ILLEGITIMATE V(D)J - MEDIATED RECOMBINATION IS LINKED TO GENDER BIAS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

Sborník

Background. The incidence of childhood acute lymphoblastic leukemia (ALL) is higher by 20% in males relative to females. Male sex is also associated with a worse response to treatment and an inferior prognosis. The mechanism behind the phenomenon of gender-specific differences is presently not understood. Patients, Methods and Results.We have initially identified a previously described deletion of the 5’ region of C20orf94 - a gene coding for an uncharacterized DNA repair-associated protein - by SNP array and high-resolution CGH array in 5 of 20 ALL samples. As the breakpoints within C20orf94 were defined to recurrent positions, we performed sequence analysis and revealed specific breakpoint junctions with typical characteristics of illegitimate V(D)J recombination. We next screened diagnostic leukemic specimens of a representative cohort of 512 patients enrolled into trial ALL-BFM 2000 by PCR. Here, C20orf94 deletions were detected in 32.0%. The deletions were significantly associated with male gender (P < 0.001) and ETV6/RUNX1-rearranged ALL (P < 0.001). Additional screening of an independent cohort of 232 ETV6/RUNX1- rearranged ALLs identified 145 positive samples and not only confirmed the high incidence of C20orf94 deletion in this subgroup, but also allowed validation of its specific association with male gender (P = 0.049). By analyzing additional 249 ETV6/RUNX1 negative patients diagnosed in 2001 and 2002 the association with male gender was also confirmed in this subgroup (P=0.029). Breakpoint sequencing analysis in additional 38 patients confirmed illegitimate V(D)J recombination in all samples. In 21 of 22 paired initial and relapse leukemic samples, C20orf94 deletions were maintained at relapse. Breakpoint analysis showed the same monoclonal sequences in nine patients indicating stability of C20orf94 deletions during disease progression. The remaining samples either developed heterogeneity of C20orf94 breakpoints at relapse subsequent to monoclonal sequences or already showed an oligoclonal pattern at initial diagnosis. We next collected information on TAL1 deletion status - a second marker associated with illegitimate V(D)J-mediated recombination in childhood ALL. It occurs in approximately 5 to 15% of T-cell ALL. Employing the ALLBFM 2000 trial and additional national trials conducted in Austria, Czech Republic, Israel and Italy, 128 (11.1%) TAL1-deleted patients were identified from an entire TAL1 deletion-screened T-ALL population of 1149 patients. TAL1 deletions were significantly more frequent in male patients (P = 0.002). Conclusions. As we found a clear association of C20orf94 deletion with ETV6/RUNX1- rearranged ALL and male sex, our results not only suggest a potential role for C20orf94 deletion and illegitimate V(D)J recombination in the pathogenesis of childhood ALL, but point towards gender-specific differences in illegitimate V(D)J-mediated recombination as one potential explanation for the observed and currently only poorly understood gender bias in childhood ALL.

Haematologica, 2012; 97(s1):  213