Cytogenetic, FISH, and molecular studies in a case of B‐cell chronic lymphocytic leukemia with karyotypic evolution

Abstract

We report the clinical, cytogenetic, fluorescence in situ hybridization (FISH) and molecular findings in a 54-yr-old male patient diagnosed with B-cell chronic lymphocytic leukemia (B-CLL), who showed progression to a diffuse large B-cell lymphoma (Richter's syndrome). Genetic studies were performed at diagnosis and during the Richter's transformation (RT). A clonal karyotype with two dicentric chromosomes, psu dic(12,21)(q24;q10) and dic(17,18)(p11.2;p11.2), was found. Both rearrangements were confirmed by FISH. Molecular cytogenetics analysis using p53 probe showed monoallelic loss of this tumor suppressor gene in 43.8% and 77.3% of cells for the first and the second studies, respectively). In both studies, deletions of D13S319 (18% and 12% of cells) and D13S25 loci (13% and 12% of cells) at 13q14 were found. Polymerase chain reaction analysis showed the MBR/JH rearrangement of the bcl-2 gene. FISH studies using LSI bcl-2/IgH probe allowed quantifying the clonal cell population with this rearrangement (4% and 6.6% of cells at diagnosis and RT, respectively). To our knowledge, this is the first case with a psu dic(12,21) described in B-CLL. The low percentage of cells with the 13q14 deletion and bcl-2/IgH rearrangement suggests that they were secondary events that resulted from clonal evolution. Our patient had a short survival (9 months) and a clear lack of response to several therapeutic agents, confirming the association of p53 gene deletion and karyotypic evolution with disease progression.

Dic(17;18)(p11.2;p11.2) is a recurring abnormality in chronic lymphocytic leukaemia associated with aggressive disease

“…Our study adds to the clinical relevance of this abnormality as, to date, very little clinical data have been associated with this abnormality. Of the reported cases, the median age at diagnosis was 59 (Espinet et al, 2000;Chena et al, 2002;Adeyinka et al, 2007) (n = 5), and 67% of patients were male. Complex karyotypes were found in 50% of these previously reported patients with this cytogenetic abnormality, and 33% had this as the sole abnormality (Dohner et al, 1995;Callet-Bauchu et al, 1999;Espinet et al, 2000;Chena et al, 2002;Adeyinka et al, 2007).…”

“…Of the reported cases, the median age at diagnosis was 59 (Espinet et al, 2000;Chena et al, 2002;Adeyinka et al, 2007) (n = 5), and 67% of patients were male. Complex karyotypes were found in 50% of these previously reported patients with this cytogenetic abnormality, and 33% had this as the sole abnormality (Dohner et al, 1995;Callet-Bauchu et al, 1999;Espinet et al, 2000;Chena et al, 2002;Adeyinka et al, 2007). Three patients are known to have been treated with fludarabine (Callet-Bauchu et al, 1999;Chena et al, 2002), and all were refractory; three patients were refractory to anthracycline-based regimens (Callet-Bauchu et al, 1999;Espinet et al, 2000;Chena et al, 2002).…”

“…It is unclear whether this is a true association or whether trisomy 12 is a common abnormality and these patients are predisposed to the development of further cytogenetic abnormalities. An extensive review of the literature identified 12 reported cases of dic(17;18)(p11.2;p11.2) (Dohner et al , 1995; Callet‐Bauchu et al , 1999; Espinet et al , 2000; Chena et al , 2002; Adeyinka et al , 2007). Our study adds to the clinical relevance of this abnormality as, to date, very little clinical data have been associated with this abnormality.…”

Impact of trisomy 12, del(13q), del(17p), and del(11q) on the immunophenotype, DNA ploidy status, and proliferative rate of leukemic B‐cells in chronic lymphocytic leukemia

“…Interestingly, this latter observation could suggest that simultaneous occurrence of both abnormalities (13q‐ and 17p‐), could induce a significant deregulation of the cell cycle control mechanisms related to P53 (35, 66), RB1 (54, 67, 68), and/or other tumor suppressor genes localized at chromosome 13q distal to 13q14.3. Although it has been suggested that cases with complex cytogenetic abnormalities might have an inferior outcome (8, 55, 69), the exact prognostic significance of the occurrence of combined cytogenetic changes in B‐CLL remains to be clarified (12).…”

Citogenética e biologia molecular em leucemia linfocítica crônica

“…27 Tais pacientes apresentam sobrevida curta, doença avançada, resposta desfavorável ou resistência a agentes alquilantes, análogos da purina e rituximab (anti-CD20). 11,[28][29][30][31][32] Há relatos de pacientes com del(17p) com resposta a alemtuzumab (anti-CD52). 11 Em relação à freqüência de anormalidades detectadas por FISH, Nascimento 33 observou, dentre os pacientes em acompanhamento na Unifesp, que 52% apresentavam anormalidades das quais 34% eram del(13q), 18% del(17p), 14% +12 e 44% mais de uma anomalia simultânea, como, del(13q)/del(17p), del(13q)/del(11q) ou +12/ del(13q).…”