Primary mediastinal large B-cell lymphoma segregating in a family: exome sequencing identifies MLL as a candidate predisposition gene.

Primary mediastinal large B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL) accounting for 2-4% of all non-Hodgkin lymphomas. We report a family of three siblings with PMBCL and their cousin with extranodal DLBCL. The histopathological characteristics of lymphomas of all four patients are similar, implying post germinal center differentiation and growth deregulation by other mechanisms than BCL2 mediated inhibition of apoptosis, and suggesting a shared biological background. We aimed to identify the genetic defect underlying lymphoma susceptibility in this family using exome sequencing and linkage analysis. The only variant segregating in all four patients and not reported in genetic databases was 5533C>A (His1845Asn) in the MLL gene. To our knowledge, this is the first time when familial clustering of PMBCL is reported. While we propose MLL as a candidate predisposition gene for this condition, this finding needs to be validated in additional cases.