Note | The YEATS4 gene is located in a region of Chromosome 12 that is subject to genomic instability and amplification in several different cancers. 117 of 508 human cancer cell lines (23%) exhibited copy number gains of YEATS4 (Pikor et al., 2015). Fusion genes have been identified by RNA-seq analysis of the samples in the Cancer Genome Atlas, as well as in other tumor samples. As many rearrangements resulting in fusions between YEATS4 and other coding genes are found in the same region of the long arm of chromosome 12 that is also subject to amplification, they may be the result of intrachromosomal inversions or deletions. However, as the mechanism of the rearrangements is unclear, the genomic alterations will be designated as translocations for the purpose of this review. |
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Entity | Bladder urothelial carcinoma |
Note | RNA-seq analysis of 414 bladder urothelial carcinomas, detected one rearrangement, t(12;12)(q15;q15), fusing exon 4 of YEATS4 out-of-frame to exon 2 of the human lysozyme (LYZ) gene (Yoshihara et al., 2015). Presumably non-sense mediated decay would prevent significant protein product accumulating. |
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| Fig. 5. Hybrid gene and protein produced by t(12;12)(q15;q15). With a breakpoint located in intron 4 of YEATS4 and intron 1 of LYZ, RNA-seq detected an out-of-frame fusion gene that could only produce a significantly truncated YEATS4 protein. |
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Entity | Brain cancer |
Note | YEATS4 was identified as an amplified sequence (GAS41) in glioblastoma multiforme (GBM) cell line TX3868, with amplification subsequently noted at higher frequency in lower grade astrocytoma grades I and II. (Fischer et al., 1997). In a larger study by Schmitt et al. (2012) of 258 glioblastoma samples from the Cancer Genome Atlas. 9 glioblastomas had high level of YEATS4 amplification. However, 26.1% of the samples exhibited reduced expression. Four genomic rearrangements involving YEATS4 have been noted in glioblastoma. Frattini et al. (2013) performed RNA-sequencing of 161 primary GBM and 24 short-term glioma sphere cultures. These authors detected a single rearrangement t(12;12)(q14.1;q15), resulting in a fusion between YEATS4 and XRCC6BP1 (X-ray repair cross-complementation group 6 binding protein 1). XRCC6BP1 (AKA ATP23) is involved in double-stranded DNA break repair (Fischer et al., 2013) and, based on homology via its metalloprotease domain, is suggested to be important in the biosynthesis of mitochondrial ATPase (Zeng et al., 2007). The detected transcript indicates that the fusion protein contains the YEATS domain fused to the majority of the peptidase M76 domain of XRCC6BP1 (missing 20 amino acids at the N-terminus) (Fig. 6). |
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| Fig. 6. Hybrid gene and protein produced by t(12;12)(q14.1;q15) that fuses YEATS4 exon 6 to exon 3 of XRCC6BP1. The Mitelman database contains records generated from paired-end whole genome-sequencing of 42 paired TCGA glioblastoma tumors and matching normal samples (Zheng et al., 2013, Yoshihara et al., 2015). A translocation t(12;12)(q15;q24) resulting in an in-frame fusion between YEATS4 exon 4 and exon 33 of EP400 (Fig. 7) was reported in the Mitelman database, however this fusion is absent from the TUMOR FUSION GENE DATA PORTAL developed by the same authors (http://54.84.12.177/PanCanFusV2/), and may not have survived further validation. The YEATS4-EP400 hybrid protein would contain contains 111 amino acids of YEATS4, containing part of the YEATS domain fused to the C-terminal 1811 amino acids of EP400, containing the SNF2 family domain and DNA_pol3_delta2 super family domain (cl26247). Yoshihara et al (2015) detected one case of a t(12;12)(q13.3;q15), generating an out-of-frame fusion of YEATS4 exon 6 to methionyl-tRNA synthetase ( MARS) exon 12 (Fig. 8). If the fusion protein is produced from the initiator methionine of YEATS4, the protein would be 187 amino acids long and contain the YEATS domain. However, one might predict that nonsense-mediated decay may reduce the accumulation of the fusion mRNA, and subsequent protein. A larger RNA-seq analysis followed by sequencing of 185 GBM samples from TCGA and Ivy center cohort also detected a fusion between YEATS4 (exon 1) and exon 4 of SLC35E3 located 601kb centromeric (Shah et al., 2013). While the fusion RNA detected would be driven from the YEATS4 promoter, the 106 amino acid fusion protein would only contain part of the triose phosphate transporter domain of SLC35E3 (Fig. 9). While it is possible that the fusion could inhibit the function of any normal YEATS4 or SLC35E3 protein in the tumor cell, it would seem more likely that the reciprocal product, if produced, would be of functional significance. However, the reciprocal SLC35E3-YEATS4 fusion transcript was not recorded. Fig. 7. Fusion between exon 4 of YEATS4 and exon 33 of EP400 (numbering based on NM_015409 and protein NP_056224). The fusion protein is 1922 amino acids long. Domain Key: Y: YEATS domain; cc: Coiled coil domain; EP400_N: pfam15790, E1A-binding protein p400, N-terminal domain is characterized by low-complexity but its function is unknown; Atroph: Atrophin-1 super family domain, a polyglutamine stretch may interact with histone acetytransferase CBP; HSA: domain found in helicases and associated with SANT domains; SNF2_N: SNF2 family N-terminal domain; SNF: SNF2 family domain; DN: DNA_pol3_delta2 super family domain (cl26247). |
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| Fig. 8. Out-of-frame fusion between YEATS4 and MARS. The hybrid gene could produce a truncated YEATS4 protein missing the coiled coil domain. Domain Key: Y: YEATS domain; cc: Coiled coil domain; GST: Glutathione S-transferase C-terminal-like, alpha helical domain of Methionyl-tRNA synthetase from higher eukaryotes; PRK12267 super family domain: Methionyl-tRNA synthetase. Fig. 9. Hybrid gene and protein produced by t(12;12)(q15;q15) that fuses YEATS4 exon 1 to exon 4 of SLC35E3. SLC35E3 encodes a protein of 313 amino acids (NP_061126) and is identified as a member of the triose-phosphate transporter (TPT) family based upon a central 278 amino acid domain. |
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Entity | Colorectal carcinoma |
Note | In a study of 86 colorectal carcinoma patients, increased expression (> 4th quartile) of YEATS4 correlated with decreased survival HR = 1.910, 95% CI: 1.005-3.632, P = 0.048 (Tao et al., 2015). One rearrangement involving YEATS4 was detected in a study of 95 rectal adenocarcinomas by RNA-seq analysis and recorded in the TUMOR FUSION GENE DATA PORTAL. The rearrangement is identical to that observed in hepatocellular adenocarcinoma, fusing YEATS4 exon 6 to the final (noncoding exon) of CPSF6 (Fig. 11). Thus, the predicted fusion protein contains a truncated YEATS4 coding sequence contain the YEATS domain, but lacking the C-terminal coiled coil domain. |
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Entity | Gastric Cancer |
Note | Quantitative real time reverse transcriptase PCR analysis of 30 Gastric cancers by Ji et al. (2017) detected increased expression of the YEATS4 transcript compared to normal adjacent tissue. 13% of samples showed decreased expression. Overexpression of YEATS4 mRNA and protein was associated with cancer stage, with highest expression observed in Stage III gastric cancer. Overall survival and disease-free survival was decreased with high expression of YEATS4 (Ji et al., 2017). The authors detected increased occupancy of the beta-catenin promoter by the YEATS4 protein, leading to histone acetylation and increased transcription of the beta catenin gene. One case of a t(12;12)(q15;q15) fusing exon 6 of YEATS4 to exon 2 of the human lysozyme gene (LYZ) was identified from 414 cases in the Tumor Fusion Gene Data Portal. The resulting fusion protein contains the YEATS domain and the hydrolytic catalytic cleft of lysozyme. This rearrangement is identical to that detected in liver hepatocarcinoma cancer (see Fig. 10). |
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Entity | Hypertension |
Note | The SNP rs7297610, located between YEATS4 and FRS2, was associated with antihypertensive response to hydrochlorothiazide. Specifically, the C/C genotypes was associated with significant improvement in blood pressure in treated African Americans. Baseline YEATS4 expression was increased in peripheral blood of C/C genotype individuals, but decreased upon treatment with hydrochlorothiazide (Duarte et al., 2013). |
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Entity | Liposarcoma |
Note | Amplification and overexpression of YEATS4 occurs in liposarcomas (Italiano et al., 2008; Barretina et al., 2010; Creytens et al., 2015). In a study of 28 well-differentiated liposarcomsas and 10 dedifferentiated liposarcomas, Italiano et al., (2008) subdivided the 12q13-15 amplicon into three independent amplicons. One amplicon, centered on MDM2 in 12q15 often contained YEATS4 with concomitant increased expression of the gene. A larger study of 77 lipomatous soft tissue tumors (including lipomas, well-differentiated liposarcomas (WDLPS), dedifferentiated liposarcomas (DDLPS) and pleomorphic liposarcomas) found that amplification of the YEATS4 gene was more frequent and at a higher level in dedifferentiated liposarcomas than in well-differentiated liposarcomas (Creytens et al., 2015). Knockdown of YEATS4 by shRNA in dedifferentiated liposarcoma independently reduced cell proliferation suggesting that YEATS4 acts as a driver gene within the 12q15 amplicon (Barretina et al., 2010). |
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Entity | Liver hepatocellular carcinoma |
Note | Two rearrangements involving YEATS4 have been detected in a study of 374 hepatocellular. carcinomas by RNA-seq analysis and recorded in the TUMOR FUSION GENE DATA PORTAL (2017). One case of a t(12;12)(q15;q15) fusing exon 6 of YEATS4 to exon 2 of the human lysozyme gene (LYZ) was identified. The resulting fusion protein contains the YEATS domain and the hydrolytic catalytic cleft of lysozyme (Fig. 10). This rearrangement is identical to that detected in stomach cancer (see below). The second rearrangement involves CPSF6 (cleavage and polyadenylation specific factor 6), located 101kb centromeric to YEATS4 (Fig. 1), and fuses exon 6 to the final, noncoding, exon of CPSF6 (Fig. 11). Thus, the fusion protein would be a truncated YEATS4 coding sequence containing the YEATS domain, but lacking the C-terminal coiled coil domain. The rearrangement is identical to that detected in rectal adenocarcinoma (see below). |
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| Fig. 10. Fusion between YEATS4 and LYZ, with a breakpoint located in intron 6 of YEATS4 and intron 2 of LYZ. The resulting fusion gene produces a fusion protein containing the YEATS domain and the Lysozyme catalytic cleft (LCC). |
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| Fig. 11. The CPSF6 protein (NP_0008938) is coded by the first 9 exons of the CPSF6 transcript (NM_007007). CPSF6 has one conserved domain (RRM_CFIm68) defined as a 'RNA recognition motif of pre-mRNA cleavage factor Im 68 kDa subunit (CFIm68 or CPSF6) and similar protein'. The 4846 base pair tenth exon is untranslated, thus the fused hybrid gene produces a truncated YEATS4 protein. |
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Entity | Lung cancer |
Note | Pikor et al., (2015) performed gene expression and copy number analysis of 261 non-small cell lung cancers (NSCLC) relative to matched normal tissues. The 432 kb region encompassing LYZ to BEST3 (Fig. 1) (and RAB3IP located telomeric to BEST3) was amplified in 20% of the samples tested. Of the 7 genes within the amplicon, only YEATS4 was both gained/amplified and concomitantly overexpressed in lung tumors with YEATS4 amplified in 18% (47/261) and overexpressed in 31% (15/48) of tumor samples originally tested. YEATS4 copy gain/amplification was detected in an additional 43/128 (33.6%) lung cancer cell lines. YEATS4 was overexpressed in 18% (15/83) of the Early Detection Research Network samples and 33% (14/42) from the Cancer Genome Atlas. 3/83 tumors showed higher amplification of YEATS4 compared to the MDM2 protooncogene, that is the main suspected driver of 12q15 amplification, suggesting that YEATS4 can provide an independent advantage over MDM2 in some lung cancers. The study validated overexpression of the YEATS4 protein in 15/59 (25.4%) tumors and 8/18 (44.4%) NSCLC cell lines. Knockdown of YEATS4 in cell lines containing YEATS4 amplification induced senescence and apoptosis in a p53/p21 mediated manner. Overexpression of YEATS4 increased resistance of normal bronchial epithelial cells to the platinum drug cisplatin and p53-MDM2 interaction inhibitor, nutlin (Pikor et al., 2015). The TUMOR FUSION GENE DATA PORTAL (2017) reports one case of a t(12;12)(q15;q15) from 541 Lung adenocarcinomas, involving YEATS4 and SLC35E3. The rearrangement fuses YEATS4 (exon 4) to exon 4 of SLC35E3 resulting in part of the YEATS domain to 65 amino acids of the triose phosphate transporter domain (Fig. 12). |
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| Fig. 12. In-frame fusion between YEATS4 and SLC35E3. SLC35E3 encodes a protein of 313 amino acids (NP_061126) and is identified as a member of the triose-phosphate transporter (TPT) family based upon a central 278 amino acid domain. The YEATS4-SLC35E3 fusion protein contains 111 amino acids of YEATS4 fused to 88 amino acids of the SLC35E3 protein containing the C-terminal 65 amino acids of the triose phosphate transporter domain. |
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Entity | Müllerian adenosarcomas of the uterus |
Note | In an analysis of 15 uterine and one ovarian Müllerian adenosarcomas, five cases showed amplification of a 900kb region stretching from SLC35E3 to BEST3, and thereby encompassing the YEATS4 locus on 12q15 (Lee et al., 2016). |
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Entity | Pancreatic cancer |
Note | YEATS4 transcript overexpression was noted in 31 pancreatic cancer samples relative to adjacent non-cancerous tissues (Jixiang et al., 2017). An expansion of this study to 93 pancreatic samples in the ONCOMINE database (Rhodes et al., 2004) further indicated clinical significance of YEATS4 expression in pancreatic cancer. Introduction of YEATS4 into a normal pancreatic epithelial cell lines promote growth invasion and motility. These effects were mediated, at least in part, by activation of the Wnt pathway and direct interaction with beta catenin (Jixiang et al., 2017). |
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Entity | Soft tissue Sarcomas (unclassified) |
Note | Five translocations were identified by Verhaak and colleagues from 263 Sarcomas and reported in the TUMOR FUSION GENE DATA PORTAL (2017). The adult sarcomas are unclassified in the National Cancer Institute Genomic Data Commons Data Portal. Each translocation fuses YEATS4 3' prime to its fusion partner. One case t(1;12)(q21.3;q15) fuses the exon 4 of KCNN3 (potassium calcium-activated channel subfamily N member 3)(based on transcript NM_002249) in-frame to exon 2 of YEATS4. The fusion protein would be 740 amino acids long and contain the calcium-activated SK potassium channel domain and part of the ion channel domain (pfam03530 and pfam07885) from KCNN3 and the YEATS4 YEATS domain and coiled coil domain (Fig. 13). In a different tumor, another in-frame fusion occurs between exon 2 of MARCH9 on 12q14.1 and exon 2 of YEATS4 (Fig. 14). MARCH9 is a member of the MARCH family of membrane-bound E3 ubiquitin ligases. The fusion protein product is 380 amino acids long, containing the C4HC3 zinc-finger like RING domain and the YEATS4 YEATS domain and coiled coil domain. The other three translocations observed fuse YEATS4 exon 7 out of frame 3-prime to its fusion partner, suggesting that these rearrangements produce a truncated protein lacking any YEATS4 components. One case of t(1;12)(q24.2;q15) fuses exon 16 of a coactivator of ligand-dependent nuclear receptors, DCAF6, to exon 7 of YEATS4 (Fig. 15). A truncated protein would contain the WD40 and cl26247 (DNA polymerase III, delta subunit) domains involved in transcriptional regulation, but miss the final 200 amino acids of the coactivator. A single t(12;12)(q21.1;q15) fuses exon 1 of the THAP domain containing, apoptosis associated protein 2 ( THAP2) out-of-frame to exon 7 of YEATS4. The "fusion' protein would also be truncated, and only contain the first 24 amino acids of the THAP2 protein, and 5 amino acids encoded out of frame from exon 7 of YEATS4 (Fig. 16). The last case noted was an out of frame fusion between exon 10 of TMTC1 and exon 7 of YEATS4 t(12;12)(p11.22;q15). If the truncated 564 amino acid 'fusion' protein is produced, it would lack the C-terminal tetratricopeptide repeats of TMTC1 (Fig. 17). |
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| Fig. 13. In-frame fusion between KCNN3 and YEATS4. Exon numbering for KCNN3 is based upon transcript NM_002249 that codes for isoform a (NP_002240). Key: Y: YEATS domain; CC: coiled coil domain; SK_C: calcium-activated SK potassium channel domain; I_T2: Ion Transporter_2 (ion channel) domain; CM: Calmodulin binding domain; Grey box: Prefoldin super family domain structure. Fig. 14. The MARCH9 gene contains 4 exons and encodes a transcript (NM_138396) of 2985 nucleotides, with a 5' untranslated region of 431 nucleotides and a 3' untranslated region of 1517 nucleotides. The full length MARCH9 protein is 346 amino acids long (NP_612405). The fusion between exon 2 of MARCH9 and exon 2 of YEATS4 could produce a fusion peptide of 380 amino acids. Fig. 15. The DCAF6 gene contains 22 exons and encodes multiple alternatively splice transcripts. Protein Isoform b (NP_001017977) was selected as the canonical form by UniProtKB, coded by a transcript 2 (NM_001017977) of 3360 nucleotides, with a 5' untranslated region of 353 nucleotides and a 3' untranslated region of 1064 nucleotides. This transcript is missing exon 11, 12, and 17. W: WDR11 repeat region. |
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| Fig. 16. The THAP2 gene contains 3 exons and encodes a transcript of 4840 nucleotides, with a 5' untranslated region of 613 nucleotides and a 3' untranslated region of 3959 nucleotides. The full length THAP2 protein is 228 amino acids long (NP_113623), containing the DNA binding THAP domain. The fusion between exon 1 of THAP2 and exon 7 of YEATS could produce a fusion peptide of only 29 amino acids in size. Fig. 17. The TMTC1 mRNA is encoded by 18 exons and is 8.75kb long with a 3' untranslated region of 6.2kb. The full length TMTC1 protein (NP_001180380) is 882 amino acid long and contains two domains: the DUF1736 (D) and the TPR-11 domain. The TMTC1-YEATS4 fusion gene would produce a 2468 nucleotide mRNA encoding 559 amino acids of TMTC1, missing the C-terminal 323 amino acid region containing most of the tetratricopeptide repeats of the TPR-11 domain. |
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