Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits

Rafnar, Thorunn; Gunnarsson, Bjarni; Stefansson, Olafur A.; Sulem, Patrick; Ingason, Andrés; Frigge, Michael L.; Stefánsdóttir, Lilja; Sigurdsson, Jon K.; Tragante, Vinicius; Steinthórsdóttir, Valgerður; Styrkársdóttir, Unnur; Stacey, Simon; Guðmundsson, Jūlı́us; Arnadottir, Gudny A.; Oddsson, Ásmundur; Zink, Florian; Halldorsson, Gisli H.; Sveinbjörnsson, Garðar; Kristjansson, Ragnar P.; Davidsson, Olafur B.; Salvarsdottir, Anna; Thoroddsen, Ásgeir; Helgadottir, Elisabet A.; Kristjánsdóttir, Katrín; Ingthorsson, Orri; Gudmundsson, Valur; Geirsson, Reynir Tómas; Arnadottir, Ragnheidur; Guðbjartsson, Daníel F.; Másson, Gísli; Asselbergs, Folkert W.; Jonasson, Jón G.; Olafsson, Karl; Þorsteinsdóttir, Unnur; Halldórsson, Bjarni V.; Þorleifsson, Guðmar; Stefánsson, Kāri

doi:10.1038/s41467-018-05428-6

Cited by 77 publications

(93 citation statements)

References 61 publications

(68 reference statements)

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“…Several loci were related to other cancers or benign tumors. SNPs in 22q11.21, 1q22 and 4q12 were found to be associated with risk of prostate cancer 27 , testicular germ cell tumor 28 and leiomyoma, respectively 29 . We hypothesize potential underlying mechanisms via hormone metabolism for these loci.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants

Shu¹,

Long²,

Cai³

et al. 2020

Nat Commun

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Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10 −8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women.

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Section: Discussionmentioning

confidence: 99%

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants

Shu¹,

Long²,

Cai³

et al. 2020

Nat Commun

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“…Previous studies using a variety of statistical approaches have reported evidence for shared genetic risks between endometriosis and OC 30,31 , and endometriosis and EC 32 . A GWAS of leiomyomas reported shared signals with endometriosis, and also evidence for a shared signal with EC 33 . It is now feasible to consider much larger studies assessing similarity of genetic architecture (genetic correlation) between these conditions and EC and OC, and cross-disease GWAS to investigate evidence of pleiotropy.…”

Section: Discussionmentioning

confidence: 99%

Co-existence of leiomyomas, adenomyosis and endometriosis in women with endometrial cancer

Johnatty

Stewart

Smith

et al. 2020

Sci Rep

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Leiomyomas, adenomyosis, and endometriosis are reported to be risk factors for endometrial carcinoma (ec), and adenomyosis and endometriosis also for ovarian carcinoma (oc). We aimed to describe the prevalence of these conditions in ec patients with or without an oc diagnosis, and to investigate their relationship with ec risk and prognostic factors in these patients. We evaluated the coexistence of these three conditions in 1399 EC patients, and compared the prevalence of epidemiological risk factors and tumor prognostic features in patients with each condition versus not. prevalence of conditions was also assessed in the subset of patients with prior/concurrent oc. The observed coexistence of leiomyomas, adenomyosis and endometriosis significantly deviated from that expected (p = 1.2 × 10 −8). patients were more likely to: report a younger age at menarche (p trend = 0.004) if they had leiomyomas; have used oral contraceptives (P = 6.6 × 10 −5) or had ≥2 fullterm pregnancies (p trend = 2.0 × 10 −9) if they had adenomyosis; be diagnosed with EC at younger age (p = 5.0 × 10 −11) if they had endometriosis. patients with prior/concurrent oc were more likely to be diagnosed at younger age (p = 5.0 × 10 −5), have endometriosis (p = 9.9 × 10 −7), and present with higher stage ec (p trend = 6.6 × 10 −5). These findings justify further consideration of these gynecologic conditions as independent risk and prognostic factors for ec. Endometrial carcinoma (EC) has a worldwide incidence of 8.4 per 100,000 persons per year, and is a leading cause of cancer mortality in women in developed countries 1,2. Incidence rates of EC are on the rise in developing countries due to increasing levels of obesity and aging populations 3. Epidemiologic risk factors for EC include age, exogenous estrogen use, and hyperestrogenic status due to obesity, early menarche age, nulliparity, and late-onset menopause 4. Gynecological conditions reported to increase the risk of EC include polycystic ovary syndrome and uterine leiomyomas (also termed fibroids). Endometriosis was also shown to be robustly associated with up to a 3-fold increased risk of clear cell and endometrioid ovarian carcinoma (OC) in large-scale meta-analysis of self-reported data 5. However, evidence to support endometriosis as a risk factor for EC from individual studies is conflicting; 6-12 risk estimates ranged from 0.78 to 2.8, and interpretation of findings has been complicated by differential consideration of endometriosis coincidental to EC diagnosis, and also by differing adjustment for confounders. Adenomyosis is a benign gynecological condition described as an extension of endometrial tissue (glands and stroma) into the myometrium. There is evidence that adenomyosis is correlated with uterine leiomyomas 13. The prevalence of adenomyosis at hysterectomy has been reported to be 20% to 30% 14. An analysis of hysterectomy samples identified adenomyosis in 66% of 197 patients found to have EC 15 , and a recent review identified 78 case reports that describe EC arising from ad...

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“…There have been six published genome-wide association studies (GWAS) of uterine leiomyoma, and some common single nucleotide polymorphisms (SNPs) associated with leiomyoma risks at 1p36.12 (CDC42/ WNT4) [14][15][16][17] , 1q24.3 (DNM3) 16 , 2p25.1 (GREB1) 14,15,17 , 2p23.2 (BABAM2) 17 , 3p24.1 (NEK10) 14 , 3q26.2 (TERC/ LRRC34) 15,17 , 3q29 15 , 4q12 (SCFD2/LNX1/PDGFRA) 14,15,17 , 4q13.3 (SULT1B1/SULT1E1) 14,15,17 , 4q22.3(PD-LIM5) 17 , 5p15.33 (TERT) 14,15,17 , 5q35.2 (ZNF346) 15,17 , 6p21.31(GRM4/HMGA1) 17 , 6q25.2 (SYNE1/ESR1) [14][15][16][17] , 9p24.33 (KANK1/DMRT1/ANKRD15/LOC105375949) [14][15][16][17] , 10p11.22(ZEB1/ARHGAP12) 17 , 10q24.33 (OBFC1) [14][15][16][17][18] , 11p15.5 (SCGB1C1/BET1L/SIRT3/RIC8A) [14][15][16][17][18] , 11p14.1(FSHB) 17 , 11p13 (WT1/PDHX/...…”

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confidence: 99%

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

Sakai

Tanikawa

Hirasawa

et al. 2020

Sci Rep

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Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P = 6.12 × 10 −25 with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma. Uterine leiomyoma is one of the most common gynaecologic benign tumours. Its estimated lifetime risk is 30-50% in Japan 1 and 70-80% in European populations 2,3. Although leiomyoma is a benign neoplasm, patients exhibit many types of symptoms, such as vaginal bleeding, pelvic pain, or infertility 4. Over 600,000 hysterectomies were performed per year in the USA due to leiomyomas, and 9.4 billion dollars for annual medical expenses were needed in the USA 5. Therefore, leiomyomas are gaining much attention in health economics. Leiomyoma growth is stimulated by sex steroids, such as oestrogen and progesterone, and several aetiological factors, such as age, early age at menarche, obesity, and parity, are linked to an increased leiomyoma risk 2,6-11. In

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Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits

Cited by 77 publications

References 61 publications

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants

Co-existence of leiomyomas, adenomyosis and endometriosis in women with endometrial cancer

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

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