Hege Vangstein Aamot

Genomic alterations reveal potential for higher grade transformation in follicular lymphoma and confirm parallel evolution of tumor cell clones

Our aim was to examine the genetics of clonal evolution in follicular lymphoma (FL) and to identify genetic alterations associated with disease progression. A total of 100 biopsies from 44 patients diagnosed with t(14;18)-positive FL were examined by array comparative genomic hybridization. In 20 patients the patterns of somatic hypermutations (SHMs) in the variable region of heavy chain gene were additionally analyzed. Gain of chromosome X in male samples was a marker for poor outcome (P < .01). Gains involving chromosome 2, 3q, and 5 were exclusively present in FL biopsies from cases with higher grade transformation and were among the copy number alterations (CNAs) associated with inferior survival. Although we noted a trend for increasing genomic complexity in initial versus late FL samples, the overall frequencies of CNAs in initial and late FL biopsies showed a surprisingly stable pattern through the course of the disease. In 27 of cases the initial samples harbored CNAs that were absent in relapse samples, indicating that tumor cell clones at relapse were not direct descendants of initially dominating clones. The pattern of SHMs confirmed parallel development of tumor cell clones in 14 cases. Our findings support the hypothesis of common progenitor cells in FL.

Peripheral T-cell lymphoma with involvement of the expanded mantle zone.

Peripheral T-cell lymphoma (PTCL) with a nodular architecture is rare. Recently, two variants have been described with infiltration of the B-cell follicle, one variant that localizes to the marginal zone with a so-called perifollicular growth pattern, and a variant that localizes to the germinal center. These lymphomas have a CD4+ phenotype and may express Bcl-6. We have studied five similar cases of PTCL with involvement of the B-cell follicle. However, our cases differ from the cases previously described by their predominant and frequently patchy involvement of the expanded mantle zone of the B-cell follicle at onset. Later biopsies in three of the cases show diffuse infiltration of the lymph node, without features of angioimmunoblastic TCL (AILT). All cases expressed Bcl-6 in addition to CD4. Cytogenetics was available in four of the cases but revealed no recurrent chromosomal aberrations or changes associated with other types of PTCL. No mutations of the BCL-6 gene were observed. Together, the cases seem to have an intermediately aggressive clinical behavior. Whether our cases are part of a spectrum of PTCLs that encompasses previously described variants with predominant marginal zone or germinal center infiltration or they represent a separate T-cell lymphoma type remains to be demonstrated by a study of more of such cases.

G-banding and molecular cytogenetic analyses of marginal zone lymphoma

We analysed the acquired chromosomal aberrations of 22 marginal zone lymphoma (MZL) patients by various genome‐wide cytogenetic techniques, such as G‐banding, multicolour fluorescence in situ hybridisation (M‐FISH), cross‐species colour banding (RxFISH), and comparative genomic hybridisation (CGH), as well as FISH with locus‐specific probes. Patients with an abnormal chromosome 3 (nu2003=u200311), the most frequently rearranged chromosome, showed a shorter median survival than patients with a normal chromosome 3 (nu2003=u200311, 74u2003months vs. 219u2003months, Pu2003<u20030·03). Four of five patients with nodal MZL had chromosome 3 abnormalities and patients with nodal MZL had a shorter median survival than patients in the other morphological subgroups of MZL (Pu2003<u20030·003). CGH analysis showed only gains of chromosome material, namely of chromosome regions 3p12–25, 3q12–21, 3q23–28, 12q13–15, 12q22–24, 19p13 and 19q13 in two to four cases each (20–40%). In two MZL, the novel unbalanced translocation der(13)t(3;13)(q24;p11) was detected as the sole karyotypic rearrangement, indicating that gain of 3q24‐qter could be an important event in the pathogenesis of these lymphomas. Another two cases showed, in addition to other abnormalities, a t(4;14)(p13;q32). Both these lymphomas had involvement of the IGH gene at 14q32, and one of them also of the RHOH/TTF gene at 4p13, which encodes a new member of the RHO protein subfamily.

Granulomatous slack skin with a translocation t(3;9)(q12;p24).

Granulomatous slack skin is a rare cutaneous T-lymphoproliferative disease characterized by pendulous skin folds. Histology typically reveals a dermal infiltrate of T cells and multinucleated giant cells showing elastophagocytosis. Specific genetic abnormalities have not yet been identified. Currently, granulomatous slack skin is classified according to the World Health Organization classification as a variant of mycosis fungoides although supporting genetic evidence is yet lacking. We present a well-documented case of a 46-year-old man with the typical histologic and clinical findings of granulomatous slack skin. Cytogenetic analysis of a skin biopsy revealed a t(3;9)(q12;p24) as the sole chromosomal abnormality. Fluorescence in situ hybridization analysis did not reveal involvement of the JAK2 gene, located at chromosome band 9p24, and previously shown to be amplified in Hodgkin lymphoma and primary mediastinal diffuse large B-cell lymphoma. Although more cases have to be reported and the putative oncogene involved in the translocation has yet to be identified, the cytogenetic findings are unlike those described for mycosis fungoides and suggests that granulomatous slack skin is a distinct primary cutaneous T-cell lymphoma.

t(14;22)(q32;q11) in non-Hodgkin lymphoma and myeloid leukaemia : molecular cytogenetic investigations

Two non‐Hodgkin lymphomas (NHL), one chronic lymphocytic leukaemia/small lymphocytic lymphoma and one diffuse large B‐cell lymphoma and three cases of myeloid leukaemia, two chronic (CML) and one acute (AML), showed, by G‐banding analysis, apparently identical chromosomal translocations t(14;22)(q32;q11), in three of the cases as the sole abnormality. Fluorescence in situ hybridisation (FISH) analysis with locus‐specific probes for ABL at 9q34 [bacterial artificial chromosomes (BACs) 835J22 and 1132H12], IGH at 14q32 [P1 artificial chromosome (PAC) 998D24] and IGL (PAC 1019H10) and BCR (BAC 74M14) at 22q11, as well as multicolour in situ hybridisation (M‐FISH) analyses were performed. A three‐way variant translocation of the classical t(9;22)(q34;q11), t(9;22;14)(q34;q11;q32), involving both BCR and ABL, was unravelled by the molecular cytogenetic investigations in the three myeloid leukaemia cases; a similar variant translocation has previously been reported in seven CML. The two cases of NHL (one NHL with a similar 14;22‐translocation has been reported previously) had no involvement of BCR or ABL, but instead the IGH and IGL genes were shown to be juxtaposed by the t(14;22)(q32;q11). How such a rearrangement with recombination of IGH and IGL might elicit a pathogenetic effect is completely unknown.

Karyotyping of diffuse large B-cell lymphomas: loss of 17p is associated with poor patient outcome

Cytogenetic studies of patients with diffuse large B‐cell lymphoma (DLBCL) have revealed a large spectrum of chromosomal abnormalities, some of which may be clinically relevant. We wanted to evaluate possible associations between commonly acquired chromosome aberrations and prognosis in a large cohort of patients.

Myelodysplastic syndrome with a t(2;11)(p21;q23-24) and translocation breakpoint close to miR-125b-1

The upregulation of oncogenes and the formation of fusion genes are commonly observed in hematological malignancies with recurring balanced translocations. However, in some malignancies exhibiting balanced chromosomal rearrangements, neither oncogene deregulation nor generation of fusion genes appears to be involved, suggesting that other mechanisms are at play. In the rare myelodysplastic syndrome (MDS) containing a t(2;11)(p21;q23-24) translocation, breakpoints near a microRNA locus, miR-125b-1, in 11q24 have been suggested to be pathogenetically involved. Here we report the detailed mapping and sequencing of the breakpoint located only 2 kilobases from miR-125b-1 in an MDS patient with a t(2;11)(p21;q23-24).