An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

Wyszynski, Asaf; Hong, Chi-Chen; Lam, Kristin; Michailidou, Kyriaki; Lytle, Christian; Yao, Song; Zhang, Yali; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Hopper, John L.; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A.; Beckmann, Matthias W.; Peto, Julian; dos‐Santos‐Silva, Isabel; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Marmé, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Nordestgaard, Børge G.; González‐Neira, Anna; Benı́tez, Javier; Neuhausen, Susan L.; Brenner, Hermann; Dieffenbach, Aida Karina; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Ito, Hidemi; Dörk, Thilo; Bogdanova, Natalia; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli‐Matti; Investigators, kConFab; Wu, Anna H.; Berg, David Van Den; Lambrechts, Diether; Wildiers, Hans; Chang‐Claude, Jenny; Rudolph, Anja; Radice, Paolo; Peterlongo, Paolo; Couch, Fergus J.; Olson, Janet E.; Giles, Graham G.; Milne, Roger L.; Haiman, Christopher A.; Henderson, Brian E.; Dumont, Martine; Teo, Soo Hwang; Wong, Tien Yin; Kristensen, Vessela N.; Wang, Zheng; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Andrulis, Irene L.; Knight, Julia A.; Devilee, Peter; Seynaeve, Caroline; García‐Closas, Montserrat; Figueroa, Jonine D.; Klevebring, Daniel; Czene, Kamila; Hooning, Maartje J.; Ouweland, Ans M.W. van den; Darabi, Hatef; Shu, Xiao‐Ou; Gao, Yu‐Tang; Cox, Angela; Blot, William J.; Signorello, Lisa B.; Shah, Mitul; Kang, Daehee; Choi, Ji‐Yeob; Hartman, Mikael; Miao, Hui; Hamann, Ute; Jakubowska, Anna; Lubiński, Jan; Sangrajrang, Suleeporn; McKay, James; Toland, Amanda E.; Yannoukakos, Drakoulis; Shen, Chen‐Yang; Wu, Pei-Ei; Swerdlow, Anthony; Orr, Nick; Simard, Jacques; Pharoah, Paul D.P.; Dunning, Alison M.; Chenevix-Trench, Georgia; Hall, Per; Bandera, Elisa V.; Amos, Chris; Ambrosone, Christine B.; Easton, Douglas F.; Cole, Michael

doi:10.1093/hmg/ddw223

Cited by 34 publications

(38 citation statements)

References 44 publications

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“…This is important as dysregulated IGFBP5 transcriptional control can act as a driver of cancer growth and metastasis, regulating cell proliferation, differentiation and metabolism using both IGF1R-dependent as well asindependent mechanisms of action (38,39). For example, copy number alterations encompassing an IGFBP5 enhancer on 2q35 modulate breast cancer risk (40). In melanoma, a recent preprint reported that inactivation of IGFBP5 distal enhancers down-regulates IGFBP5 expression and promotes melanomagenesis by inducing an IGF1R-AKT signalling-dependent increase in glycolysis and metabolic reprogramming (41).…”

Section: Discussionmentioning

confidence: 99%

The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor

Coe

Tan

Shapiro

et al. 2019

Preprint

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The MITF and SOX10 transcription factors regulate the expression of genes important for melanoma proliferation, invasion and metastasis. Despite growing evidence of the contribution of long noncoding RNAs (lncRNAs) in cancer, including melanoma, their functions within MITF-SOX10 transcriptional programmes remain poorly investigated. Here we identified 245 candidate melanoma associated lncRNAs whose loci are co-occupied by MITF-SOX10 and that are enriched at active enhancer-like regions. We characterise the function and molecular mechanism of action of one of these lncRNAs, Disrupted In Renal Carcinoma 3 (DIRC3), and show that it operates as a MITF-SOX10 regulated tumour suppressor. DIRC3 depletion in human melanoma cells leads to increased anchorage-independent growth, a hallmark of malignant transformation, whilst melanoma patients classified by low DIRC3 expression have decreased survival. DIRC3 is a nuclear lncRNA that functions locally to activate expression of its neighbouring IGFBP5 tumour suppressor through modulating chromatin structure and suppressing SOX10 binding to putative regulatory elements within the DIRC3 locus. In turn, DIRC3 dependent regulation of IGFBP5 impacts the expression of genes involved in multiple cancer associated processes. Our work indicates that lncRNA components of the MITF-SOX10 networks are an important new class of melanoma regulators and candidate therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor

Coe

Tan

Shapiro

et al. 2019

Preprint

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“…GWAS have identified 107 SNPs that are independently associated with breast cancer risk 2–32 . Association studies focused on ER-negative disease, or BRCA1 mutation carriers, who are more likely to develop ER-negative disease (70–80% of cases) 33 , have identified 11 of these SNPs 3,9,12,19,29,30 .…”

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confidence: 99%

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Milne¹,

Kuchenbaecker²,

Michailidou³

et al. 2017

Nat Genet

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338

332

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Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10−8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 14% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

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“…One additional variant, rs11571833 at chromosome 13q13, was not genotyped and could not be imputed in all 3 studies; this variant had a minor allele frequency of 0.006 in the 1000 Genomes AFR population. These 74 risk variants include stronger markers than the index SNP found in GWAS as well as independent signals discovered through subsequent fine-mapping studies (Supplemental Table S1) (1, 3, 4, 8, 10, 11). …”

Section: Methodsmentioning

confidence: 99%

Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry

Feng

Rhie

Huo

et al. 2017

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Genome-wide association studies have identified ~100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Due to different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry. Methods We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER and ROOT). Results Fifty-four of the 74 variants (73%) were found to have odds ratios that were directionally consistent with those previously reported, of which twelve were nominally statistically significant (P < 0.05). Through fine-mapping, in six regions (3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13) we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (11q13, 16q12/TOX3) we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality. Conclusions Through fine-mapping of known susceptibility regions we have revealed alleles that better characterize breast cancer risk in women of African ancestry. Impact The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry.

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An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

Cited by 34 publications

References 44 publications

The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor

The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry

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