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Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study

BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PART...

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Autores principales: Karlsson, Questa, Brook, Mark N., Dadaev, Tokhir, Wakerell, Sarah, Saunders, Edward J., Muir, Kenneth, Neal, David E., Giles, Graham G., MacInnis, Robert J., Thibodeau, Stephen N., McDonnell, Shannon K., Cannon-Albright, Lisa, Teixeira, Manuel R., Paulo, Paula, Cardoso, Marta, Huff, Chad, Li, Donghui, Yao, Yu, Scheet, Paul, Permuth, Jennifer B., Stanford, Janet L., Dai, James Y., Ostrander, Elaine A., Cussenot, Olivier, Cancel-Tassin, Géraldine, Hoegel, Josef, Herkommer, Kathleen, Schleutker, Johanna, Tammela, Teuvo L.J., Rathinakannan, Venkat, Sipeky, Csilla, Wiklund, Fredrik, Grönberg, Henrik, Aly, Markus, Isaacs, William B., Dickinson, Jo L., FitzGerald, Liesel M., Chua, Melvin L.K., Nguyen-Dumont, Tu, Schaid, Daniel J., Southey, Melissa C., Eeles, Rosalind A., Kote-Jarai, Zsofia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier B.V 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381233/
https://www.ncbi.nlm.nih.gov/pubmed/33436325
http://dx.doi.org/10.1016/j.euo.2020.12.001
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author Karlsson, Questa
Brook, Mark N.
Dadaev, Tokhir
Wakerell, Sarah
Saunders, Edward J.
Muir, Kenneth
Neal, David E.
Giles, Graham G.
MacInnis, Robert J.
Thibodeau, Stephen N.
McDonnell, Shannon K.
Cannon-Albright, Lisa
Teixeira, Manuel R.
Paulo, Paula
Cardoso, Marta
Huff, Chad
Li, Donghui
Yao, Yu
Scheet, Paul
Permuth, Jennifer B.
Stanford, Janet L.
Dai, James Y.
Ostrander, Elaine A.
Cussenot, Olivier
Cancel-Tassin, Géraldine
Hoegel, Josef
Herkommer, Kathleen
Schleutker, Johanna
Tammela, Teuvo L.J.
Rathinakannan, Venkat
Sipeky, Csilla
Wiklund, Fredrik
Grönberg, Henrik
Aly, Markus
Isaacs, William B.
Dickinson, Jo L.
FitzGerald, Liesel M.
Chua, Melvin L.K.
Nguyen-Dumont, Tu
Schaid, Daniel J.
Southey, Melissa C.
Eeles, Rosalind A.
Kote-Jarai, Zsofia
author_facet Karlsson, Questa
Brook, Mark N.
Dadaev, Tokhir
Wakerell, Sarah
Saunders, Edward J.
Muir, Kenneth
Neal, David E.
Giles, Graham G.
MacInnis, Robert J.
Thibodeau, Stephen N.
McDonnell, Shannon K.
Cannon-Albright, Lisa
Teixeira, Manuel R.
Paulo, Paula
Cardoso, Marta
Huff, Chad
Li, Donghui
Yao, Yu
Scheet, Paul
Permuth, Jennifer B.
Stanford, Janet L.
Dai, James Y.
Ostrander, Elaine A.
Cussenot, Olivier
Cancel-Tassin, Géraldine
Hoegel, Josef
Herkommer, Kathleen
Schleutker, Johanna
Tammela, Teuvo L.J.
Rathinakannan, Venkat
Sipeky, Csilla
Wiklund, Fredrik
Grönberg, Henrik
Aly, Markus
Isaacs, William B.
Dickinson, Jo L.
FitzGerald, Liesel M.
Chua, Melvin L.K.
Nguyen-Dumont, Tu
Schaid, Daniel J.
Southey, Melissa C.
Eeles, Rosalind A.
Kote-Jarai, Zsofia
author_sort Karlsson, Questa
collection PubMed
description BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0–9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (p(difference) = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1–1.7). CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families. PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.
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spelling pubmed-83812332021-08-30 Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study Karlsson, Questa Brook, Mark N. Dadaev, Tokhir Wakerell, Sarah Saunders, Edward J. Muir, Kenneth Neal, David E. Giles, Graham G. MacInnis, Robert J. Thibodeau, Stephen N. McDonnell, Shannon K. Cannon-Albright, Lisa Teixeira, Manuel R. Paulo, Paula Cardoso, Marta Huff, Chad Li, Donghui Yao, Yu Scheet, Paul Permuth, Jennifer B. Stanford, Janet L. Dai, James Y. Ostrander, Elaine A. Cussenot, Olivier Cancel-Tassin, Géraldine Hoegel, Josef Herkommer, Kathleen Schleutker, Johanna Tammela, Teuvo L.J. Rathinakannan, Venkat Sipeky, Csilla Wiklund, Fredrik Grönberg, Henrik Aly, Markus Isaacs, William B. Dickinson, Jo L. FitzGerald, Liesel M. Chua, Melvin L.K. Nguyen-Dumont, Tu Schaid, Daniel J. Southey, Melissa C. Eeles, Rosalind A. Kote-Jarai, Zsofia Eur Urol Oncol Priority Article BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0–9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (p(difference) = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1–1.7). CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families. PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier. Elsevier B.V 2021-08 /pmc/articles/PMC8381233/ /pubmed/33436325 http://dx.doi.org/10.1016/j.euo.2020.12.001 Text en © 2020 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Priority Article
Karlsson, Questa
Brook, Mark N.
Dadaev, Tokhir
Wakerell, Sarah
Saunders, Edward J.
Muir, Kenneth
Neal, David E.
Giles, Graham G.
MacInnis, Robert J.
Thibodeau, Stephen N.
McDonnell, Shannon K.
Cannon-Albright, Lisa
Teixeira, Manuel R.
Paulo, Paula
Cardoso, Marta
Huff, Chad
Li, Donghui
Yao, Yu
Scheet, Paul
Permuth, Jennifer B.
Stanford, Janet L.
Dai, James Y.
Ostrander, Elaine A.
Cussenot, Olivier
Cancel-Tassin, Géraldine
Hoegel, Josef
Herkommer, Kathleen
Schleutker, Johanna
Tammela, Teuvo L.J.
Rathinakannan, Venkat
Sipeky, Csilla
Wiklund, Fredrik
Grönberg, Henrik
Aly, Markus
Isaacs, William B.
Dickinson, Jo L.
FitzGerald, Liesel M.
Chua, Melvin L.K.
Nguyen-Dumont, Tu
Schaid, Daniel J.
Southey, Melissa C.
Eeles, Rosalind A.
Kote-Jarai, Zsofia
Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study
title Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study
title_full Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study
title_fullStr Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study
title_full_unstemmed Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study
title_short Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study
title_sort rare germline variants in atm predispose to prostate cancer: a practical consortium study
topic Priority Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381233/
https://www.ncbi.nlm.nih.gov/pubmed/33436325
http://dx.doi.org/10.1016/j.euo.2020.12.001
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