Genetic factors in familial manifestation of primary mediastinal large B-cell lymphoma over two generations.

Primary mediastinal large B-cell lymphoma (PMBL) is a rarely occurring lymphoid malignancy, which typically affects young adults and presents itself as an anterior mediastinal mass. Gene expression profiling, as well as somatic genetic analysis revealed that it is closely related to classical Hodgkin lymphoma, whereas morphologically it tends to resemble diffuse large B-cell lymphoma. Familial clustering of PMBL is rare - only two reports have been published to date. While generally accepted that positive family history is associated with increased risk of developing a lymphoma, genetic risk factors, which might predispose to PMBL are largely unknown. We performed germline and tumor genetic analysis by whole exome sequencing and array-CGH of a family, in which the father and the son both developed a PMBL. Germline investigations of both affected patients and of their two unaffected family members has not been able to provide a single risk factor associated with lymphoma predisposition. In addition, genes that were previously implicated in increased risk for PMBL, namely MLL (KMT2A) and TIRAP, were found to be intact in all investigated family members. Somatic genetic investigations identified known as well as novel genetic aberrations in tumors of affected subjects. We conclude that predisposition to a PMBL might be inherited through a combination of low- or moderate-risk factors and provide a shortlist of most likely selected candidates, which can be used in future studies.

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