Molecular characterization of sorted malignant B cells from patients clinically identified with mantle cell lymphoma.

Mantle Cell lymphoma (MCL) is a tumor with poor prognosis. A few studies have examined the molecular landscape by next generation sequencing and provided valuable insights into recurrent lesions driving this heterogeneous cancer. However, none have attempted to cross-link the individual genomic and transcriptomic profile in sorted MCL cells in order to perform individual molecular characterizations of the lymphomas. Such approaches are relevant as MCL is heterogenous by nature, and thorough molecular diagnostics may potentially benefit the patient with more focused treatment options. Here, we use sorted lymphoma cells from four patients at diagnosis and relapse by intersecting the coding DNA and mRNA. In spite of only few patients included, this method enabled us to pinpoint a specific set of expressed somatic mutations and to present an overall expression profile different from the normal B cell counterparts, and to track molecular aberrations from diagnosis to relapse. Changes of single nucleotide coding variants, subtle clonal changes in large copy number alterations, subclonal involvement and changes in expression levels in the clinical course provided detailed information on each of the individual malignancies. In addition to mutations in known genes (e.g. TP53, CCND1, NOTCH1, ATM), we identified others, not linked to MCL, such as a nonsense mutation in SPEN and MYD88 missense mutation in one patient, which along with copy number alterations showed molecular resemblance towards splenic marginal zone lymphoma. The detailed exonic and transcriptomic portrait of the individual MCL patients by the methodology presented here could help in diagnostics, surveillance and a potentially more precise usage of therapeutic drugs by efficient screen of biomarkers.