Oncogenic mutations and chromosomal aberrations in primary extranodal diffuse large B-cell lymphomas of the thyroid--a study of 21 cases.

Abstract

Primary extranodal diffuse large B-cell lymphomas of the thyroid (ptDLBCL) constitute a rare entity, which until now was not fully explored. Due to recently published data genetically linking ptDLBCL to a subset of thyroid carcinoma, we assessed the occurrence of oncogenic mutations and copy number alterations. A high-resolution array-based comparative genomic hybridization approach was applied to quantify genomic aberrations in a study population of 21 ptDLBCL patients. In addition, we investigated the frequency of mutations involving the BRAF, NRAS, and MYD88 genes in correlation with immunohistochemical data. Chromosomal gains were recurrently detected at 6p21.33-p21.31, 6p22.2, 12p13.31, 14q31.1, 14q32.33, 19p13.3, and 22q11.22; numeric losses were most frequently observed at 6p21.3-p21.31, 10q26.3, 19p13.3, 20q13.33, and 21q11.2. Aberrations affecting 6p22.2 and 14q32.33 as well as 22q11.22 differed slightly between germinal center B-cell (GCB) and non-GCB groups. Statistically significant deviations were detected at 20q13.33 and 21q11.2. These specific alterations do not seem to occur in thyroid carcinomas or other DLBCL, according to previously published literature. Analysis of BRAF and NRAS showed mutation frequencies of 4.8 and 9.5%, respectively. No MYD88 mutations could be detected in any of the analyzed cases. Fluorescence in situ hybridization demonstrated breakage events involving the BCL2, BCL6, and cMYC locus in 14.3, 9.5, and 9.5%, respectively. Our study revealed ptDLBCL to be predominantly composed of the GCB type, harboring no MYD88 mutations and showing infrequent mutations in the BRAF and NRAS genes. Additionally, array comparative genomic hybridization showed no overlapping alterations between ptDLBCL and thyroid carcinomas or other nodal or extranodal DLBCL.