5′-UTR FAS mutation pattern and frequency in nodal diffuse large B-cell lymphoma similar to normal germinal center B cells

The FAS gene codes for a cell surface receptor involved in death signaling and belongs to the tumor necrosis factor receptor family. During the B-cell maturation process, the FAS protein plays an important role in the antigen dependent selection process in the germinal center by elimination of B cells with low affinity or non functional B cell receptor. Mutations restricted to the 50-UTR region of the FAS gene are observed in a proportion of normal germinal center B cells. On the basis of the pattern of mutations, these are thought to be the result of an aberrant somatic hypermutation process [1]. Loss of functional FAS results in survival and proliferation of undesirable B cells during the selection process and is related to lymphomagenesis. Somatic mutations in the FAS gene are indeed found in B-cell lymphoma [2], supporting a role in the pathogenesis of lymphoma. The mutations are mostly found in lymphomas presenting at extra nodal location, usually map within exons 7 – 9, which codes for the death domain of the FAS protein and lead to defective FAS signaling. In a high percentage of the FAS mutation positive cases, features suggestive of autoreactive disease were present [2]. Scholl and colleagues [3] found an association between FAS mutations in the 50-UTR of the FAS gene and nodal presentation in a series of 38 primary nodal DLBCL cases. These 50-UTR mutations presenting exclusively in nodal DLBCL cases might be related to the aberrant somatic hypermutation process. The frequency of such mutations (4 of 38 primary nodal DLBCL [3] cases) is similar to the mutation frequency observed in normal germinal center B cells [1]. However, the frequencies of 50-UTR mutations in other genes known to be associated with the aberrant somatic hypermutation process observed in extra nodal lymphomas, like PIM1, c-MYC, RhoH/TTF, and PAX5 [4,5], is much higher and suggests that FAS is not a primary target of the aberrant somatic hypermutation process. No mutations in the 50-UTR and the coding region were found in 9 primary extranodal DLBCL cases [3]. The lack of FAS mutations in the 50-UTR in extranodal DLBCL confirmed the previous findings of Gronbaek et al. and Montesinos-Rongen et al. [2,5]. In these two studies mutations were observed predominantly in the death domain of the FAS gene in extranodal DLBCL cases. These data suggests an association of FAS death domain mutations in lymphomas presenting at extranodal locations. However, the lack of death domain mutations in DLBCL cases with nodal presentation can not be generalized to other lymphoma subtypes presenting at nodal locations since FAS mutations mapping in this region have been observed in Hodgkin lymphoma and follicular lymphoma, albeit at a low frequency [1,6 – 8]. Next, Scholl et al. [3] performed a further analysis of the data currently available in the literature on FAS gene mutation in DLBCL cases to see if their findings are consistent with previous publications in DLBCL. In total, 17 additional nodal and 52 additional extra nodal cases were reported in the 6 studies discussed by Scholl et al. [3] Most of the studies mentioned in Table I of their paper contained only extra nodal DLBCL cases and revealed that all mutations were observed outside the 50-UTR region, which apparently confirms the findings of Scholl et al. However, in three of these studies the authors have only screened the coding region and not the