A20 (TNFAIP3) Inactivation Is a Rare Event in Follicular Lymphoma2013-03-01 18:29:51
Laboratory Investigations; 2013 Mar; 93:315-71
Sonam Prakash, Jiong Yan, Kui Nie, Susan Mathew, Swarna Gogineni, Yifang Liu, Daniel M Knowles, Attilio Orazi, Wayne Tam
A20, also known as TNF alpha-induced protein 3 (TNFAIP3), is located on chromosome band 6q23 and is a negative regulator of NFkB activation pathway. Loss of A20 resulting in increased NFkB signaling has been shown to play a role in some B-cell lymphomas. A few previous studies, that included only a small number of follicular lymphoma (FL) cases, demonstrated A20 deletion/mutation in a small subset of FL. The aim of this study was to investigate A20 expression and genetic alterations in a large cohort of FL to elucidate its role in FL pathogenesis and progression.
We constructed a tissue micro array (TMA) of 169 cases of FL and 15 cases of follicular hyperplasia as controls. Conventional karyotype was available on 32 of these 169 cases. Immunohistochemistry (IHC) for A20, CD3 and CD20 to evaluate the percentage of B-cells showing loss of A20, as well as FISH analysis for A20 deletion was performed on the TMA. Additionally, on each case genomic DNA was extracted from an extra tissue core from the paraffin block and direct sequencing on the coding region and splice sites of A20 was performed. The results of A20 expression were correlated between the different methodologies and with the histologic grade.
The 169 cases of FL included histologic grade 1 (83 cases), 2 (60 cases), and 3 (26 cases); 4 cases showed subsequent transformation to diffuse large B-cell lymphoma. By karyotype, 4 of 32 cases showed del(6q23) (2 cases with histologic grade 3 and 1 case each with histologic grade 1 and 2). FISH analysis on the TMA was informative on 73 of 169 FL cases, none of which showed deletion of A20. These 73 cases did not include cases with del(6q23) by karyotype. By IHC, all 169 cases of FL showed positivity for A20 in the majority of the B-cells (>50% of B-cells). Direct sequencing was informative in 106 FL cases none of which showed mutations involving A20, including the cases with del(6q23) on karyotype.
This study represents the largest cohort of FL cases with comprehensive evaluation of A20. Inactivation of A20 is a rare event in FL. The expression of A20 by IHC and absence of A20 mutations in cases of FL, including cases with del(6q23) by karyotype, suggests that a gene other than A20 might be the pathogenetically relevant target in the 6q23 region.