

[26] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA

来源：

EUROPEAN UROLOGY | 2022年 / 81卷 / 03期

基金：

美国国家卫生研究院;

关键词：

Attenuated; Genetic testing; Germline; Hypomorphic mutation; Inherited cancer syndrome; Li-Fraumeni syndrome; Pathogenic variant; Prostate cancer; Screening; TP53; LI-FRAUMENI SYNDROME; MUTATION CARRIERS; IMPLEMENTATION; CAPTURE; BREAST;

D O I：

10.1016/j.eururo.2021.10.036

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

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. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology.

引用

页码：243 / 250

页数：8

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