Ultra-Rare Mutation in Long-Range Enhancer Predisposes to Thyroid Carcinoma with High Penetrance

He, Hao; Li, Wei; Wu, Dayong; Nagy, Rebecca; Liyanarachchi, Sandya; Akagi, Keiko; Jendrzejewski, Jarosław; Jiao, Hong; Hoag, Kevin W.; Wen, Bernard; Srinivas, Mukund; Waidyaratne, Gavisha; Wang, Rui; Wójcicka, Anna; Lattimer, Ilene; Stachlewska, Elżbieta; Czetwertyńska, Małgorzata; Długosińska, Joanna; Gierlikowski, Wojciech; Płoski, Rafał; Krawczyk, Marek; Jażdżewski, Krystian; Kere, Juha; Symer, David E.; Jin, Victor X.; Wang, Qianben; Chapelle, Albert de la

doi:10.1371/journal.pone.0061920

Cited by 38 publications

(40 citation statements)

References 53 publications

(51 reference statements)

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“…Increasingly evidences implicate that enhancers are functionally important in key cellular processes including cell development, differentiation and apoptosis. eRNAs are generated by the transcription of active enhancers and involve in the development of various diseases by regulating the expression of multiple genes . GREB1 is shown to be one of the most oestrogen‐specific genes and plays an important role in oestrogen‐mediated transcriptional activation.…”

Section: Discussionmentioning

confidence: 99%

Oestrogen promotes tumorigenesis of bladder cancer by inducing the enhancer RNA—eGREB1

Ding

Liu

et al. 2018

J Cellular Molecular Medi

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In recent years, studies have shown that enhancer RNAs (eRNAs) can be transcribed from enhancers. Increasing evidence has revealed that eRNAs play critical roles in the development of various cancers. Oestrogen‐associated eRNAs are closely related to breast cancer. In view of the gender differences in bladder cancer (BCa), we suppose that oestrogen‐associated eRNAs are also involved in tumorigenesis of BCa. In our study, we first demonstrated that eGREB1 derived from the enhancer of an oestrogen‐responsive gene—GREB1 was up‐regulated in BCa tissues, and the expression level of eGREB1 is positively associated with the histological grade and TNM stage of BCa. Knockdown of eGREB1 by CRISPR‐Cas13a could inhibit cell proliferation, migration and invasion and induce apoptosis in BCa cells T24 and 5637. Besides, we exhibited the promoting effect of oestrogen on BCa cells. What's more, down‐regulation of eGREB1 could improve the malignant biological characteristics of BCa cells induced by oestrogen. In conclusion, our data indicated that eGREB1 plays oncogenic role and oestrogen may promote the occurrence and progression of BCa by inducing eGREB1 production. Our findings provide new insights into the prevention of BCa and develop a novel therapeutic target for the treatment of BCa.

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Section: Discussionmentioning

confidence: 99%

Oestrogen promotes tumorigenesis of bladder cancer by inducing the enhancer RNA—eGREB1

Ding

Liu

et al. 2018

J Cellular Molecular Medi

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“…This revealed a locus on chromosome 4q32; on multi-point non-parametric linkage (NPL) analysis, the maximum 23:12 NPL Z-score was 18.5 (He et al 2013b). The haplotype was found in all except for 1 affected family member with PTC, as well as 4 members with benign thyroid disease.…”

Section: Enhancer At Chromosome 4q32mentioning

confidence: 92%

“…The reported susceptibility genes include SRGAP1 (He et al 2013a), TITF-1/NKX2-1 (Ngan et al 2009), FOXE1 (Pereira et al 2015) and telomere-telomerase complex (Capezzone et al 2008a(Capezzone et al , 2011. Chromosomal loci reported to be associated with non-syndromic FNMTC include TCO (19q13.2) (Canzian et al 1998), fPTC/ PRN (1q21) (Malchoff et al 2000), FTEN (8p23.1-p22) (Cavaco et al 2008b), NMTC1 (2q21) (McKay et al 2001), MNG1 (14q32) (Bignell et al 1997), 6q22 ), 8q24 ) and 4q32 (He et al 2013b). However, the candidate genes at these genetic loci remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Familial non-medullary thyroid cancer: unraveling the genetic maze

Yang¹,

Ngeow²

2016

Endocrine-Related Cancer

101

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Familial non-medullary thyroid cancer (FNMTC) constitutes 3-9% of all thyroid cancers. Out of all FNMTC cases, only 5% in the syndromic form has well-studied driver germline mutations. These associated syndromes include Cowden syndrome, familial adenomatous polyposis, Gardner syndrome, Carney complex type 1, Werner syndrome and DICER1 syndrome. It is important for the clinician to recognize these phenotypes so that genetic counseling and testing can be initiated to enable surveillance for associated malignancies and genetic testing of family members. The susceptibility chromosomal loci and genes of 95% of FNMTC cases remain to be characterized. To date, 4 susceptibility genes have been identified (SRGAP1 gene (12q14), TITF-1/NKX2.1 gene (14q13), FOXE1 gene (9q22.33) and HABP2 gene (10q25.3)), out of which only the FOXE1 and the HABP2 genes have been validated by separate study groups. The causal genes located at the other 7 FNMTCassociated chromosomal loci (TCO (19q13.2), fPTC/ PRN (1q21), FTEN (8p23.1-p22), NMTC1 (2q21), MNG1 (14q32), 6q22, 8q24) have yet to be identified. Increasingly, gene regulatory mechanisms (miRNA and enhancer elements) are recognized to affect gene expression and FNMTC tumorigenesis. With newer sequencing technique, along with functional studies, there has been progress in the understanding of the genetic basis of FNMTC. In our review, we summarize the FNMTC studies to date and provide an update on the recently reported susceptibility genes including novel germline SEC23B variant in Cowden syndrome, SRGAP1 gene, FOXE1 gene and HABP2 genes in non-syndromic FNMTC.

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“…Based on this premise, new candidate genes have been reported as associated with familial PTC including HABP2, SRGAP1 , PARP4 and SRRM2 [12–15]. …”

Section: Introductionmentioning

confidence: 99%

HABP2 p.G534E variant in patients with family history of thyroid and breast cancer

et al. 2017

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Familial Papillary Thyroid Carcinoma (PTC) has been described as a hereditary predisposition cancer syndrome associated with mutations in candidate genes including HABP2. Two of 20 probands from families with history of PTC and breast carcinoma (BC) were evaluated by whole exome sequencing (WES) revealing HABP2 p.G534E. Sanger sequencing was used to confirm the involvement of this variant in three families (F1: 7 relatives; F2: 3 and F3: 3). The proband and his sister (with no malignant tumor so far) from F1 were homozygous for the variant whereas one relative with PTC from F2 was negative for the variant. Although the proband of the F3 with PTC was HABP2 wild type, three relatives presented the variant. Five of 170 healthy Brazilian individuals with no family history of BC or PTC and three of 50 sporadic PTC presented the p.G534E. These findings suggested no association of this variant with our familial PTC cases. Genes potentially associated with deregulation of the extracellular matrix organization pathway (CTSB, TNXB, COL4A3, COL16A1, COL24A1, COL5A2, NID1, LOXL2, MMP11, TRIM24 and MUSK) and DNA repair function (NBN and MSH2) were detected by WES, suggesting that other cancer-associated genes have pathogenic effects in the risk of familial PTC development.

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Ultra-Rare Mutation in Long-Range Enhancer Predisposes to Thyroid Carcinoma with High Penetrance

Cited by 38 publications

References 53 publications

Oestrogen promotes tumorigenesis of bladder cancer by inducing the enhancer RNA—eGREB1

Oestrogen promotes tumorigenesis of bladder cancer by inducing the enhancer RNA—eGREB1

Familial non-medullary thyroid cancer: unraveling the genetic maze

HABP2 p.G534E variant in patients with family history of thyroid and breast cancer

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