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Multiple Myeloma Sequences Reveal Prognostic Immunoglobulin Translocation

NEW YORK (GenomeWeb) – Recurrent translocations involving the immunoglobulin lambda (IgL) antibody locus may provide previously unappreciated clues to treatment response and patient outcomes in multiple myeloma, according to new research from an Emory University-led team.

"This could be different than other markers that we currently use in myeloma, because it may influence which drugs physicians may choose in both initial treatment as well as maintenance therapy," senior author Lawrence Boise, vice chair for basic research in the Winship Cancer Institute and Emory University School of Medicine's hematology and medical oncology department, said in a statement.

Using whole-genome sequence data for samples from nearly 800 multiple myeloma patients profiled for the longitudinal Multiple Myeloma Research Foundation-funded "Clinical Outcomes in Multiple Myeloma to Personal Assessment," or CoMMpass study, including cases from North America and Europe, Boise and his colleagues searched for structural variants with potential ties to survival.

Their findings, published online yesterday in Nature Communications, suggested that rearrangements that linked IgL to oncogenes such as MYC are associated with resistance to a standard multiple myeloma treatment called lenalidomide (marketed by Celgene as Revlimid). Multiple myeloma patients with the risky IgL translocations also had shorter-than-usual survival times, the investigators reported, and were about half as likely to survive for at least three years compared to IgL-translocation-free cases.

"Most patients who have an IgL translocation are actually being diagnosed as having standard risk disease, so this study has helped explain why some patients who we think will do well end up relapsing and dying early."

Generally speaking, multiple myeloma therapies are highly effectively, the team explained. But risky forms of the disease do exist, and roughly 20 percent of patients experience relapse and/or death in the first couple years after diagnosis.

The alterations turned up in nearly one in 10 cases assessed for the new analysis, which focused on long-insert, whole-genome paired-end sequence data produced on CD138+ myeloma and matched peripheral blood germline samples collected from 795 individuals with multiple myeloma at the time of diagnosis.

The team's search for deletions, duplications, inversions, and translocations unearthed 21 structural variants per myeloma case, on average. As found in the past, translocations involving the immunoglobulin locus IgH were the most common, turning up in more than 40 percent of cases. But some 20 different parts of the genome were recurrently altered with at least 2 percent frequency, and roughly two-thirds of the cases included at least one rearrangement.

Although they looked into several rearrangements identified in the tumors, the researchers gave special attention to the IgL translocations and their consequences after discovering that patients with these rearrangements had decreased average survival times. That was particularly true of the 32 cases with IgL-MYC translocations.

Some 41 percent of the translocations moved IgL near MYC, while others placed the active immune gene near genes such as MAP3K14 or CD40, the team reported. The IgL translocations did not appear to coincide with any of the seven known gene expression subtypes for multiple myeloma based on available genome and RNA sequence data for 629 samples, though copy number profiles for almost 800 cases hinted that they were more common in so-called hyperdiploid cases.

With the help of chromatin immunoprecipitation sequencing on three myeloma cell lines expressing IgK, IgL, or translocated IgL, the authors found that the IgL locus "contains multiple strong enhancer elements that are bound by [the Ikaros transcription factor-coding gene] IKZF1." Even so, available patient data indicated that the multiple myeloma cases marked by IgL translocations did not seem to respond to so-called IMiD drugs that target IKZF1.

From these and other data, the authors concluded that IgL-MYC translocations as a marker of poor prognosis, independent of other genetic abnormalities, with implications for diagnosis and treatment."

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