Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

Joshua A. Betts; Mahdi Moradi Marjaneh; Fares Al-Ejeh; Yi Chieh Lim; Wei Shi; Haran Sivakumaran; Romain Tropée; Ann Marie Patch; Michael B. Clark; Nenad Bartonicek; Adrian P. Wiegmans; Kristine M. Hillman; Susanne Kaufmann; Amanda L. Bain; Brian S. Gloss; Joanna Crawford; Stephen Kazakoff; Shivangi Wani; Shu W. Wen; Bryan Day; Andreas Möller; Nicole Cloonan; John Pearson; Melissa A. Brown; Timothy R. Mercer; Nicola Waddell; Kum Kum Khanna; Eloise Dray; Marcel E. Dinger; Stacey L. Edwards; Juliet D. French

doi:10.1016/j.ajhg.2017.07.007

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

Joshua A. Betts
, Mahdi Moradi Marjaneh
, Fares Al-Ejeh
, Yi Chieh Lim
, Wei Shi
, Haran Sivakumaran
, Romain Tropée
, Ann Marie Patch
, Michael B. Clark
, Nenad Bartonicek
, Adrian P. Wiegmans
, Kristine M. Hillman
, Susanne Kaufmann
, Amanda L. Bain
, Brian S. Gloss
, Joanna Crawford
, Stephen Kazakoff
, Shivangi Wani
, Shu W. Wen
, Bryan Day

Andreas Möller, Nicole Cloonan, John Pearson, Melissa A. Brown, Timothy R. Mercer, Nicola Waddell, Kum Kum Khanna, Eloise Dray, Marcel E. Dinger, Stacey L. Edwards, Juliet D. French

Research output: Contribution to journal › Article › peer-review

75 Scopus citations

Abstract

Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promoter. We further show that CUPID1 and CUPID2 are predominantly expressed in hormone-receptor-positive breast tumors and play a role in modulating pathway choice for the repair of double-strand breaks. These data reveal a mechanism for the involvement of this region in breast cancer.

Original language	English (US)
Pages (from-to)	255-266
Number of pages	12
Journal	American Journal of Human Genetics
Volume	101
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2017.07.007
State	Published - Aug 3 2017
Externally published	Yes

Keywords

11q13
DNA repair
GWAS
breast cancer
enhancer
long noncoding RNAs

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2017.07.007

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Betts, J. A., Moradi Marjaneh, M., Al-Ejeh, F., Lim, Y. C., Shi, W., Sivakumaran, H., Tropée, R., Patch, A. M., Clark, M. B., Bartonicek, N., Wiegmans, A. P., Hillman, K. M., Kaufmann, S., Bain, A. L., Gloss, B. S., Crawford, J., Kazakoff, S., Wani, S., Wen, S. W., ... French, J. D. (2017). Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage. American Journal of Human Genetics, 101(2), 255-266. https://doi.org/10.1016/j.ajhg.2017.07.007

Betts, JA, Moradi Marjaneh, M, Al-Ejeh, F, Lim, YC, Shi, W, Sivakumaran, H, Tropée, R, Patch, AM, Clark, MB, Bartonicek, N, Wiegmans, AP, Hillman, KM, Kaufmann, S, Bain, AL, Gloss, BS, Crawford, J, Kazakoff, S, Wani, S, Wen, SW, Day, B, Möller, A, Cloonan, N, Pearson, J, Brown, MA, Mercer, TR, Waddell, N, Khanna, KK, Dray, E, Dinger, ME, Edwards, SL & French, JD 2017, 'Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage', American Journal of Human Genetics, vol. 101, no. 2, pp. 255-266. https://doi.org/10.1016/j.ajhg.2017.07.007

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title = "Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage",

abstract = "Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promoter. We further show that CUPID1 and CUPID2 are predominantly expressed in hormone-receptor-positive breast tumors and play a role in modulating pathway choice for the repair of double-strand breaks. These data reveal a mechanism for the involvement of this region in breast cancer.",

keywords = "11q13, DNA repair, GWAS, breast cancer, enhancer, long noncoding RNAs",

author = "Betts, \{Joshua A.\} and \{Moradi Marjaneh\}, Mahdi and Fares Al-Ejeh and Lim, \{Yi Chieh\} and Wei Shi and Haran Sivakumaran and Romain Trop{\'e}e and Patch, \{Ann Marie\} and Clark, \{Michael B.\} and Nenad Bartonicek and Wiegmans, \{Adrian P.\} and Hillman, \{Kristine M.\} and Susanne Kaufmann and Bain, \{Amanda L.\} and Gloss, \{Brian S.\} and Joanna Crawford and Stephen Kazakoff and Shivangi Wani and Wen, \{Shu W.\} and Bryan Day and Andreas M{\"o}ller and Nicole Cloonan and John Pearson and Brown, \{Melissa A.\} and Mercer, \{Timothy R.\} and Nicola Waddell and Khanna, \{Kum Kum\} and Eloise Dray and Dinger, \{Marcel E.\} and Edwards, \{Stacey L.\} and French, \{Juliet D.\}",

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year = "2017",

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doi = "10.1016/j.ajhg.2017.07.007",

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AU - Betts, Joshua A.

AU - Moradi Marjaneh, Mahdi

AU - Al-Ejeh, Fares

AU - Lim, Yi Chieh

AU - Shi, Wei

AU - Sivakumaran, Haran

AU - Tropée, Romain

AU - Patch, Ann Marie

AU - Clark, Michael B.

AU - Bartonicek, Nenad

AU - Wiegmans, Adrian P.

AU - Hillman, Kristine M.

AU - Kaufmann, Susanne

AU - Bain, Amanda L.

AU - Gloss, Brian S.

AU - Crawford, Joanna

AU - Kazakoff, Stephen

AU - Wani, Shivangi

AU - Wen, Shu W.

AU - Day, Bryan

AU - Möller, Andreas

AU - Cloonan, Nicole

AU - Pearson, John

AU - Brown, Melissa A.

AU - Mercer, Timothy R.

AU - Waddell, Nicola

AU - Khanna, Kum Kum

AU - Dray, Eloise

AU - Dinger, Marcel E.

AU - Edwards, Stacey L.

AU - French, Juliet D.

PY - 2017/8/3

Y1 - 2017/8/3

N2 - Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promoter. We further show that CUPID1 and CUPID2 are predominantly expressed in hormone-receptor-positive breast tumors and play a role in modulating pathway choice for the repair of double-strand breaks. These data reveal a mechanism for the involvement of this region in breast cancer.

AB - Breast cancer risk is strongly associated with an intergenic region on 11q13. We have previously shown that the strongest risk-associated SNPs fall within a distal enhancer that regulates CCND1. Here, we report that, in addition to regulating CCND1, this enhancer regulates two estrogen-regulated long noncoding RNAs, CUPID1 and CUPID2. We provide evidence that the risk-associated SNPs are associated with reduced chromatin looping between the enhancer and the CUPID1 and CUPID2 bidirectional promoter. We further show that CUPID1 and CUPID2 are predominantly expressed in hormone-receptor-positive breast tumors and play a role in modulating pathway choice for the repair of double-strand breaks. These data reveal a mechanism for the involvement of this region in breast cancer.

KW - 11q13

KW - DNA repair

KW - GWAS

KW - breast cancer

KW - enhancer

KW - long noncoding RNAs

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Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

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