Distinct Cytogenetic Aberrations during the Course of Mantle Cell Lymphoma (MCL).

BACKGROUND: Apart from t(11;14)(q13;q32), MCL is also characterized by other nonrandom cytogenetic findings. These additional aberrations are well studied at diagnosis and believed to represent clonal evolution during lymphomagenesis, but little is known about karyotypic changes during the course of the disease.

METHODS: The study included 33 patients with MCL. In all cases, an interphase FISH assay was performed at diagnosis on lymphoma cells from peripheral blood, bone marrow or touch imprints of involved sites. Commercial probes were employed for the detection of t(11;14), +12, 13q−, and abnormalities of ATM, p53, p16, TEL, c-MYC and BCL6 genes. In 14 cases, the same FISH screening was repeated at least once (up to four times) during the course of the disease, at relapse or in the context of partial or no response.

RESULTS: The most frequent additional findings at diagnosis were ATM deletion in 15 cases (45.5%) and 13q− in 12 cases (36.4%), followed by p16 deletion (3 cases; 1 homozygous), p53 deletion (2 cases), and +12, duplication of the CCND1/IGH fusion gene and BCL6 triplication, in one case each. 11 of the 14 cases studied at follow-up showed karyotypic evolution, with acquisition of p16 deletion (6 cases; 4 homozygous), TEL deletion (5 cases; 2 on the basis of monosomy 12), duplication of the CCND1/IGH fusion (3 cases), p53 deletion (2 cases), and c-MYC amplification (1 case). There was no case with acquisition of ATM deletion, 13q− or +12, but in two cases with 13q− in a minor subclone at diagnosis the aberration was estimated to involve the total of the lymphoma cells at relapse. Interestingly, new BCL6 aberrations were seen in 3 cases (triplication in one and amplification in the other two, including the case with gene triplication at diagnosis) and were detected at the third or the fourth repetition of the screening. The longest survival after detection of these aberrations was 3 months.

CONCLUSIONS: Our data suggest that in most cases of MCL clonal evolution also occurs during the course of the disease, with the acquisition of multiple additional chromosomal lesions. Despite the small number of patients in our series, it seems that some of the aberrations (like ATM deletion or 13q−) are most commonly already present at diagnosis, while others (such as monosomy 12 and/or TEL deletion) appear more often or even exclusively on follow-up. From the clinical point of view, we found that the most informative finding is the overrepresentation of the BCL6 gene, apparently associated with aggressive behavior and perhaps the terminal stage of MCL.