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

Abstract

BackgroundChronic 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 PresentationWe 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.ConclusionsTaken 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13039-015-0203-y) contains supplementary material, which is available to authorized users.

Two Distinct <b><i>BCL2</i></b> Rearrangements, Each Observed in 2 Independent Subclones, Evolving from a Founder Clone with Trisomy 12 in a Unique Case of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

“…BCL2 rearrangements characteristically observed in follicular lymphoma have been uncommonly reported in CLL/SLL [9,10,11,12]. More unusual are cases of CLL/SLL with double-hit translocations involving BCL2 and IG loci.…”

“…More unusual are cases of CLL/SLL with double-hit translocations involving BCL2 and IG loci. Lau et al [11] reported a case of CLL with trisomy 12, t(14;18) ( IGH-BCL2 ), and t(8;14) (IGH-MYC) within the same clone, while Alpatov et al [9] reported a case of CLL with trisomy 12, t(14;18), and t(14;19) ( IGH-BCL3 ) within the same clone. In addition, 2 case series of CLL/SLL, harboring t(14;18) translocations also revealed trisomy 12 in approximately 13/22 (59%) and 6/12 (50%) cases, which is higher than the reported 15-20% observed in common CLL/SLL [4,10,12].…”

“…Nevertheless, neoplasms with juxtaposition of BCL2 with an immunoglobulin gene will result in overexpression of the antiapoptotic protein BCL2, thus contributing to oncogenesis [2,13]. To date, only 2 cases of CLL/SLL harboring double-hit translocations involving IGH and BCL2 have been reported; however, both translocations were observed within the same clone [9,11]. We report a 74-year-old male diagnosed with CLL/SLL found to have 2 independent subclones on conventional cytogenetic analysis, each with distinct BCL2 rearrangements ( IGK-BCL2 and IGH-BCL2 ), evolving from a founder clone with trisomy 12 as the sole abnormality.…”

“…Importantly, CLL/ SLL can also acquire cytogenetic aberrations that result in clonal evolution and disease progression [7,8]. BCL2 (18q21) rearrangements with immunoglobulin gene partners (IGK [2p11.2], IGH [14q32.33], or IGL [22q11.22]) are characteristically observed in follicular lymphoma and diffuse large B cell lymphoma (DLBCL), but have also been reported, albeit rarely, in splenic marginal zone lymphoma (SMZL) and CLL/SLL [9,10,11,12]. Nevertheless, neoplasms with juxtaposition of BCL2 with an immunoglobulin gene will result in overexpression of the antiapoptotic protein BCL2, thus contributing to oncogenesis [2,13].…”

Coexistence of t(2;14;11)(p16.1;q32;q23) and t(14;19)(q32;q13.3) chromosome translocations in a patient with chronic lymphocytic leukemia

“…[ 8 – 10 ] The most frequent translocation in CLL is t(14;19) (q32;q13), which juxtaposes IGH and BCL3 resulting in overexpression of BCL3 [ 11 ] and is usually associated with unfavorable clinical outcome and trisomy 12. [ 8 , 12 ] It was proposed that these 2 changes might cooperate for malignant transformation. [ 13 ] In contrast, patients with del(13q) have a better survival than the patients with other cytogenetic abnormalities.…”