BCOR Involvement in Cancer

Figures & data

Figure 1. Structure and functional domains of BCOR, including BCL-6- and MLLT3-binding domains, ANK repeats and the PUFD domain.

A schematic representation of the exon structure is also shown below the protein domains.

Table 1. PRC 1.1 complex components.

	Principal interactions	Functional notes
PRC1.1 subunits
BCOR	PCGF1, KDM2B, BCL6, MLLT3, IRF8	PRC1.1 core protein. It seems able to bind AF9, a protein associated with SEC complex, but the relevance of this interaction has not been determined
BCORL1	PCGF1, KDM2B, CTBP1, HDACs	PRC1.1 core protein, alternatively to BCoR. It does not bind BCL-6, but the transcriptional corepressor CTBP1. Interacts with different Class II HDACs
PCGF1	BCOR, KDM2B, RYBP, YAF2	PRC1.1 core protein
KDM2B	BCOR, PCGF1, SKP1, unmethylated CpG islands	PRC1.1 core protein. It demethylates H3K36me3/me2. It can participate in the formation of the SCF complex
RING1a/RING1b	PCGF1, RYBP, YAF2, CBX8	Canonical and noncanonical PRC1s core protein. It ubiquitinates H2AK119
UBP7	BCOR, PCGF1, CBX8, RING1a/b, PCGF2/MEL18, PCGF4/BMI1, PTEN, MDM2, P53, DMNT	De-ubiquitinating action. It can be associated with other noncanonical PRC1 as well as the classic PRC1.
SKP1	KDM2B, other SCF proteins	Ubiquitinating action. It binds KDM2B. It participates in the formation of the SCF complex
RYBP/YAF2	PGGF1, RING1b, YY1	They may link PRCs to YY1
Associated proteins
YY1	RYBP, YAF2, DNA, INO80 complex, P53, HDACs	Transcription factor. The real relevance in the in vivo PRCs recruitment is not yet determined
CBX8	RING1a/b, H3K27me3, PCGF1/2/3/5/6, PHC1/2, MLLT1	It recruits the PRCs that contain it at H3K27me3 histones, establishing a functional cross-link with the PRC2s. Not present in PRC1.1
BCL6	BCOR, NCOR1, SMRT, HDACs, NuRD, MET3, DNA	Transcription factor. It recruits PRC1.1 by link with BCOR. It also has PRC independent activity: it is able to bind other proteins involved in gene silencing

PRC: Polycomb repressive complex.

Figure 2. Schematic representation of the polycomb repressive complex 1.1 model.

The core complex is composed of the catalytic enzyme RING1A/B that forms a dimer with PCGF1 through the RING finger domains, and that deposits an ubiquitin moiety to histone H2A at Lys119 (H2AK119ub). BCOR binds to PCGF1 by means of its PUFD domain, while RYBP is bound to the RAWUL domain of RING1A/B. Recruitment to chromatin is due to KDM2B that recognizes nonmethylated CpG islands by its CXXC-binding domain. Other members of the complex are SKP1, that associates with KDM2B, and USP7, acting as a deubiquitinating enzyme.

PUFD: PCGF Ub-like fold discriminator.

Figure 3. Schematic representation of different BCOR alterations, including internal tandem duplications and chimeric fusion transcripts.

The numbers inside the boxes represent the exons, while open boxes indicate UTR regions. (A) ITD–BCOR, (B) BCOR–CCNB3, (C) BCOR–MAML3, (D) ZC3H7B–BCOR and (E) BCOR–RARA.

ITD: Internal tandem duplication.

Table 2. BCOR mutations in different tumor hystotypes.

Tumor family	Tumor hystotype	Examined subgroup	BCOR		Molecular methods^†	Ref.
			Genetic alteration %	Genetic alteration type
Sarcomas	Clear cell sarcoma of the kidney	–	91% (10/11)	ITD-exon 15	RNA-seq/targeted RT-PCR	[35]
			85% (23/27)	ITD-exon 15	WES/RNA-seq	[32]
			9.1% (1/11)	BCOR–CCNB3 fusion	RNA-seq/targeted RT-PCR	[35]
			83% (132/159)	ITD-exon 15	PCR/targeted RT-PCR	[34]
			91% (20/22)	ITD-exon 15	RNA-seq	[33]
			100% (8/8)	ITD-exon 15	RNA-seq	[31]
			75% (3/4)	ITD-exon 15	RNA-seq/targeted RT-PCR/FISH	[36]
			Two case reports	BCOR–CCNB3 fusion	FISH	[41]
			Five case reports	ITD-exon 15	Targeted PCR	[42]
			100% (20/20)	ITD-exon 15	Targeted PCR	[30]
	Primitive myxoid mesenchymal tumor of infancy	–	100% (5/5)	ITD-exon 15	Targeted PCR	[43]
			86% (6/7)	ITD-exon 15	RNA-seq/targeted RT-PCR/FISH	[36]
			One case report	ITD-exon 15	Targeted PCR	[42]
			One case report	ITD-exon 15	Targeted PCR	[44]
	Undifferentiated/unclassified sarcomas: various hystologies	–	1.5% (11/753)	BCOR–CCNB3 fusion	Targeted RT-PCR	[45]
			14% (6/43)	BCOR–CCNB3 fusion	RNA-seq	[46]
	Undifferentiated/unclassified sarcomas: (Ewing-like) small blue round cell or spindle cell URCS	–	4% (24/594)	BCOR–CCNB3 fusion	RNA-seq	[47]
			6.5% (12/184)	Five BCOR–CCNB3 fusions, one BCOR–MAML3 fusion, one ZC3H7B–BCOR fusion, five BCOR-ITD	RNA-seq	[48]
			13% (11/87)	BCOR–CCNB3 fusion	RNA-seq/targeted RT-PCR/FISH	[49]
			12% (2/17)	BCOR–CCNB3 fusion	Targeted RT-PCR/FISH	[50]
			2.5% (5/200)	BCOR–CCNB3 fusion	Targeted RT-PCR	[51]
			Ten cases	BCOR–CCNB3 fusion	Targeted RT-PCR	[52]
			5% (2/41)	BCOR–CCNB3 fusion	Targeted RT-PCR/FISH	[53]
			4.3% (7/164)	BCOR–CCNB3 fusion	Targeted RT-PCR/FISH	[54]
			One case report	KMT2D–BCOR fusion	RNA-seq/targeted RT-PCR	[55]
		Soft tissue URCSs	Four case reports	BCOR–CCNB3 fusion	Targeted RT-PCR	[56]
			41% (9/22)	ITD-exon 15	RNA-seq/targeted RT-PCR/FISH	[36]
		SBRCSs lacking EWSR1, FUS, SYT and CIC gene rearrangements	22% (19/86)	11 BCOR–CCNB3 fusion, two BCOR–MAML3 fusions, two ZC3H7B–BCOR fusions, four other BCOR rearrangments	FISH	[57]
		BCOR–CCNB3 fusion positive sarcomas	36 case reports	BCOR–CCNB3 fusion	RNA-seq/targeted RT-PCR	[55]
	Various hystologies	Round cell sarcoma of bone	4% (24/594)	BCOR–CCNB3 fusion	n.a.	[58]
		Soft tissue tumors	1.5% (2/133)	BCOR–CCNB3 fusion	RNA-microarray	[59]
	Endometrial stromal sarcoma	–	29% (9/31)	Five ZC3H7B–BCOR fusion, three BCOR–ZC3H7B fusion, one ITD exon 15	Various	[60]
			9% (3/27)	Two ZC3H7B–BCOR fusion, one ZC3H7B–BCOR fusion + BCOR–ZC3H7B fusion	Various	[61]
			Two case reports	One ZC3H7B–BCOR fusion, one ZC3H7B–BCOR fusion + BCOR–ZC3H7B fusion	RNA-seq/targeted RT-PCR	[62]
			Three case reports	ZC3H7B–BCOR fusions	Targeted RT-PCR/FISH	[63]
			17 case reports	ZC3H7B–BCOR fusions	Targeted RNA NGS/FISH	[64]
			Three case reports	ITD-exon 15	Targeted PCR	[65]
	Rhabdomyosarcoma	–	8.3% (5/60)	Frameshift insert/deletion, nonsense	WES/RNA-seq	[66]
			7% (10/147)	Seven frameshift insert/deletion, one nonsense, two focal homozygous deletion	WGS/WES/RNA-seq	[67]
		Anaplastic RMS	One case report	Frameshift insertion	Targeted PCR	[68]
		PAX-fusion negative RMS	9.5% (9/94)	Six frameshift insert/deletion, one nonsense, two focal homozygous deletion	WGS/WES/RNA-seq	[67]
		PAX-fusion positive RMS	1.9% (1/53)	Frameshift insert/deletion	WGS/WES/RNA-seq	[67]
	Ossifying fibromyxoid tumor	–	2.5% (1/39)	ZC3H7B–BCOR fusion	RNA-seq	[69]
CNS neoplasm:	CNS neoplasms	‘CNS-HG-NET-BCOR altereted’ cluster of methylation tumor	79% (15/19)	ITD-exon 15	DNA and RNA NGS/targeted PCR	[70]
			Five case reports	ITD-exon 15	Targeted PCR	[42]
			One case report	ITD-exon 15	Targeted PCR	[71]
	Medulloblastoma	–	2% (4/189)	One nonsense, three frameshift insert/deletion	Various	[72]
			2.2% (1/46)	Nonsense	WGS/WES	[73]
			1.6% (2/125)	Frameshift insert/deletion	WGS/WES	[74]
			3% (3/92)	Nonsense, frameshift insert/deletion	WES	[75]
		Sonic-hedgehog-driven MB	7% (4/58)	One nonsense, three frameshift insert/deletion	Various	[72]
			5.2% (7/133)	Missense, nonsense, frameshift insert/deletion	WGS/WES	[76]
		Sonic-hedgehog-driven MB in infants (age <3)	8% (4/50)	n.a.	WGS/WES	[76]
		Sonic-hedgehog-driven MB in children (age 3 ≤ × <18)	3% (1/33)	n.a.	WGS/WES	[76]
		Sonic-hedgehog-driven MB in adults (age ≥18)	4% (2/50)	n.a.	WGS/WES	[76]
	Retinoblastoma	–	10% (7/71)	One missense, two nonsense, two frameshift insert/deletions, two large deletions	WES	[77]
			13% (6/46)	Frameshift insert/deletion, large deletion	WGS/SNP array	[78]
			4.2% (4/94)	Focal deletion	WGS/SNP array	[79]
	Gliomas, various hystologies	Recurrent high-grade astroblastoma	25% (1/4)	Frameshift insert/deletion	Targeted DNA NGS/array CGH	[80]
		pGBM and DIPG	4,3% (14/326)	Nonsense, frameshift insert/deletion	WGS/WES/RNA-seq	[81]
		Diffuse glioma	14% (1/7)	Missense	WES	[82]
Hemolymphopoietic system tumors	Myeloid neoplasm	MDS	5.3% (6/114)	Nonsense, frameshift insert/deletion, splice site	WES	[83]
			2.8% (2/71)	Deletion (Xp11.4)	Targeted DNA NGS/array CGH	[84]
			4.2% (40/944)	Various	Targeted DNA NGS/array CGH	[85]
			7% (2/29)	Nonsense, frameshift insert/deletion	WES	[86]
			4.2% (15/354)	Eight frameshift insert/deletion, five nonsense and two splice site	Targeted PCR	[87]
		MDS with multilineage dysplasia	8% (2/25)	Frameshift insertion, splice site	WES	[83]
		MDS with excess blasts	5.4% (2/37)	Frameshift deletion, nonsense	WES	[83]
		AML with chromosome 11 trisomy	4% (1/23)	n.a.	Targeted DNA NGS	[88]
		AML with chromosome 13 trisomy	25% of 34	n.a.	WES/targeted DNA NGS	[89]
		Cohesin-altered myeloid neoplasm	11.4% (14/123)	n.a.	WES/targeted DNA NGS	[90]
		Cohesin-WT myeloid neoplasm	5% (47/937)	n.a.	WES/targeted DNA NGS	[90]
		Unselected AML	8% (72/494 adult, vs 3/179 in children)	n.a.	DNA and RNA NGS	[91]
			5% of 143	n.a.	WES/targeted DNA NGS	[92]
			8.7% (58/664)	n.a.	Targeted DNA NGS	[93]
		Primary AML in adults	3% (6/197)	n.a.	Targeted DNA NGS	[94]
			1.6% (4/247)	n.a.	WES / Targeted DNA NGS	[92]
			5% (83/1603)	n.a.	Targeted DNA NGS	[95]
			5% (19/377)	Missense, nonsense, frameshift insert/deletion, splice site	Targeted DNA NGS	[96]
		Aged ≤65 with intermediate cytogenetic prognosis	15.2% (7/46)	n.a.	Targeted DNA NGS	[96]
		AML with balanced chromosomic rearrangements	8% (18/224, but 38% in cases with inv(3)(q21q26.2/t(3;3)(q21q26.2))	n.a.	Targeted DNA NGS	[95]
		AML with unbalanced chromosomic rearrangements	9% (31/349)	n.a.	Targeted DNA NGS	[95]
		Secondary AML	7.2% (16/221)	n.a.	WES/targeted DNA NGS	[92]
		RUNX1-mutated	18% (29/163)	n.a.	Targeted DNA NGS	[97]
			10.8% (13/1381)	n.a.	Targeted DNA NGS	[98]
		Normal karyotype AML	2.5% (1/40)	Focal deletion	Targeted DNA NGS	[99]
			4.2% (10/262)	n.a.	Targeted PCR	[100]
			4% (27/716)	n.a.	Targeted DNA NGS	[95]
		Normal karyotype	17.1% (14/82)	Frameshift insert/deletion, nonsense, splice site	Targeted PCR	[100]
		Pediatric normal karyotype AML	6.3% (3/48)	Missense	Targeted PCR	[101]
		Pediatric AML	1.1% (2/182)	One frameshift insert/deletion, one splice site	WES/targeted DNA NGS	[102]
			1.1% (4/369)	n.a.	Targeted PCR	[103]
			5% (2/40)	Frameshift insert/deletion, nonsense	Targeted DNA NGS/SNP array	[104]
			4.8% (4/83)	Missense	Targeted PCR	[101]
		Acute promyelocytic leukemia	One case report	BCOR–RARα	5′-RACE-PCR	[105]
			One case report	BCOR–RARα	Targeted PCR	[106]
		CMML	10% (15/150)	n.a.	WES/targeted DNA NGS	[107]
			7.4% (3/54)	One frameshift insert/deletion, three nonsense	Targeted PCR	[87]
			7.7% (2/26)	Frameshift insertion, splice site	WES	[83]
	Lymphoid neoplasm	Extranodal NK/T-cell lymphoma nasal type	17% ([5/30] or 20.6% [7/34] including cell lines)	Two missense, two frameshift insertion/deletion, three nonsense	WES/targeted DNA NGS/RNA-seq	[108]
			32% (8/25)	Frameshift insert/deletion, large deletion, nonsense, splice site	Targeted DNA NGS	[109]
			21% (24/113 including cell lines)	n.a.	Targeted DNA NGS	[109]
		T-cell prolymphocytic leukemia	9% (2/23)	Missense	Targeted DNA NGS	[110]
			8% (4/51)	Deletion (Xp11.4, 50%)	Targeted DNA NGS/array CGH	[111]
		Chronic lymphocytic leukemia	3% (4/149)	Three frameshift insert/deletion, one nonsense	WES/SNP array	[112]
			1.6% 10/643	n.a.	Targeted DNA NGS	[113]
			6.3% (3/48)	Missense, frameshift insert/deletion	Targeted DNA NGS	[114]
			1.2% (5/428)	Nonsense, frameshift insert/deletion	WGS/WES/RNA-seq/array CGH	[115]
		Splenic diffuse red pulp lymphoma	24% (10/42)	Three frameshift insert/deletion, two nonsense, one splice site, four large deletions	WES/targeted DNA NGS/array CGH	[116]
	Other	Mixed-phenotype acute leukemia	8.3% (1/12)	n.a.	Targeted DNA NGS	[117]
Carcinomas	Salivary glands cancer, various hystologies	Recurrent and metastatic SGC	8% (4/50)	Missense	Targeted DNA NGS	[118]
	Adenoid cystic carcinoma	Metastatic ACCs	60% (3/5)	Frameshift insertion, nonsense	WGS/RNA-seq	[119]
	Endometrial carcinoma	POLE-negative nonultramutated endometrioid endometrial carcinoma	13% (10/76)	Missense, splice site	WES/targeted DNA NGS	[120]
	Gynecologic carcinosarcoma		n.a.	n.a (missense N1459S 2 time recurrent)	WES	[121]
	Thymoma and thymic carcinoma	B3 thymoma	50% (3/6)	Missense, frameshift insert/deletion	WES	[122]
			One case report	Frameshift insert/deletion	WGS/RNA-seq/array CGH	[123]

^† Only the techniques used in the individual studies to establish BCOR mutational status have been reported.

5′-RACE PCR: 5′-Rapid amplification of cDNA ends polymerase chain reaction; ACC: Adenoid cystic carcinoma; AML: Acute myeloid leukemia; Array CGH: Array comparative genome hybridization; CMML: Chronic myelo-monocytic leukemia; DIPG: Diffuse intrinsic pontine glioma; FISH: Fluorescent in situ hybridization; ITD: Internal tandem duplication; MB: Medulloblastoma; MDS: Myelodysplastic syndrome; n.a.: Not available; NK: Natural killer; NGS: Next-generation sequencing; pGBM: Pediatric glioblastoma; RNA-seq: RNA sequencing; RT-PCR: Real-time PCR; SGC: Salivary glands cancer; URCS: Undifferentiated round-cell sarcoma; WES: Whole exome sequencing; WGS: Whole genome sequencing; WT: Wild type.

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