NEW YORK (GenomeWeb) – A team from the US and Germany has uncovered new diffuse large B cell lymphoma (DLBCL) subtypes through a multi-omic analysis of hundreds of primary DLBCL tumors, including subtypes with apparent ties to DLBCL development and outcomes.
As they reported online today in Nature Medicine, the researchers did exome sequencing and array-based expression profiling on matched tumor and normal samples from more than 300 individuals with DLBCL, searching for DLBCL drivers and other informative somatic mutations, copy number changes, small insertions or deletions, and larger structural variants. Their analysis led to five main clusters of genetically heterogeneous DLBCL tumors, containing distinct potential gene targets, mutational signatures, and pathogenesis patterns.
"[W]e 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," co-senior author Margaret Shipp, a medical oncology researcher affiliated with the Dana-Farber Cancer Institute and Harvard Medical School, said in a statement.
Shipp noted that the current analysis "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."
While more than 60 percent of DLBCL patients can be successfully treated using a combination therapy known as R-CHOP, the team explained, other DLBCL patients go on to develop recurrent or progressive forms of the lymphoid disease, which represents roughly one-third of non-Hodgkin lymphoma cases.
And while prior studies have delved into DLBCL's cell of origin and several other tumor features, the authors noted that "previous genomic studies of this disease have largely focused on single types of alterations: mutations, [somatic copy number alterations], or [structural variants]."
For their new analysis, Shipp and her colleagues used Illumina GAII or HiSeq 2000 instruments to sequence protein-coding portions of the genome captured with Agilent SureSelect Human All Exon kits from tumor and matched normal samples from 304 newly diagnosed DLBCL cases.
Using new and available computational tools, the team analyzed the exomes to search for somatic mutations and mutation clustering in candidate cancer genes, along with molecular features in the DLBCL tumors that ranged from mutational signatures to indels, copy number changes, and larger chromosomal rearrangements.
By incorporating progression-free survival and overall survival data for 259 patients who were treated with the R-CHOP approach and followed for an average of about six-and-a-half years, the team detected a relatively low-risk group of marginal zone or extrafollicular B cell precursor cell-originating DLBCL tumors marked by activated B-cell (ABC) expression patterns, for example.
It also saw two prognostically different groups of germinal center B-cell (GCB) DLBCL tumors: a higher risk group containing PTEN alterations, structural variants affecting BCL2, and epigenetic enzyme mutations and a lower risk group with BCR/PI3K, JAK/STAT, BRAF, and histone alterations.
Within a group of tumors lacking both ABC and GCB features, on the other hand, the researchers identified biallelic inactivation of the tumor suppressor gene TP53 and loss of the CDKN2A gene that corresponded to genomically instable DLBCL tumors with poorer clinical outcomes.
Based on the numerous and diverse types of alterations identified across the tumor set, Shipp said, "it's unlikely that simply focusing on one genetic alteration will be enough to target therapeutically," adding, "By understanding the genetic basis of that heterogeneity, we will be able to apply more specifically targeted agents that have the highest likelihood of impacting the right pathways in the right patients."