Soft Tissues: Lipoblastoma with t(8;8)(q12;q12) RAB2A/PLAG1

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Soft Tissues: Lipoblastoma with t(8;8)(q12;q12) RAB2A/PLAG1

Written	2014-10	Hideki Yoshida, Mitsuru Miyachi, Hajime Hosoi
		Department of Pediatrics, Graduate School of MedicalScience, Kyoto Prefectural University of Medicine, Kajii-cho Hirokoji, Kamigyo-ku, Kyoto, Japan, E-mail address: hhosoi@koto.kpu-m.ac.jp

(Note : for Links provided by Atlas : click)

Abstract

Abstract Review on lipoblastoma with t(8;8)(q12;q12) RAB2A /PLAG1, with data on clinics, and the genes involved.

Identity

Atlas_Id 6627

Phylum Soft Tissues::Lipoblastoma

Clinics and Pathology

Disease is a rapidly growing, benign neoplasm. It is a mesenchymal tumor of fetal white fat tissue that appears most commonly in children under three years of age and affects males three times more often than females (McVay et al., 2006). It can present anywhere in the body, but is most commonly seen in the trunk and extremities. Surgical excision is usually curative, with a recurrence rate of about 20% (Jimenez, 1986; Hicks et al., 2001). Histologically, lipoblastoma shows a characteristic lobular architecture, with lobules containing lipoblasts embedded in a myxoid matrix, whereas lipoma is a tumor composed of only mature fat without lobulation (Weiss, 1996; Kuhnen et al., 2002; de Saint Aubain Somerhausen et al., 2008; Morerio et al., 2009).

Cytogenetics

Cytogenetics
Morphological t(8;8)(q12.1;q12.1)

Genes involved and Proteins

Gene Name RAB2A

Location 8q12.1

Dna / Rna The RAB2A gene contains 8 exons spanning 106 kbp of genomic distance that was mapped to chromosome 8q12.1. It has two alternative splicing forms (one without exon 2) as a result of the use of alternative polyadenylation sites (GeneCards CID:GC08P061429 (http://www.genecards.org/cgi-bin/carddisp.pl?gene=RAB2A), UniProt P61019-RAB2A_HUMAN(http://www.uniprot.org/uniprot/P61019)).

Protein The gene encodes a protein of 212 amino acids (23 kDa). The shorter isoform is missing 847-1149 aa. The protein is a member of the Rab family, whose members are small molecular weight guanosine triphosphatases (GTPases) that contain highly conserved domains involved in GTP binding and hydrolysis. The Rabs are membrane-bound proteins, involved in vesicular fusion and trafficking (Ali et al., 2004; Mountjoy et al., 2008). RAB2a is a pre-Golgi intermediate and transports proteins from the endoplasmic reticulum (ER) to the Golgi complex (Tisdale EJ et al., 1996) (GeneCards CID:GC08P061429 (http://www.genecards.org/cgi-bin/carddisp.pl?gene=RAB2A), UniProt P61019-RAB2A_HUMAN(http://www.uniprot.org/uniprot/P61019)).

Gene Name PLAG1

Location 8q12.1

Dna / Rna The gene spans about 50 kb and includes 5 exons. The size of the transcript is about 7 kb. It has two alternative splicing forms (one without exon 2) (GeneCards GCID:GC08M057073 (http://www.genecards.org/cgi-bin/carddisp.pl?gene=PLAG1), UniProt Q6DJT9-PLAG1_HUMAN (http://www.uniprot.org/uniprot/Q6DJT9)).

Protein The gene encodes a 500-aa zinc finger protein (74 kDa) with two putative nuclear localization signals (Kas et al., 1997). When activated, it acts as a transcription factor that up-regulates target genes, such as IGFII, leading to uncontrolled cell proliferation. When overexpressed in cultured cells, it increases the proliferation rate and transformation. Other target genes such as CRLF1, CRABP2, CRIP2, PIGF are strongly induced in cells with PLAG1 induction. PLAG1 is a proto-oncogene whose ectopic expression can trigger the development of lipoblastomas and pleomorphic adenomas of the salivary gland (Hensen et al., 2002; Voz et al., 2004; Zatkova et al., 2004) (GeneCards GCID:GC08M057073 (http://www.genecards.org/cgi-bin/carddisp.pl?gene=PLAG1), UniProt Q6DJT9-PLAG1_HUMAN (http://www.uniprot.org/uniprot/Q6DJT9)).

Result of the chromosomal anomaly

Hybrid Gene
Note The fusion occurs as a result of a cryptic, intrachromosomal rearrangement in tumors with apparently normal karyotypes. Comparison of the fusion gene with the wild type reveals that the fusion gene is associated with t(8;8)(q12.1;q12.1) translocation. The first exon of RAB2A is fused to either exon 2 or exon 3 of PLAG1 (Yoshida et al., 2014).

Description PLAG1 has a genomic fusion breakpoint in intron 1 resulting in alternative splicing of exon 2. The start codon of PLAG1 is located in exon 4 (Van Dyck et al., 2007), and the coding sequence of PLAG1 is preserved (Yoshida et al., 2014). This supports the molecular mechanism of overexpression of PLAG1 through promoter swapping: as a result of the translocation, the constitutively active promoter of the partner gene drives the ectopic expression of PLAG1 (Hibbard et al., 2000)

Detection RT-PCR using total RNA extracted from frozen tumor tissue. The RAB2A/PLAG1 fusion transcript was amplified with primers 5' CTTCCTCACAGCCCCTCACT-3' (forward), and, 5'- GGAACTGCCCAACTCCACTA-3'(reverse). RAB2A/PLAG1-fusion transcripts of 485 bp and 590 bp were detected (Yoshida et al., 2014).

Fusion Protein
Note No fusion protein exist for reasons the above.

Expression Localisation PLAG1 protein localizes to the nucleus (Bahrami et al.,2012).

Bibliography

Multiple regions contribute to membrane targeting of Rab GTPases.

Ali BR, Wasmeier C, Lamoreux L, Strom M, Seabra MC

J Cell Sci. 2004; 117: 6401-6412.

PMID 15561774

PLAG1 alteration in carcinoma ex pleomorphic adenoma: immunohistochemical and fluorescence in situ hybridization studies of 22 cases.

Bahrami A, Dalton JD, Shivakumar B, Krane JF

Head and Neck Pathology. 2012; 6(3): 328-335

PMID 22485045

The tumorigenic diversity of the three PLAG family members is associated with different DNA binding capacities.

Hensen K, Van Valckenborgh IC, Kas K, Van de Ven WJ, Voz ML

Cancer Research. 2002; 62(5):1510-1517.

PMID 11888928

PLAG1 fusion ongogenesis in lipoblastoma.

Hibbard MK, Kozakewich HP, Dal Cin P, Sciot R, Tan X, Xiao S, Fletcher JA

Cancer Research. 2000;60(17):4869-4872.

PMID 10987300

Lipoblastoma and lipoblastomatosis in infancy and childhood: histopathologic, ultrastructural, and cytogenetic features.

Hicks J, Dilley A, Patel D, Barrish J, Zhu SH, Brandt M

Ultrastructural pathology. 2001; 25(4):321-333.

PMID 11577778

Lipoblastoma in infancy and childhood.

Jimenez JF

Journal of surgical oncology. 1986; 32(4):238-244.

PMID 3736068

Promoter swapping between the genes for a novel zinc finger protein and beta-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations.

Kas K, Voz ML, Röijer E, Aström AK, Meyen E, Stenman G, Van de Ven WJ

Nature Genetics. 1997 ; 15(2): 170-174.

PMID 9020842

Atypical lipomatous tumor in a 14-year-old patient: distinction from lipoblastoma using FISH analysis.

Kuhnen C, Mentzel T, Fisseler-Eckhoff A, Debiec-Rychter M, Sciot R

Virchows Archiv. 2002; 441(3): 299-302.

PMID 12242528

Surgical management of lipoblastoma.

McVay MR, Keller JE, Wagner CW, Jackson RJ, Smith SD

Journal of Pediatric surgery. 2006; 41(6):1067-1071.

PMID 16769336

Differential diagnosis of lipoma-like lipoblastoma.

Morerio C, Nozza P, Tassano E, Rosanda C, Granata C, Conte M, Panarello C

Pediatric Blood & Cancer. 2009; 52(1): 132-134.

PMID 18798558

GTP-binding mutants of rab1 and rab2 are potent inhibitors of vesicular transport from the endoplasmic reticulum to the Golgi complex.

Tisdale EJ, Bourne JR, Khosravi-Far R, Der CJ, Balch WE

J Cell Biol. 1992; 119(4):749-761.

PMID 1429835

PLAG1, the prototype of the PLAG gene family: versatility in tumour development (review).

Van Dyck F, Declercq J, Braem CV, Van de Ven WJ

International Journal of Oncology. 2007; 30(4): 765-774.

PMID 17332914

Microarray screening for target genes of the proto-oncogene PLAG1

Voz ML, Mathys J, Hensen K, Pendeville H, Van Valckenborgh I, Van Huffel C, Chavez M, Van Damme B, De Moor B, Moreau Y, Van de Ven WJ

Oncogene. 2004; 23(1):179-191.

PMID 14712223

Lipomatous tumors.

Weiss SW

Monographs in Pathology. 1996; 38 :207-239.

PMID 8744279

Identification of COL3A1 and RAB2A as novel translocation partner genes of PLAG1 in lipoblastoma.

Yoshida H, Miyachi M, Ouchi K, Kuwahara Y, Tsuchiya K, Iehara T, Konishi E, Yanagisawa A, Hosoi H

Genes, chromosomes & cancer. 2014; 53(7):606-611.

PMID 24700772

Amplification and overexpression of the IGF2 regulator PLAG1 in hepatoblastoma.

Zatkova A, Rouillard JM, Hartmann W, Lamb BJ, Kuick R, Eckart M, von Schweinitz D, Koch A, Fonatsch C, Pietsch T,Hanash SM, Wimmer K

Genes, chromosomes & cancer. 2004; 39(2):126-137.

PMID 14695992

Lipoblastoma in adolescents and young adults: report of six cases with FISH analysis.

de Saint Aubain Somerhausen N, Coindre JM, Debiec-Rychter M, Delplace J, Sciot R

Histopathology. 2008; 52(3): 238-244.

PMID 18269579

Citation

This paper should be referenced as such :

Hideki Yoshida, Mitsuru Miyachi, Hajime Hosoi

Soft Tissues: Lipoblastoma with t(8;8)(q12;q12) RAB2A/PLAG1

Atlas Genet Cytogenet Oncol Haematol. 2015;19(7):481-483.

Free journal version : [ pdf ] [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/t88q12q12LipoblastID6627.html

Translocations implicated (Data extracted from papers in the Atlas)

t(8;8)(q12;q12) RAB2A/PLAG1

External links

Mitelman database t(8;8)(q12;q12) RAB2A/PLAG1 [Case List] t(8;8)(q12;q12) RAB2A/PLAG1 [Association List] Mitelman database (CGAP - NCBI)

arrayMap arrayMap ((UZH-SIB Zurich) [auto + random 100 samples .. if exist ] [tabulated segments]

Disease database Soft Tissues: Lipoblastoma with t(8;8)(q12;q12) RAB2A/PLAG1

REVIEW articles automatic search in PubMed

Last year articles automatic search in PubMed

Home Genes Leukemias Solid Tumors Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.

Gene Name	RAB2A
Location	8q12.1
Dna / Rna	The RAB2A gene contains 8 exons spanning 106 kbp of genomic distance that was mapped to chromosome 8q12.1. It has two alternative splicing forms (one without exon 2) as a result of the use of alternative polyadenylation sites (GeneCards CID:GC08P061429 (http://www.genecards.org/cgi-bin/carddisp.pl?gene=RAB2A), UniProt P61019-RAB2A_HUMAN(http://www.uniprot.org/uniprot/P61019)).
Protein	The gene encodes a protein of 212 amino acids (23 kDa). The shorter isoform is missing 847-1149 aa. The protein is a member of the Rab family, whose members are small molecular weight guanosine triphosphatases (GTPases) that contain highly conserved domains involved in GTP binding and hydrolysis. The Rabs are membrane-bound proteins, involved in vesicular fusion and trafficking (Ali et al., 2004; Mountjoy et al., 2008). RAB2a is a pre-Golgi intermediate and transports proteins from the endoplasmic reticulum (ER) to the Golgi complex (Tisdale EJ et al., 1996) (GeneCards CID:GC08P061429 (http://www.genecards.org/cgi-bin/carddisp.pl?gene=RAB2A), UniProt P61019-RAB2A_HUMAN(http://www.uniprot.org/uniprot/P61019)).

Gene Name	PLAG1
Location	8q12.1
Dna / Rna	The gene spans about 50 kb and includes 5 exons. The size of the transcript is about 7 kb. It has two alternative splicing forms (one without exon 2) (GeneCards GCID:GC08M057073 (http://www.genecards.org/cgi-bin/carddisp.pl?gene=PLAG1), UniProt Q6DJT9-PLAG1_HUMAN (http://www.uniprot.org/uniprot/Q6DJT9)).
Protein	The gene encodes a 500-aa zinc finger protein (74 kDa) with two putative nuclear localization signals (Kas et al., 1997). When activated, it acts as a transcription factor that up-regulates target genes, such as IGFII, leading to uncontrolled cell proliferation. When overexpressed in cultured cells, it increases the proliferation rate and transformation. Other target genes such as CRLF1, CRABP2, CRIP2, PIGF are strongly induced in cells with PLAG1 induction. PLAG1 is a proto-oncogene whose ectopic expression can trigger the development of lipoblastomas and pleomorphic adenomas of the salivary gland (Hensen et al., 2002; Voz et al., 2004; Zatkova et al., 2004) (GeneCards GCID:GC08M057073 (http://www.genecards.org/cgi-bin/carddisp.pl?gene=PLAG1), UniProt Q6DJT9-PLAG1_HUMAN (http://www.uniprot.org/uniprot/Q6DJT9)).

Hybrid Gene
Note	The fusion occurs as a result of a cryptic, intrachromosomal rearrangement in tumors with apparently normal karyotypes. Comparison of the fusion gene with the wild type reveals that the fusion gene is associated with t(8;8)(q12.1;q12.1) translocation. The first exon of RAB2A is fused to either exon 2 or exon 3 of PLAG1 (Yoshida et al., 2014).
Description	PLAG1 has a genomic fusion breakpoint in intron 1 resulting in alternative splicing of exon 2. The start codon of PLAG1 is located in exon 4 (Van Dyck et al., 2007), and the coding sequence of PLAG1 is preserved (Yoshida et al., 2014). This supports the molecular mechanism of overexpression of PLAG1 through promoter swapping: as a result of the translocation, the constitutively active promoter of the partner gene drives the ectopic expression of PLAG1 (Hibbard et al., 2000)
Detection	RT-PCR using total RNA extracted from frozen tumor tissue. The RAB2A/PLAG1 fusion transcript was amplified with primers 5' CTTCCTCACAGCCCCTCACT-3' (forward), and, 5'- GGAACTGCCCAACTCCACTA-3'(reverse). RAB2A/PLAG1-fusion transcripts of 485 bp and 590 bp were detected (Yoshida et al., 2014).
Fusion Protein
Note	No fusion protein exist for reasons the above.
Expression Localisation	PLAG1 protein localizes to the nucleus (Bahrami et al.,2012).

Mitelman database	t(8;8)(q12;q12) RAB2A/PLAG1 [Case List] t(8;8)(q12;q12) RAB2A/PLAG1 [Association List] Mitelman database (CGAP - NCBI)
arrayMap	arrayMap ((UZH-SIB Zurich) [auto + random 100 samples .. if exist ] [tabulated segments]


Disease database	Soft Tissues: Lipoblastoma with t(8;8)(q12;q12) RAB2A/PLAG1

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed