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Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C

Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these var...

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Autores principales: Hu, Chunling, Nagaraj, Anil Belur, Shimelis, Hermela, Montalban, Gemma, Lee, Kun Y., Huang, Huaizhi, Lumby, Carolyn A., Na, Jie, Susswein, Lisa R., Roberts, Maegan E., Marshall, Megan L., Hiraki, Susan, LaDuca, Holly, Chao, Elizabeth, Yussuf, Amal, Pesaran, Tina, Neuhausen, Susan L., Haiman, Christopher A., Kraft, Peter, Lindstrom, Sara, Palmer, Julie R., Teras, Lauren R., Vachon, Celine M., Yao, Song, Ong, Irene, Nathanson, Katherine L., Weitzel, Jeffrey N., Boddicker, Nicholas, Gnanaolivu, Rohan, Polley, Eric C., Mer, Georges, Cui, Gaofeng, Karam, Rachid, Richardson, Marcy E., Domchek, Susan M., Yadav, Siddhartha, Hruska, Kathleen S., Dolinsky, Jill, Weroha, S. John, Hart, Steven N., Simard, Jacques, Masson, Jean Yves, Pang, Yuan-Ping, Couch, Fergus J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10390864/
https://www.ncbi.nlm.nih.gov/pubmed/37253112
http://dx.doi.org/10.1158/0008-5472.CAN-22-2319
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author Hu, Chunling
Nagaraj, Anil Belur
Shimelis, Hermela
Montalban, Gemma
Lee, Kun Y.
Huang, Huaizhi
Lumby, Carolyn A.
Na, Jie
Susswein, Lisa R.
Roberts, Maegan E.
Marshall, Megan L.
Hiraki, Susan
LaDuca, Holly
Chao, Elizabeth
Yussuf, Amal
Pesaran, Tina
Neuhausen, Susan L.
Haiman, Christopher A.
Kraft, Peter
Lindstrom, Sara
Palmer, Julie R.
Teras, Lauren R.
Vachon, Celine M.
Yao, Song
Ong, Irene
Nathanson, Katherine L.
Weitzel, Jeffrey N.
Boddicker, Nicholas
Gnanaolivu, Rohan
Polley, Eric C.
Mer, Georges
Cui, Gaofeng
Karam, Rachid
Richardson, Marcy E.
Domchek, Susan M.
Yadav, Siddhartha
Hruska, Kathleen S.
Dolinsky, Jill
Weroha, S. John
Hart, Steven N.
Simard, Jacques
Masson, Jean Yves
Pang, Yuan-Ping
Couch, Fergus J.
author_facet Hu, Chunling
Nagaraj, Anil Belur
Shimelis, Hermela
Montalban, Gemma
Lee, Kun Y.
Huang, Huaizhi
Lumby, Carolyn A.
Na, Jie
Susswein, Lisa R.
Roberts, Maegan E.
Marshall, Megan L.
Hiraki, Susan
LaDuca, Holly
Chao, Elizabeth
Yussuf, Amal
Pesaran, Tina
Neuhausen, Susan L.
Haiman, Christopher A.
Kraft, Peter
Lindstrom, Sara
Palmer, Julie R.
Teras, Lauren R.
Vachon, Celine M.
Yao, Song
Ong, Irene
Nathanson, Katherine L.
Weitzel, Jeffrey N.
Boddicker, Nicholas
Gnanaolivu, Rohan
Polley, Eric C.
Mer, Georges
Cui, Gaofeng
Karam, Rachid
Richardson, Marcy E.
Domchek, Susan M.
Yadav, Siddhartha
Hruska, Kathleen S.
Dolinsky, Jill
Weroha, S. John
Hart, Steven N.
Simard, Jacques
Masson, Jean Yves
Pang, Yuan-Ping
Couch, Fergus J.
author_sort Hu, Chunling
collection PubMed
description Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C(−/−) cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C-depleted cancer cells. Case–control association studies of deleterious variants in women with breast and ovarian cancer and noncancer controls showed associations with moderate breast cancer risk [OR, 3.92; 95% confidence interval (95% CI), 2.18–7.59] and high ovarian cancer risk (OR, 14.8; 95% CI, 7.71–30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers. SIGNIFICANCE: Functional analysis of the impact of a large number of missense variants on RAD51C function provides insight into RAD51C activity and information for classification of the cancer relevance of RAD51C variants.
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spelling pubmed-103908642023-08-02 Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C Hu, Chunling Nagaraj, Anil Belur Shimelis, Hermela Montalban, Gemma Lee, Kun Y. Huang, Huaizhi Lumby, Carolyn A. Na, Jie Susswein, Lisa R. Roberts, Maegan E. Marshall, Megan L. Hiraki, Susan LaDuca, Holly Chao, Elizabeth Yussuf, Amal Pesaran, Tina Neuhausen, Susan L. Haiman, Christopher A. Kraft, Peter Lindstrom, Sara Palmer, Julie R. Teras, Lauren R. Vachon, Celine M. Yao, Song Ong, Irene Nathanson, Katherine L. Weitzel, Jeffrey N. Boddicker, Nicholas Gnanaolivu, Rohan Polley, Eric C. Mer, Georges Cui, Gaofeng Karam, Rachid Richardson, Marcy E. Domchek, Susan M. Yadav, Siddhartha Hruska, Kathleen S. Dolinsky, Jill Weroha, S. John Hart, Steven N. Simard, Jacques Masson, Jean Yves Pang, Yuan-Ping Couch, Fergus J. Cancer Res Translational Cancer Biology Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C(−/−) cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C-depleted cancer cells. Case–control association studies of deleterious variants in women with breast and ovarian cancer and noncancer controls showed associations with moderate breast cancer risk [OR, 3.92; 95% confidence interval (95% CI), 2.18–7.59] and high ovarian cancer risk (OR, 14.8; 95% CI, 7.71–30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers. SIGNIFICANCE: Functional analysis of the impact of a large number of missense variants on RAD51C function provides insight into RAD51C activity and information for classification of the cancer relevance of RAD51C variants. American Association for Cancer Research 2023-08-01 2023-05-30 /pmc/articles/PMC10390864/ /pubmed/37253112 http://dx.doi.org/10.1158/0008-5472.CAN-22-2319 Text en ©2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Translational Cancer Biology
Hu, Chunling
Nagaraj, Anil Belur
Shimelis, Hermela
Montalban, Gemma
Lee, Kun Y.
Huang, Huaizhi
Lumby, Carolyn A.
Na, Jie
Susswein, Lisa R.
Roberts, Maegan E.
Marshall, Megan L.
Hiraki, Susan
LaDuca, Holly
Chao, Elizabeth
Yussuf, Amal
Pesaran, Tina
Neuhausen, Susan L.
Haiman, Christopher A.
Kraft, Peter
Lindstrom, Sara
Palmer, Julie R.
Teras, Lauren R.
Vachon, Celine M.
Yao, Song
Ong, Irene
Nathanson, Katherine L.
Weitzel, Jeffrey N.
Boddicker, Nicholas
Gnanaolivu, Rohan
Polley, Eric C.
Mer, Georges
Cui, Gaofeng
Karam, Rachid
Richardson, Marcy E.
Domchek, Susan M.
Yadav, Siddhartha
Hruska, Kathleen S.
Dolinsky, Jill
Weroha, S. John
Hart, Steven N.
Simard, Jacques
Masson, Jean Yves
Pang, Yuan-Ping
Couch, Fergus J.
Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C
title Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C
title_full Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C
title_fullStr Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C
title_full_unstemmed Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C
title_short Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C
title_sort functional and clinical characterization of variants of uncertain significance identifies a hotspot for inactivating missense variants in rad51c
topic Translational Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10390864/
https://www.ncbi.nlm.nih.gov/pubmed/37253112
http://dx.doi.org/10.1158/0008-5472.CAN-22-2319
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