t(2;7)(p11;q21) IGK/CDK6
t(7;14)(q21;q32) IGH/CDK6
t(7;22)(q21;q11) IGL/CDK6

2021-02-01   Elise Chapiro , Elise Chapiro , Elise Chapiro 

1.Cytogénétique Hématologique, Service dHématologie Biologique, Hpital Pitié-Salpêtrière, APHP,.Sorbonne Université. Centre de Recherche des Cordeliers, INSERM UMRS_1138, Cell Death and Drug Resistance in Lymphoproliferative Disorders Team, Paris, France elise.chapiro@aphp.fr; florence.nguyen-khac@psl.aphp.fr (EC, FNK), Laboratoire dHématologie, Hpital Robert Debré, Reims, France bgaillard@chu-reims.fr (BG)
2.Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France

Abstract

Translocations involving the CDK6 gene are rare but recurrent abnormalities in mature B-cell neoplasms, mainly marginal zone lymphoma and chronic lymphocytic leukemia. Four different translocations have been described: t(2;7)(p11;q21) (the most frequent), t(7;14)(q21;q32), t(7;14)(q21;q11) and t(7;22)(q21;q11), leading to juxtaposition of the CDK6 gene with the IGK, IGH, TRA or IGL locus, respectively, and thus CDK6 overexpression.

Clinics and Pathology

Disease

To date, t(2;7) and its variants have been documented in about 100 cases: mainly marginal zone lymphoma (sMZL) (about 2/3 of patients) and Chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (~15%), but also high-grade B-cell lymphoma not otherwise specified, unclassified small B-cell lymphoma and monoclonal B-cell lymphocytosis (marginal-zone type). One case of nodal MZL, one bronchus-associated lymphoid tissue (BALT) lymphoma, and one gastric MALT (mucosa-associated lymphoid tissue) lymphoma were also reported.

Epidemiology

The frequency is estimated to 0.32% of mature B-cell neoplasms (Gaillard et al., 2020).

Cytology

A small proportion of prolymphocytic cells are mixed with classical marginal zone cells in about 70% of t(CDK6)+ MZL (Gaillard et al., 2020).

Pathology

The expression of CD5 is frequent in t(CDK6)+ lymphomas (more than half of cases) (Gaillard et al., 2020).

Prognosis

Prognosis seems good. In a series of 47 t(CDK6)+ MZL and small B-cell lymphomas, the 5-year overall survival (OS) rate was above 80%. The presence of del(17p) or a TP53 mutation does not appear to influence OS (Gaillard et al., 2020).

Note

The great majority of t(CDK6)+ MZL and small B-cell lymphomas carry IGHV mutations. The most frequent IGHV genes identified are V3-23 and V4-59 (14% and 10% respectively). The IGHV1-02*04 gene, the most frequent allele in classical splenic MZL, is not found.
Mutations in TP53 gene are frequent (27%). No mutations in NOTCH2 (Gaillard et al., 2020).

Cytogenetics

Atlas Image
Figure 2. Top: t(2;7)(p11;q21) : FISH IGK (DC BA)(316G9) (SG) (526L16-1021F11)(SO) (2p11) - Courtesy Karolien Beel, Peter Meeus and Lucienne Michaux (CME Leuven); Second to fourth rows: - Courtesy Elise Chapiro (Paris) A and B: t(2;7)(p11;q21) A. FISH with the home-made break-apart CDK6 probe (RP11-246N14 labeled in FITC + RP11-90H9 labeled in Rhodamine). B. IGK (2p11) break-apart probe (Cytocell). C and D: t(7;14)(q21;q11) C. Home-made break-apart CDK6 probe (RP11-246N14 labeled in FITC + RP11-90H9 labeled in Rhodamine). D. TRAD (14q11) break-apart probe (Cytocell). E and F: t(7;14)(q21;q32) E. Home-made break-apart CDK6 probe (RP11-246N14 labeled in FITC + RP11-90H9 labeled in Rhodamine). F. IGH (14q32) break-apart probe Vysis (Abbott).

Cytogenetics morphological

The translocation t(2;7) is described in the great majority of cases (> 90%), mainly splenic marginal zone lymphomas (sMZL) and chronic lymphocytic leukemia (CLL). Variant translocations are more frequent in CLL; t(7;22) IGL/CDK6 (reported in only one case) and t(7;14) IGH/CDK6 are restricted to CLL. The t(7;14) TRA/CDK6 has been described in four cases: two CLL and two sMZL.

Cytogenetics molecular

FISH analyses revealed that the breakpoint in IGK is located in the IGKV proximal region in the majority of the patients. In one third, the breakpoint is more centromeric (in the IGKV distal region).
Atlas Image
Figure 3.

Additional anomalies

Additional abnormalities are found in 2/3 of cases. Complex karyotypes (>3 abnormalities) are frequent (about half of cases). The most frequent additional chromosomal aberrations are: del(17p)) involving the TP53 gene, del(13q14), del(8p), trisomy 3, 8q gain, trisomy 12 and trisomy 18. Del(7q) is rare contrary to classical sMZL.

Genes Involved and Proteins

Gene name
CDK6 (cyclin dependent kinase 6)
Location
7q21.2
Note
Alias: PLSTIRE
Protein description
CDK6 is highly homologous to CDK4. CDK6 has a kinase-dependent activity in the cell cycle progression (regulation of the G1 early phase), survival, differentiation, and senescence that requires binding to D-type cyclin (CCND1, CCND2 and CCND3). CDK6 also acts as a chromatin-bound cofactor that in a kinase-independent manner induces transcription of genes regulating angiogenesis, cell cycle inhibition, stem cell activation and immune response. (for review, see Nebenfuehr et al., 2020).
Gene name
IGH (Immunoglobulin Heavy)
Location
14q32.33
Note
Alias: IGHDY1, IGH@
Protein description
Immunoglobulin heavy chain: part of the B-cell receptor (BCR).
Gene name
IGK: (Immunoglobulin Kappa)
Location
2p11.2
Note
Alias: IGK@
Protein description
Immunoglobulin light chain: part of the B-cell receptor (BCR)
Gene name
TRA (T Cell Receptor Alpha)
Location
14q11.2
Note
Alias: TCRA, TRA@
Protein description
T-cell receptor alpha: part of the T-cell receptor complex
Gene name
IGL (Immunoglobulin Lambda)
Location
22q11.2
Note
Alias: IGL@
Protein description
Immunoglobulin light chain: part of the B-cell receptor (BCR)

Result of the Chromosomal Anomaly

Description

The translocation juxtaposes CDK6 close to IG(/TCR) enhancers which are constitutively active in B-cells. The sequencing of the t(2;7) breakpoints revealed that junction sites on 2p11 localized to the recombination signal sequences (RSS) of a gene segment belonging to the VK3 family of IGK variable genes, while the breakpoints on 7q21 mapped to an RSS-like element located approximately 0.5 kb upstream of the transcription start site of the CDK6 gene. These observations strongly suggest that the VJ or VDJ recombination machinery is involved in the formation of this translocation (Parker et al., 2013).

Oncogenesis

Overexpression of CDK6 was demonstrated (Corcoran et al., 1999; Brito-Babapulle et al., 2002; Hayette et al., 2003).

Bibliography

Reference NumberPubmed IDLast YearTitleAuthors

Summary

Fusion gene

IGK/CDK6 IGK (14q32.33) CDK6 (7q21.2) M t(2;7)(p11;q21)

Fusion gene

IGH/CDK6 IGH (14q32.33) CDK6 (7q21.2) M t(7;14)(q21;q32)

Fusion gene

IGL/CDK6 IGL (22q11.22) CDK6 (7q21.2) M t(7;22)(q21;q11)
Atlas Image
Figure 1. Translocation t(2;7)(p11;q21) and variants. Left: t(2;7)(p11;q21) IGK /CDK6. R-banding, Top: - Courtesy Karolien Beel, Peter Meeus and Lucienne Michaux (CME Leuven); Middle (R-banding) and Bottom (G-banding): - Courtesy Baptiste Gaillard (Reims), Elise Chapiro (Paris) and Audrey Bidet (Bordeaux); Center and Right: t(7;14)(q21;q11) and t(7;14)(q21;q32) - Courtesy Baptiste Gaillard (Reims), Elise Chapiro (Paris) and Audrey Bidet (Bordeaux)

Citation

Elise Chapiro ; Elise Chapiro ; Elise Chapiro

t(2;7)(p11;q21) IGK/CDK6
t(7;14)(q21;q32) IGH/CDK6
t(7;22)(q21;q11) IGL/CDK6

Atlas Genet Cytogenet Oncol Haematol. 2021-02-01

Online version: http://atlasgeneticsoncology.org/haematological/1361/t(7;14)(q21;q32)

Historical Card

2009-02-01 t(2;7)(p11;q21) IGK/CDK6
t(7;14)(q21;q32) IGH/CDK6
t(7;22)(q21;q11) IGL/CDK6 by  Jean-Loup Huret 

Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France