Whole Exome Sequencing in Multiple Myeloma to Identify Somatic Single Nucleotide Variants and Key Translocations Involving Immunoglobulin Loci and MYC.

Multiple myeloma is a malignancy of terminally differentiated plasma cells in the bone marrow. These plasma cells produce high levels of immunoglobulin which cause end-organ damage. Rearrangements within the immunoglobulin loci are a physiological part of B cell development, but these DNA level double-strand breaks may result in interchromosomal translocations. There are five main translocations involving the Ig loci: t(4;14) 12%, t(6;14) 1%, t(11;14) 15%, t(14;16) 3%, and t(14;20) 2%. These are primary events, found in all cells within the tumor clone and are associated with different prognosis. The t(4;14), t(14;16), and t(14;20) are associated with a poor prognosis, whereas the others are associated with a more favorable prognosis. Rearrangements at the MYC locus are also associated with a poor prognosis and increased expression of MYC. MYC rearrangements are frequent (25%) and involve interchromosomal translocations involving Ig loci or other partners, but also include intrachromosomal inversions, duplications and deletions. As such, the Ig and MYC loci are key players in the myeloma genome and including these in any genomic studies is key to understanding the relationship with other abnormalities. We have designed a custom capture of the Ig and MYC loci which can be added to exome or targeted captures to inform on these key events. This saves on performing additional tests to determine these events, which are generally mandatory for any genetic investigations in myeloma. This custom capture is also relevant to other B cell malignancies where MYC and Ig translocations occur.