Quantifying the Role of Aberrant Somatic Hypermutation in Transformation of Follicular Lymphoma

Somatic hypermutation (SHM) aberrantly targets proto-oncogenes in various non-Hodgkin's lymphoma. To test the association of SHM with transformation of follicular lymphoma (FL), we sequenced mutational hot spots in five proto-oncogenes (BCL6, PAX5, RHOH, MYC and PIM1) in 32 low-grade FL (lgFL) with follicular histology and 26 transformed FL (tFL) with diffuse large cell histology. No difference was detected in the fraction of specimens mutated (75% of lgFL and 77% of tFL) or in the mutation load (0.08 for lgFL vs. 0.06 mutations/100 bp/allele for tFL). Serial specimens were examined from 25 patients showing stable low-grade FL (slgFL; n=6) or a low-grade FL that later transformed into diffuse large cell lymphoma (tFL; n=19). slgFL and tFL patients accumulated similar numbers of mutations in the interval between biopsies. These data indicate that mutations attributable to aberrant SHM occur with similar frequency in low-grade and transformed FL; transformation is not associated with a higher rate of aberrant SHM. Moreover, the frequency of mutations attributable to aberrant SHM in tFL was significantly lower than that reported for de novo diffuse large B cell lymphoma, suggesting differing oncogenic mechanisms in transformed follicular lymphoma and de novo diffuse large B cell lymphoma.