08 May 2018

Scientists have identified five genetic subtypes that could help categorise patients of diffuse large B cell lymphoma (DLBCL) to customise their treatment options, it has been announced. 

Genomic analysis by scientists at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, USA, say the genetic subtypes can help to identify likely therapeutic targets.

Dr Margaret Shipp, chief of Dana-Farber's Hematologic Neoplasia division and director of the Lymphoma Program of the Dana-Farber/Harvard Cancer Center, said: “These genetic signatures also clearly suggest that we want to think about using a combination of targeted agents, because in DLBCL, combinations of genetic alterations occur together in specific subtypes.”

About 60% of DLBCL patients can be treated successfully with a combination of four chemotherapies plus a targeted drug that inhibits a B cell surface protein.

However treatment options for the “very substantial fraction” of patients who develop recurrent disease are less successful.

Although existing clinical tests can predict which patients with DLBCL can be treated effectively with standard treatments, they do not help inform the improvement of treatment for other patients. 

The study aimed to integrate data on three types of genetic alterations that can drive tumours - mutations to genes, changes in gene copy numbers and chromosomal rearrangements - and define previously unappreciated disease substructure.

Dr Shipp said: "Specific genes that were perturbed by mutations could also be altered by changes in gene copy numbers or by chromosomal rearrangements, underscoring the importance of evaluating all three types of genetic alterations.

 “Most importantly, we saw that there were five discrete types of DLBCL that were distinguished one from another on the basis of the specific types of genetic alterations that occurred in combination."

They examined the tumour subtypes by RNA data associated with cell of origin and discovered that each of the two major cell-of-origin subtypes could be split into separate categories with distinct genetic signatures.

An additional subtype, which is defined by TP53 gene alterations and associated genomic instability, was unrelated to the cell of origin.

The researchers then found clear links between given genetic subtypes and how patients responded to standard treatment.

"We feel this research opens the door to a whole series of additional investigations to understand how the combinations of these genetic alterations work together, and then to use that information to benefit patients with targeted therapies," says Dr Shipp.

Source: Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nature Medicine 30 April 2018; doi:10.1038/s41591-018-0016-8

Link: https://www.nature.com/articles/s41591-018-0016-8


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