Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

Ghoussaini, Maya; French, Juliet D.; Michailidou, Kyriaki; Nord, Silje; Beesley, Jonathan; Canisus, Sander; Hillman, Kristine M.; Kaufmann, Susanne; Sivakumaran, Haran; Marjaneh, Mahdi Moradi; Lee, Jason S.; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; Dicks, Ed; Milne, Roger L.; Hopper, John L.; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A.; Beckmann, Matthias W.; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Marmé, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Flyger, Henrik; Benı́tez, Javier; González‐Neira, Anna; Alonso, María R.; Pita, Guillermo; Neuhausen, Susan L.; Anton‐Culver, Hoda; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Hamann, Ute; Tessier, Daniel C.; Denis, Vincent; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Ito, Hidemi; Dörk, Thilo; Bogdanova, Natalia; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli‐Matti; Wu, Anna H.; Berg, David Van Den; Lambrechts, Diether; Floris, Giuseppe; Chang‐Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Mônica; Couch, Fergus J.; Hallberg, Emily; Giles, Graham G.; Haiman, Christopher A.; Marchand, Loı̈c Le; Goldberg, Mark S.; Teo, Soo Hwang; Yip, Cheng Har; Børresen‐Dale, Anne‐Lise; Wang, Zheng; Cai, Qiuyin; Winqvist, Robert; Pylkäs, Katri; Andrulis, Irene L.; Devilee, Peter; Tollenaar, Rob A.E.M.; García-Closas, Montserrat; Figueroa, Jonine D.; Hall, Per; Czene, Kamila; Brand, Judith S.; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J.; Koppert, Linetta B.; Li, Jingmei; Shu, Xiao‐Ou; Zheng, Ying; Cox, Angela; Cross, Simon S.; Shah, Mitul; Rhenius, Valerie; Choi, Ji‐Yeob; Kang, Daehee; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Luccarini, Craig; Conroy, Don; Jakubowska, Anna; Lubiński, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Olswold, Curtis; Slager, Susan L.; Shen, Chen‐Yang; Hou, Ming‐Feng; Swerdlow, Anthony; Schoemaker, Minouk J.; Simard, Jacques; Pharoah, Paul D.P.; Kristensen, Vessela N.; Chenevix-Trench, Georgia; Easton, Douglas F.; Dunning, Alison M.; Edwards, Stacey L.

doi:10.1016/j.ajhg.2016.07.017

Cited by 63 publications

(68 citation statements)

References 26 publications

(50 reference statements)

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“…Sequential conditional analysis was performed to clarify the independent effects among significant loci (P ≤ 1.00 × 10 −4 ), and conditional significance level was set at P ≤ 1.00 × 10 −3 for the overall lung cancer risk. 29,30 We used the linear regression model to evaluate the associations between identified SNPs and telomere length in peripheral blood leukocytes. All analyses were performed using plink 1.9 and R software (version 3.1.1).…”

Section: Discussionmentioning

confidence: 99%

“…Based on the advances of ENCODE project and 1000 Genomes project, we defined TERT‐CLPTM1L region as chr5: 753 287 ∼ 1 753 287 (hg19, 500 kb upstream and downstream from TERT gene). Similar strategy was adopted by Dunning et al in their fine mapping study for breast cancer …”

Section: Methodsmentioning

confidence: 99%

“…Similar strategy was adopted by Dunning et al 29 in their fine mapping study for breast cancer. 29,30…”

Section: Determination Of Tert-clptm1l Regionmentioning

confidence: 99%

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Fine mapping in TERT‐CLPTM1L region identified three independent lung cancer susceptibility signals: A large‐scale multi‐ethnic population study

Fan

et al. 2018

Molecular Carcinogenesis

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Genome-wide association studies (GWAS) and fine mapping studies have identified multiple lung cancer susceptibility variants in TERT-CLPTM1L region. However, it is still unclear about the relationship between these risk variants and the independent lung cancer risk signals in this region. Therefore, we evaluated the independent susceptibility signals for lung cancer and explored the potential functional variants in this region. Sequential conditional analysis was used to detect the independent susceptibility loci based on four lung cancer GWAS datasets with 12 843 lung cases and 12 639 controls. Comprehensively functional annotations were performed for each independent signal. Three independent susceptibility signals were identified in multi-ethnic population. For the first signal, rs2736100 showed the most significant association with lung cancer risk (C > A, OR = 0.82, 95%CI: 0.79-0.85, P = 1.98 × 10 ). Rs36019446 was the top-ranked site (A > G, OR = 0.88, 95%CI: 0.84-0.92, P = 1.74 × 10 ) in the second signal. For the third signal, rs326048 was the leading SNP (A > G, OR = 0.91, 95%CI: 0.87-0.95, P = 1.38 × 10 ). The following subgroup analysis found the same three loci among Asian population. Further, we compared the difference between various subgroup populations. Functional annotations revealed that rs2736100, rs27996 (r = 0.85 with rs36019446) and rs326049 (r = 0.73 with rs326048) could be potential functional variants in these three risk signals, respectively. In conclusion, although multiple variants have been found associated with lung cancer risk in TERT-CLPTM1L region, our findings indicated that there are three independent lung cancer susceptibility signals in this region.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Fine mapping in TERT‐CLPTM1L region identified three independent lung cancer susceptibility signals: A large‐scale multi‐ethnic population study

Fan

et al. 2018

Molecular Carcinogenesis

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“…It is unlikely, though possible, that these physiological differences are related to prognosis of ER+ breast cancer. CYP2D6 has very weak affinity for testosterone[41], suggesting a possible relationship with ER+ breast cancer occurrence or prognosis, however, associations of CYP2D6 polymorphisms with occurrence of ER+ breast cancer have not been detected in very large genome-wide screens[42]. …”

Section: Discussionmentioning

confidence: 99%

CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study

Hertz

Kidwell

Hilsenbeck

et al. 2017

Breast Cancer Res Treat

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Purpose: A number of studies have tested the hypothesis that breast cancer patients with low-activity CYP2D6 genotypes achieve inferior benefit from tamoxifen treatment, putatively due to lack of metabolic activation to endoxifen. Studies have provided conflicting data, and meta-analyses suggest a small but significant increase in cancer recurrence, necessitating additional studies to allow for accurate effect assessment. We conducted a retrospective pharmacogenomic analysis of a prospectively collected community-based cohort of patients with estrogen receptor-positive breast cancer to test for associations between low-activity CYP2D6 genotype and disease outcome in 500 patients treated with adjuvant tamoxifen monotherapy and 500 who did not receive any systemic adjuvant therapy. Methods: Tumor-derived DNA was genotyped for common, functionally consequential CYP2D6 polymorphisms (*2, *3, *4, *6, *10, *41 and copy number variants) and assigned a CYP2D6 activity score (AS) ranging from none (0) to full (2). Patients with poor metabolizer (PM, AS=0) phenotype were compared to patients with AS>0 and in secondary analyses AS was analyzed quantitatively. Clinical outcome of interest was recurrence free survival (RFS) and analyses using long-rank test were adjusted for relevant clinical covariates (nodal status, tumor size, etc.). Results: CYP2D6 AS was not associated with RFS in tamoxifen treated patients in univariate analyses (p>0.2). In adjusted analyses, increasing AS was associated with inferior RFS (Hazard ratio (HR)=1.43, 95% confidence interval: 1.00–2.04, p=0.05). In patients that did not receive tamoxifen treatment, increasing CYP2D6 AS, and AS>0, were associated with superior RFS (each p=0.0015). Conclusions: This population-based study does not support the hypothesis that patients with diminished CYP2D6 activity achieve inferior tamoxifen benefit. These contradictory findings suggest that the association between CYP2D6 genotype and tamoxifen treatment efficacy is null or near null, and unlikely to be useful in clinical practice.

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“…Rather than altering protein sequence, and consequently protein function or structure, it seems that most raSNPs, or those in linkage disequilibrium with them, may act in cis to regulate the expression levels of target genes located distally and proximally [3][4][5] . The biological effect of raSNPs has so far been detected by expression quantitative trait loci analysis (eQTL) 3,[6][7][8] , but also, though less frequently, through the analysis of differential allelic expression (DAE) 9,10 . A few functional studies for BC raSNPs have confirmed this cis-regulatory role, but have mainly focused on their potential to alter transcription factor binding sites 3,[6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk

Jacinta-Fernandes

Xavier

Magno

et al. 2019

Preprint

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Most breast cancer (BC) risk-associated variants (raSNPs) identified in genome-wide association studies (GWAS) are believed to cis-regulate the expression of genes. We hypothesise that cis-regulatory variants contributing to disease risk may be affecting miRNA genes and/or miRNA-binding. To test this we adapted two miRNA-binding prediction algorithms -TargetScan and miRanda -to perform allele-specific queries, and integrated differential allelic expression (DAE) and expression quantitative trait loci (eQTL) data, to query 150 genome-wide significant (P ≤ 5 × 10 −8 ) raSNPs, plus proxies. We found that no raSNP mapped to a miRNA gene, suggesting that altered miRNA targeting is an unlikely mechanism involved in BC risk. Also, 11.5% (6 out of 52) raSNPs located in 3'UTRs of putative miRNA target genes were predicted to alter miRNA::mRNA pair binding stability in five candidate target genes. Of these, we propose RNF115, at locus 1q21.1, as a strong novel target gene associated with BC risk, and re-inforce the role of miRNA mediated cis-regulation at locus 19p13.11. We believe that integrating allele-specific querying in miRNA-binding prediction, and data supporting cis-regulation of expression, improves the identification of candidate target genes in BC risk, as well as in other common cancers and complex diseases. Results Some BC risk variants locate to the 3'UTR of PCGs, but none to miRNA genesTo evaluate the contribution to BC risk of genetic variation modelling miRNA::mRNA binding, we first assessed how many GWAS SNPs and their proxies were located in either miRNA genes or 3'UTRs of PCGs. We identified 2749 raSNPs, resulting from 150 BC GWAS-SNPs (Additional file 1: Table S1) and their proxies, of which almost one third (805 raSNPs) were solely annotated to "gene deserts" (585 raSNPs) or intergenic regions (220 raSNPs). The remainder 1944 raSNPs were located in either ncRNA genes or PCG's (Figure 1), in a total of 161 unique Ensembl gene IDs, correspondent to 129 HGNC (HUGO Gene Nomenclature Committee) symbols.Next we assessed how many would change the miRNA gene sequence, thus affecting their biogenesis or target genes. Interestingly, none of the raSNPs mapped to miRNA genes, even after the LD threshold was lowered to r 2 ≥ 0.2 when defining proxy SNPs (results not shown). This suggests that altered miRNA biogenesis or altered seed region sequence are unlikely mechanisms associated with BC risk. However, 13 SNPs were annotated as downstream or upstream variants of miRNA genes (Additional file 1: Table S2), raising the possibility of them being regulating the expression of the miRNA itself. However, we did not pursue this hypothesis further due to unavailability of DAE or eQTL data for these particular miRNA genes.The vast majority of the raSNPs located within PCGs were in non-coding regions (1881 out of 1915, 98%) (Figure 1), consistent with previous reports 17 . SNPs located at the 3'UTR of the mRNA sequence of PCGs could potentially modify, create or destroy miRNA binding sites and we found 52 raSNPs (1.9% of ...

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Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

Cited by 63 publications

References 26 publications

Fine mapping in TERT‐CLPTM1L region identified three independent lung cancer susceptibility signals: A large‐scale multi‐ethnic population study

Fine mapping in TERT‐CLPTM1L region identified three independent lung cancer susceptibility signals: A large‐scale multi‐ethnic population study

CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study

Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk

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