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Rare double-hit with two translocations involving IGH both, with BCL2 and BCL3, in a monoclonal B-cell lymphoma/leukemia.

Alpatov R, Carstens B, Harding K, Jarrett C, Balakhani S, Lincoln J, Brzeskiewicz P, Guo Y, Ohene-Mobley A, LeRoux J, McDaniel V, Meltesen L, Minka D, Patel M, Manavi C, Swisshelm K - Mol Cytogenet (2015)

Bottom Line: Interestingly, the duplicated region contained ERCC2 gene, which encodes a DNA excision repair protein involved in the cancer-prone syndrome, xeroderma pigmentosum.Taken together our findings indicate the existence of double-translocation driven oncogenic events involving both IGH loci and proto-oncogenes BCL2 and BCL3.Importantly, the IGH;BCL3 translocation was characterized by the duplication of the genomic region adjacent to BCL3, containing a major DNA repair factor, ERCC2.

View Article: PubMed Central - PubMed

Affiliation: Colorado Genetics Laboratory, Department of Pathology, University of Colorado School of Medicine, 3055 Roslyn Street, Suite 200, Denver, CO 80238 USA.

ABSTRACT

Background: Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disease characterized by multiple recurring clonal cytogenetic anomalies and is the most common leukemia in adults. Chromosomal abnormalities associated with CLL include trisomy 12 and IGH;BCL3 rearrangement [t(14;19)(q32;q13)] that juxtaposes a proto-oncogenic gene BCL3 and an immunoglobulin heavy chain, a translocation that may be associated with shorter survival. In addition to the IGH;BCL3 rearrangement, other translocations involving 14q32 locus are involved in various lymphoproliferative pathologies pointing toward the significance of IGH locus in oncogenic progression. Significantly, in the majority of B-cell neoplasms that carry an IGH;BCL3 rearrangement, it is a sole translocation involving an IGH locus.

Case presentation: We report a patient who, in addition to trisomy 12, carried a rare double-hit translocation characterized by the IGH;BCL3 translocation and an additional clonal IGH;BCL2 translocation involving IGH and another proto-oncogene BCL2, t(14;18)(q32;q21), commonly found in follicular lymphoma. Further single nucleotide polymorphism (SNP) array-based analysis detected a duplication of the 58.8 kb region at 19q13.32 adjacent to the BCL3 translocation junction on chromosome 19q13. Interestingly, the duplicated region contained ERCC2 gene, which encodes a DNA excision repair protein involved in the cancer-prone syndrome, xeroderma pigmentosum.

Conclusions: Taken together our findings indicate the existence of double-translocation driven oncogenic events involving both IGH loci and proto-oncogenes BCL2 and BCL3. Importantly, the IGH;BCL3 translocation was characterized by the duplication of the genomic region adjacent to BCL3, containing a major DNA repair factor, ERCC2.

No MeSH data available.


Related in: MedlinePlus

Single Nucleotide Polymorphism (SNP) array analysis. a Confirmation of an extra copy of chromosome 12. In the Log R ratio panel (left) chromosomal boundaries between the q terminal of chromosome 11, chromosome 12, and the p terminal of chromosome 13 are demarcated by lines. The expanded chromosome 12 view (right), shows an isolated view of chromosome 12 (B-Allele frequency). b Microduplication of the genomic region containing ERCC2 gene. c Genomic mapping of ERCC2 gene located in the 19q13.32 cytogenetic band, proximal to the BCL3 gene locus (19q13.31). d Placement of the ERCC2 gene relative to the hypothesized IGH;BCL3 rearrangement junction depicted in the schematics (the possibility exists that ERCC2 duplication occurred on the non-translocated chromosome 19 as stated in text)
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Fig5: Single Nucleotide Polymorphism (SNP) array analysis. a Confirmation of an extra copy of chromosome 12. In the Log R ratio panel (left) chromosomal boundaries between the q terminal of chromosome 11, chromosome 12, and the p terminal of chromosome 13 are demarcated by lines. The expanded chromosome 12 view (right), shows an isolated view of chromosome 12 (B-Allele frequency). b Microduplication of the genomic region containing ERCC2 gene. c Genomic mapping of ERCC2 gene located in the 19q13.32 cytogenetic band, proximal to the BCL3 gene locus (19q13.31). d Placement of the ERCC2 gene relative to the hypothesized IGH;BCL3 rearrangement junction depicted in the schematics (the possibility exists that ERCC2 duplication occurred on the non-translocated chromosome 19 as stated in text)

Mentions: Further studies using single nucleotide polymorphism arrays on the patient’s DNA sample detected the presence of an extra chromosome 12, confirming our karyotype analysis (Fig. 5a). Interestingly, we also detected a microduplication event at the cytogenetically defined BCL3 translocation junction (19q13.1) containing a major nucleotide excision repair gene ERCC2 (ISCN arr[hg19](12)X3,19q13.32(45,835,983-45,894,768)x3), (Fig. 5b-d). Polymorphisms in this gene are associated with xeroderma pigmentosum (XP), XP associated with Cockayne syndrome (XP/CS), and trichothiodystrophy (TTD) [9]. However, we do not exclude the possibility that ERCC2 duplication occurred on the intact chromosome 19.Fig. 5


Rare double-hit with two translocations involving IGH both, with BCL2 and BCL3, in a monoclonal B-cell lymphoma/leukemia.

Alpatov R, Carstens B, Harding K, Jarrett C, Balakhani S, Lincoln J, Brzeskiewicz P, Guo Y, Ohene-Mobley A, LeRoux J, McDaniel V, Meltesen L, Minka D, Patel M, Manavi C, Swisshelm K - Mol Cytogenet (2015)

Single Nucleotide Polymorphism (SNP) array analysis. a Confirmation of an extra copy of chromosome 12. In the Log R ratio panel (left) chromosomal boundaries between the q terminal of chromosome 11, chromosome 12, and the p terminal of chromosome 13 are demarcated by lines. The expanded chromosome 12 view (right), shows an isolated view of chromosome 12 (B-Allele frequency). b Microduplication of the genomic region containing ERCC2 gene. c Genomic mapping of ERCC2 gene located in the 19q13.32 cytogenetic band, proximal to the BCL3 gene locus (19q13.31). d Placement of the ERCC2 gene relative to the hypothesized IGH;BCL3 rearrangement junction depicted in the schematics (the possibility exists that ERCC2 duplication occurred on the non-translocated chromosome 19 as stated in text)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4696310&req=5

Fig5: Single Nucleotide Polymorphism (SNP) array analysis. a Confirmation of an extra copy of chromosome 12. In the Log R ratio panel (left) chromosomal boundaries between the q terminal of chromosome 11, chromosome 12, and the p terminal of chromosome 13 are demarcated by lines. The expanded chromosome 12 view (right), shows an isolated view of chromosome 12 (B-Allele frequency). b Microduplication of the genomic region containing ERCC2 gene. c Genomic mapping of ERCC2 gene located in the 19q13.32 cytogenetic band, proximal to the BCL3 gene locus (19q13.31). d Placement of the ERCC2 gene relative to the hypothesized IGH;BCL3 rearrangement junction depicted in the schematics (the possibility exists that ERCC2 duplication occurred on the non-translocated chromosome 19 as stated in text)
Mentions: Further studies using single nucleotide polymorphism arrays on the patient’s DNA sample detected the presence of an extra chromosome 12, confirming our karyotype analysis (Fig. 5a). Interestingly, we also detected a microduplication event at the cytogenetically defined BCL3 translocation junction (19q13.1) containing a major nucleotide excision repair gene ERCC2 (ISCN arr[hg19](12)X3,19q13.32(45,835,983-45,894,768)x3), (Fig. 5b-d). Polymorphisms in this gene are associated with xeroderma pigmentosum (XP), XP associated with Cockayne syndrome (XP/CS), and trichothiodystrophy (TTD) [9]. However, we do not exclude the possibility that ERCC2 duplication occurred on the intact chromosome 19.Fig. 5

Bottom Line: Interestingly, the duplicated region contained ERCC2 gene, which encodes a DNA excision repair protein involved in the cancer-prone syndrome, xeroderma pigmentosum.Taken together our findings indicate the existence of double-translocation driven oncogenic events involving both IGH loci and proto-oncogenes BCL2 and BCL3.Importantly, the IGH;BCL3 translocation was characterized by the duplication of the genomic region adjacent to BCL3, containing a major DNA repair factor, ERCC2.

View Article: PubMed Central - PubMed

Affiliation: Colorado Genetics Laboratory, Department of Pathology, University of Colorado School of Medicine, 3055 Roslyn Street, Suite 200, Denver, CO 80238 USA.

ABSTRACT

Background: Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disease characterized by multiple recurring clonal cytogenetic anomalies and is the most common leukemia in adults. Chromosomal abnormalities associated with CLL include trisomy 12 and IGH;BCL3 rearrangement [t(14;19)(q32;q13)] that juxtaposes a proto-oncogenic gene BCL3 and an immunoglobulin heavy chain, a translocation that may be associated with shorter survival. In addition to the IGH;BCL3 rearrangement, other translocations involving 14q32 locus are involved in various lymphoproliferative pathologies pointing toward the significance of IGH locus in oncogenic progression. Significantly, in the majority of B-cell neoplasms that carry an IGH;BCL3 rearrangement, it is a sole translocation involving an IGH locus.

Case presentation: We report a patient who, in addition to trisomy 12, carried a rare double-hit translocation characterized by the IGH;BCL3 translocation and an additional clonal IGH;BCL2 translocation involving IGH and another proto-oncogene BCL2, t(14;18)(q32;q21), commonly found in follicular lymphoma. Further single nucleotide polymorphism (SNP) array-based analysis detected a duplication of the 58.8 kb region at 19q13.32 adjacent to the BCL3 translocation junction on chromosome 19q13. Interestingly, the duplicated region contained ERCC2 gene, which encodes a DNA excision repair protein involved in the cancer-prone syndrome, xeroderma pigmentosum.

Conclusions: Taken together our findings indicate the existence of double-translocation driven oncogenic events involving both IGH loci and proto-oncogenes BCL2 and BCL3. Importantly, the IGH;BCL3 translocation was characterized by the duplication of the genomic region adjacent to BCL3, containing a major DNA repair factor, ERCC2.

No MeSH data available.


Related in: MedlinePlus