Cytogenetic Alterations Are Differently Associated with Disease Progression Depending on t(14;18) in Follicular Lymphoma

[Introduction] Follicular Lymphoma (FL) is characterized by indolent clinical behavior and subsequent histological transformation which links to aggressive clinical course and poor outcome. The hallmark of cytogenetic abnormality in FL is the translocation t(14;18)(q32;q21), which is found in more than 75% of cases. Several other cytogenetic abnormalities, which might contribute to disease progression, have been found. However, the prognostic and biological significance of cytogenetic or genomic features of FL has not been fully revealed. Last year we have shown clear evidence that cytogenetic abnormalities, +21 and 3q27, were independent prognostic factor in the rituximab era. Next we evaluated the pattern of chromosomal abnormalities in FL and the relation between cytogenetic and biological feature in this study.

[Patients and Methods] Cells from lymph nodes or other sites of disease at diagnosis from 201 patients with FL admitted to our hospital and affiliated hospitals between 2001 and 2013 were cytogenetically analyzed using standard methods of G-banding. Ninety nine (49.3%) men and 102 (50.7%) women with a median age of 59 years (range, 28 - 83 years) were included in the analysis. The median follow up period was 48.3 months. Forty three patients (21.4%) were Stage I or II; 156 patients (77.6%) were Stage III or IV; and 2 patients (1%) were unknown. Eighty patients (39.8%) were follicular lymphoma international prognostic index (FLIPI) low, 55 patients (27.4%) were intermediate, and 43 patients (21.4%) were high; and 23 patients (11.4%) were unknown. The distribution of FL pathological subgroups was as follows: FL Grade 1 - 2, 142 patients (70.6%); FL Grade 3a, 30 (15.0%); and unknown, 29 (14.4%). One hundred and fifty seven patients (78.1%) received Rituximab-containing chemotherapy as an initial treatment.

[Result] t(14;18)(q32;q21) was the most common abnormality observed in 119 patients (59.2%). Other numerical or structural abnormalities that were identified in more than 5% of the patients were as follows: +X (17.9%), del(6)(q) / −6 (16.9%), +7 (14.4%), abnormality of 1q12-21 / 1q (12.9%), del(13)(q) / -13 (11.9%), abnormality of 3q27 (10.4%), abnormality of 10q22-24 (10.0%), +12 / dup(12)(q) (10.0%), abnormality of 1p21-22 / 1p(9.0%), +18 (9.0%), del(17)(p) / −17 (5.0%), and the number of cytogenetic aberration higher than 3 (54.7%). Patients with the number of cytogenetics aberration higher than 3 significantly correlated with higher FLIPI grade (p= 0.0028). As is the case with much higher number of aberration (higher than 4, p= 0.0019 and higher than 5, p= 0.0024). The higher number of cytogenetic aberration also showed a trend of good correlation with advanced stage of Ann Arbor system. These suggest that additional chromosomal aberration closely related to disease progression in FL. To investigate the relationship between the disease progression and each cytogenetic abnormality logistic regression analysis was performed. In all cohort +X (Oods Ratio (OR) 2.604, 95%CI 1.184 - 5.751, p= 0.0175) and +12 / dup(12)(q) (OR 3.955, 95%CI 1.397 - 12.22, p= 0.0095) were significant abnormalities for higher FLIPI grade. To evaluate significance of t(14;18) multivariate analysis was performed for both FLs with and without t(14;18) again. In FLs with t(14;18) the same cytogenetic abnormalities, +X (OR 3.293, 95%CI 1.212 - 9.459, p= 0.0216,) and +12 / dup(12)(q) (OR 6.748, 95%CI 1.779 - 33.998, p= 0.0042), were detected as significant factor for disease progression. On the contrary in FLs without t(14;18) quite different cytogenetic abnormalities, such as +5 (OR 4.01e7, 95%CI 2.180 - , p= 0.0144) and +21 (OR 11.065, 95%CI 1.318 - 232.1, p= 0.0267), were chosen. However, these cytogenetic abnormalities did not influence patients' survival except for +21.

[Conclusion] In patients with FL disease progression was closely associated with cytogenetic abnormalities, +X and +12 / dup(12)(q) in those with t(14;18). However, in patients without t(14;18) disease progression developed in distinct manner with respect of cytogenetic alteration. Important cytogenetic alterations for disease progression may be different from those for survival in Rituximab era.