Untangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers

Abstract The MRE11–RAD50–NBS1 (MRN) complex is critical for genomic stability. Although germline mutations in MRN may increase breast cancer susceptibility, such mutations are extremely rare. Here, we have conducted a comprehensive clinicopathological study of MRN in sporadic breast cancers. We have...

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Autores principales:	Adel Alblihy, Ahmed Shoqafi, Michael S. Toss, Mashael Algethami, Anna E. Harris, Jennie N. Jeyapalan, Tarek Abdel-Fatah, Juliette Servante, Stephen Y. T. Chan, Andrew Green, Nigel P. Mongan, Emad A. Rakha, Srinivasan Madhusudan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/56ed86e24ee6429fa04c2441b2232edb
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spelling	oai:doaj.org-article:56ed86e24ee6429fa04c2441b2232edb2021-11-21T12:31:47ZUntangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers10.1038/s41523-021-00350-52374-4677https://doaj.org/article/56ed86e24ee6429fa04c2441b2232edb2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00350-5https://doaj.org/toc/2374-4677Abstract The MRE11–RAD50–NBS1 (MRN) complex is critical for genomic stability. Although germline mutations in MRN may increase breast cancer susceptibility, such mutations are extremely rare. Here, we have conducted a comprehensive clinicopathological study of MRN in sporadic breast cancers. We have protein expression profiled for MRN and a panel of DNA repair factors involved in double-strand break repair (BRCA1, BRCA2, ATM, CHK2, ATR, Chk1, pChk1, RAD51, γH2AX, RPA1, RPA2, DNA-PKcs), RECQ DNA helicases (BLM, WRN, RECQ1, RECQL4, RECQ5), nucleotide excision repair (ERCC1) and base excision repair (SMUG1, APE1, FEN1, PARP1, XRCC1, Pol β) in 1650 clinical breast cancers. The prognostic significance of MRE11, RAD50 and NBS1 transcripts and their microRNA regulators (hsa-miR-494 and hsa-miR-99b) were evaluated in large clinical datasets. Expression of MRN components was analysed in The Cancer Genome Atlas breast cancer cohort. We show that low nuclear MRN is linked to aggressive histopathological phenotypes such as high tumour grade, high mitotic index, oestrogen receptor- and high-risk Nottingham Prognostic Index. In univariate analysis, low nuclear MRE11 and low nuclear RAD50 were associated with poor survival. In multivariate analysis, low nuclear RAD50 remained independently linked with adverse clinical outcomes. Low RAD50 transcripts were also linked with reduced survival. In contrast, overexpression of hsa-miR-494 and hsa-miR-99b microRNAs was associated with poor survival. We observed large-scale genome-wide alterations in MRN-deficient tumours contributing to aggressive behaviour. We conclude that MRN status may be a useful tool to stratify tumours for precision medicine strategies.Adel AlblihyAhmed ShoqafiMichael S. TossMashael AlgethamiAnna E. HarrisJennie N. JeyapalanTarek Abdel-FatahJuliette ServanteStephen Y. T. ChanAndrew GreenNigel P. MonganEmad A. RakhaSrinivasan MadhusudanNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Adel Alblihy Ahmed Shoqafi Michael S. Toss Mashael Algethami Anna E. Harris Jennie N. Jeyapalan Tarek Abdel-Fatah Juliette Servante Stephen Y. T. Chan Andrew Green Nigel P. Mongan Emad A. Rakha Srinivasan Madhusudan Untangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers
description	Abstract The MRE11–RAD50–NBS1 (MRN) complex is critical for genomic stability. Although germline mutations in MRN may increase breast cancer susceptibility, such mutations are extremely rare. Here, we have conducted a comprehensive clinicopathological study of MRN in sporadic breast cancers. We have protein expression profiled for MRN and a panel of DNA repair factors involved in double-strand break repair (BRCA1, BRCA2, ATM, CHK2, ATR, Chk1, pChk1, RAD51, γH2AX, RPA1, RPA2, DNA-PKcs), RECQ DNA helicases (BLM, WRN, RECQ1, RECQL4, RECQ5), nucleotide excision repair (ERCC1) and base excision repair (SMUG1, APE1, FEN1, PARP1, XRCC1, Pol β) in 1650 clinical breast cancers. The prognostic significance of MRE11, RAD50 and NBS1 transcripts and their microRNA regulators (hsa-miR-494 and hsa-miR-99b) were evaluated in large clinical datasets. Expression of MRN components was analysed in The Cancer Genome Atlas breast cancer cohort. We show that low nuclear MRN is linked to aggressive histopathological phenotypes such as high tumour grade, high mitotic index, oestrogen receptor- and high-risk Nottingham Prognostic Index. In univariate analysis, low nuclear MRE11 and low nuclear RAD50 were associated with poor survival. In multivariate analysis, low nuclear RAD50 remained independently linked with adverse clinical outcomes. Low RAD50 transcripts were also linked with reduced survival. In contrast, overexpression of hsa-miR-494 and hsa-miR-99b microRNAs was associated with poor survival. We observed large-scale genome-wide alterations in MRN-deficient tumours contributing to aggressive behaviour. We conclude that MRN status may be a useful tool to stratify tumours for precision medicine strategies.
format	article
author	Adel Alblihy Ahmed Shoqafi Michael S. Toss Mashael Algethami Anna E. Harris Jennie N. Jeyapalan Tarek Abdel-Fatah Juliette Servante Stephen Y. T. Chan Andrew Green Nigel P. Mongan Emad A. Rakha Srinivasan Madhusudan
author_facet	Adel Alblihy Ahmed Shoqafi Michael S. Toss Mashael Algethami Anna E. Harris Jennie N. Jeyapalan Tarek Abdel-Fatah Juliette Servante Stephen Y. T. Chan Andrew Green Nigel P. Mongan Emad A. Rakha Srinivasan Madhusudan
author_sort	Adel Alblihy
title	Untangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers
title_short	Untangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers
title_full	Untangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers
title_fullStr	Untangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers
title_full_unstemmed	Untangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers
title_sort	untangling the clinicopathological significance of mre11-rad50-nbs1 complex in sporadic breast cancers
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/56ed86e24ee6429fa04c2441b2232edb
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Untangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers

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