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

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

doi:10.1016/j.ajhg.2017.07.007

Cited by 80 publications

(91 citation statements)

References 36 publications

(32 reference statements)

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“…In addition, NTN4 has been shown to be an independent biomarker for prognosis of survival in breast cancer 29,30 . We and others have demonstrated that SNPs can alter chromatin loop formation between promoters and enhancers 31,32 .…”

Section: Discussionmentioning

confidence: 85%

High-throughput allelic expression imbalance analyses identify candidate breast cancer risk genes

Marjaneh

Sivakumaran

Hillman

et al. 2019

Preprint

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Fine-mapping of breast cancer GWAS regions has identified 195 high confidence signals containing more than 5,000 credible causal variants (CCVs). The CCVs are predominantly noncoding and enriched in regulatory elements and thus may confer the risk by altering gene expression in cis. We analyzed allelic expression imbalance (AEI) of genes surrounding known breast cancer signals, using normal breast and breast tumor transcriptome data and imputed genotypes. Fourteen genes, including NTN4, were identified whose expression was associated with CCV genotype. We showed that CCVs at this signal were located within an enhancer that physically interacts with the NTN4 promoter. Furthermore, knockdown of NTN4 in breast cells increased cell proliferation in vitro and tumor growth in vivo. Here, we present the most comprehensive AEI analysis of breast cancer CCVs resulting in identification of new candidate risk genes.

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Section: Discussionmentioning

confidence: 85%

High-throughput allelic expression imbalance analyses identify candidate breast cancer risk genes

Marjaneh

Sivakumaran

Hillman

et al. 2019

Preprint

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“…RNA yield and purity were evaluated on a NanoDrop and agarose gel electrophoresis. The reaction mixture for reverse transcription was prepared as previously described (26). Briefly, 800 ng total RNA resuspended in RNasefree water was combined with 2.5 μM random hexamer and 500 μM RNase-free dNTPs (both Invitrogen ™ ), heated at 65°C for 5 min, cooled on ice for at least one minute while adding 4 µl SuperScript ™ III reaction buffer, 5 mM dithiothreitol, 40 U RNase out RNase inhibitor and 200 U SuperScript ™ II RT (all from Invitrogen ™ ) to each sample, except "no RT" control tubes.…”

Section: Lentiviral Particles Production and Cell Infectionmentioning

confidence: 99%

The chromatin remodeler SMARCD3 regulates cell cycle progression and its expression predicts survival outcome in ER+ breast cancer

Tropée

Avalos

Gough

et al. 2019

Preprint

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Chromatin remodeling plays an essential role in regulating transcriptional networks and timing of gene expression. Chromatin remodelers such as SWItch/Sucrose Non-Fermentable (SWI/SNF) harbor many protein components, with the catalytic subunit providing ATPase activity to displace histones along or from the DNA molecules, and associated subunits ensuring tissue specificity and transcriptional or cotranscriptional activities. Mutations in several of the SWI/SNF subunits have been linked to cancer. Here, we describe how SMARCD3/Baf60c expression is associated with hormone positive (ER+) breast cancer. The level SMARCD3, as detected by immunohistochemistry in breast cancer patient samples, is correlated with differential long-term disease-free survival. In contrast, the expression level of SMARCD1/Baf60a and SMARCD2/Baf60b, which are mutually exclusive within the SWI/SNF complex and have a partially redundant function, lacks predictive value in breast cancer patient samples. Lower proliferation rates are observed in SMARCD3 depleted cells, which reflects a failure to fully progress through G2/M, and an increase in endoreplication. In the absence of SMARCD3, p21 accumulates in cells but does not halt the cell cycle, and DNA damage accumulates and remains unrepaired. Taken together, our data begin to explain why ER+ breast cancer patients with low SMARCD3 expressing tumors exhibit reduced survival rates compared to patients expressing normal or higher levels of SMARCD3. SMARCD3 might act as a tumor suppressor role through regulation of cell cycle checkpoints and could be a reliable and specific breast cancer prognostic biomarker. SignificanceMutations in chromatin remodelers are a leading cause of cancer. Estrogen Receptor positive (ER+) breast cancers represent approximately 80% of all cases diagnosed. Although these tumors can be treated with hormone therapy, most breast cancer fatalities occur in ER+ breast cancer patients, due to metastasis. Low expression of SMARCD3 in ER+ cancer is associated with diminished survival rates. As such, SMARCD3 could be used as a predictive biomarker for survival. In addition, we have identified a role for SMARCD3 in the cell cycle, which could at least partially explain its protective role in breast cancer. While catalytic subunits are often viewed as the major components in chromatin remodeling function, we show here new evidence that mutations or silencing of SMARCD3 may also contribute to genomic instability and thus development of breast cancer.

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“…While fine‐mapping approaches are well described in the literature, it is challenging to elucidate the functional relevance of GWAS SNPs, which are predominantly from noncoding regions conferring potential gene regulatory roles. Thus far, 15 breast cancer associated GWAS variants have been fine‐mapped and characterized for putative biological roles …”

Section: Introductionmentioning

confidence: 99%

“…Thus far, 15 breast cancer associated GWAS variants have been fine-mapped and characterized for putative biological roles. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] We previously reported six putative risk variants 21 for breast cancer from a GWAS in European populations (Alberta, Canada), hereafter described also as Caucasian populations, of which four SNPs were from different chromosomes showing association with sporadic (age of disease onset, >40 Years of age and no family history) breast cancer risk. One SNP rs1429142 on Chr4q31.22, showed consistent associations in three independent cohorts for overall risk (Stages 1-3, p = 1.5 × 10 −7 adjusted for body mass index [BMI]; OR 1.28).…”

Section: Introductionmentioning

confidence: 99%

Fine‐mapping of a novel premenopausal breast cancer susceptibility locus at Chr4q31.22 in Caucasian women and validation in African and Chinese women

Kumaran

Ghosh

Joy

et al. 2019

Intl Journal of Cancer

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We previously identified a novel breast cancer susceptibility variant on chromosome 4q31.22 locus (rs1429142) conferring risk among women of European ancestry. Here, we report replication of findings, validation of the variant in diverse populations and fine‐mapping of the associated locus in Caucasian population. The SNP rs1429142 (C/T, minor allele frequency 18%) showed association for the overall breast cancer risk in Stages 1–4 (n = 4,331 cases/4271 controls; p = 4.35 × 10−8; odds ratio, ORC‐allele,1.25), and an elevated risk among premenopausal women (n = 1,503 cases/4271 controls; p = 5.81 × 10−10; ORC‐allele 1.40) in European populations. SNP rs1429142 was associated with premenopausal breast cancer risk in women of African (T/C; p‐value 1.45 × 10−02; ORC‐allele 1.2) but not from Chinese ancestry. Fine‐mapping of the locus revealed several potential causal variants which are present within a single association signal, revealed from the conditional regression analysis. Functional annotation of the potential causal variants revealed three putative SNPs rs1366691, rs1429139 and rs7667633 with active enhancer functions inferred based on histone marks, DNase hypersensitive sites in breast cell line data. These putative variants were bound by transcription factors (C‐FOS, STAT1/3 and POL2/3) with known roles in inflammatory pathways. Furthermore, Hi‐C data revealed several short‐range interactions in the fine‐mapped locus harboring the putative variants. The fine mapped locus was predicted to be within a single topologically associated domain, potentially facilitating enhancer–promoter interactions possibly leading to the regulation of nearby genes.

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

Cited by 80 publications

References 36 publications

High-throughput allelic expression imbalance analyses identify candidate breast cancer risk genes

High-throughput allelic expression imbalance analyses identify candidate breast cancer risk genes

The chromatin remodeler SMARCD3 regulates cell cycle progression and its expression predicts survival outcome in ER+ breast cancer

Fine‐mapping of a novel premenopausal breast cancer susceptibility locus at Chr4q31.22 in Caucasian women and validation in African and Chinese women

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