Diffuse large B cell lymphoma future or investigational therapies
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]
Overview
A phase III trial, CALGB 50303, is now comparing R-EPOCH with R-CHOP in patients with newly diagnosed diffuse large B cell lymphoma. One area of active research is on separating patients into groups based on their prognosis and how likely they are to benefit from different drugs. James Cerhan and colleagues,[1] tried to determine genetic susceptibility to diffuse large B cell lymphoma by meta-analysis of three genome-wide association studies (GWAS). As a result of this study, five SNPs were obtained in four loci significantly associated with the disease, which may be related to the following genes: EXOC2, PVT1, NCOA1 and HLA-B.
Research
A second regimen under evaluation is R-EPOCH (rituximab with etoposide-prednisone-vincristine-doxorubicin-cyclophosphamide), which demonstrated a 5-year progression-free survival (PFS) of 79% in a phase II trial. A phase III trial, CALGB 50303, is now comparing R-EPOCH with R-CHOP in patients with newly diagnosed diffuse large B cell lymphoma.[2]
One area of active research is on separating patients into groups based on their prognosis and how likely they are to benefit from different drugs. Methods like gene expression profiling and next-generation sequencing may result in more effective and more personalized treatment.[3][4]
Recent studies
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James Cerhan and colleagues,[1] try to determine genetic susceptibility that exists for this cancer by meta-analysis of three genome-wide association studies (GWAS). For this, a total of 3,857 cases and 7,666 controls were analyzed. This study is divided into three stages, which can differentiate into two phases:[1]
– Discovery Phase: Stages 1 and 2.
– Phase replication: Stage 3.
Stage 1
At this early stage, to study the genetic susceptibility, a GWAS with DLBCL cases and controls of European ancestry from 22 studies of non-Hodgkin lymphoma (NHL) was performed. To determine the subtype of NHL, hierarchical classification proposed by the World Health Organization (WHO) was used. All cases of DLBCL with enough DNA and a subset of controls, matched for age and sex, along with 4% duplicates were genotyped. They were selected in this stage 611.844 SNPs that exceeded the quality criteria, genomic significance values, alignment and other statistical values.
Stage 2
At this stage the data of three independent previous GWAS, including two unpublished so far (GELA / EPIC and May) and one already published (USCF), with a total of 1,196 cases and 1,445 controls. The analysis was restricted to common SNPs on the basis of the 1000 Genomes Project version 3 because the data used were from different platforms. The criteria of quality control for these studies were adjusted to analyze all cases under the same conditions. In the meta-analysis of all SNPs of steps 1 and 2, 19 significant SNPs were identified, and 134 with a suggestive level of significance; 123 of the total were located in the HLA region on chromosome 6.
Stage 3
In the last stage, replication studies and technical validation were performed. The genotyping of 8 SNPs de novo was performed in the most significant HLA loci outside the region and one within it.
Results
As a result of this study, five SNPs were obtained in four loci significantly associated with the disease, which may be related to the following genes: EXOC2, PVT1, NCOA1 and HLA-B.
– EXOC2: This gene is near to the locus rs116446171 located in the region 6p25.3, in the same haplotype. This gene encodes a protein that forms part of a large multiprotein complex responsible for vesicle trafficking and the maintenance. This protein plays an important role in the maintenance of epithelial cell polarity, cell motility, cytokinesis, proliferation and metastasis, which plays a crucial role in carcinogenic processes.
– PVT1: This study has linked two variants for 8q24.21 locus (rs13255292 and rs4736601). This region gives rise to an antisense RNA, involved in the activation of MYC. The proximity of PVT1 and MYC oncogene, which is known to be deregulated in some DLBCLs suggests that germline variation in this region may also contribute to the risk of developing the disease.
– NCOA1: The SNP rs79480871 located in 2p13.3 as susceptibility locus was identified near NCOA1. It is a coactivator for steroid hormones, and the synthesized protein is involved in clathrin-mediated endocytosis. But the connection between the SNP and NCOA1 gene was not clear, because this polymorphism doesn't belong to the same haplotype, so a further study of this region is required.
– HLA-B: The strongest association in the HLA region was with HLA-B, the SNP rs2523607 and allele HLA-B08: 01, with a very high value linkage. HLA-B encodes a heavy chain of HLA class I, that heterodimerizes with a light chain. The HLA class I has a central role in the presentation of self or foreign antigens, processed intracellularly, to cytotoxic T lymphocytes. HLA molecules of class I have been associated with many diseases and cancers of the immune system. The results suggest a possible association of other loci within the HLA region with this disease, but further study is needed to evaluate this possibility.
References
- ↑ 1.0 1.1 1.2 Cerhan, James R; Berndt, Sonja I; Vijai, Joseph; Ghesquières, Hervé; McKay, James; Wang, Sophia S; Wang, Zhaoming; Yeager, Meredith; Conde, Lucia; De Bakker, Paul I W; Nieters, Alexandra; Cox, David; Burdett, Laurie; Monnereau, Alain; Flowers, Christopher R; De Roos, Anneclaire J; Brooks-Wilson, Angela R; Lan, Qing; Severi, Gianluca; Melbye, Mads; Gu, Jian; Jackson, Rebecca D; Kane, Eleanor; Teras, Lauren R; Purdue, Mark P; Vajdic, Claire M; Spinelli, John J; Giles, Graham G; Albanes, Demetrius; et al. (2014). "Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma". Nature Genetics. 46 (11): 1233–8. doi:10.1038/ng.3105. PMC 4213349. PMID 25261932.
- ↑ http://www.onclive.com/publications/oncology-live/2012/april-2012/Beyond-R-CHOP-21-Whats-New-in-Diffuse-Large-B-Cell-Lymphoma[full citation needed]
- ↑ Sehn, L. H. (2012). "Paramount prognostic factors that guide therapeutic strategies in diffuse large B-cell lymphoma". Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program. 2012: 402–9. doi:10.1182/asheducation-2012.1.402. PMID 23233611. Unknown parameter
|doi_brokendate=ignored (help) - ↑ Barton, S.; Hawkes, E. A.; Wotherspoon, A.; Cunningham, D. (2012). "Are We Ready to Stratify Treatment for Diffuse Large B-Cell Lymphoma Using Molecular Hallmarks?". The Oncologist. 17 (12): 1562–73. doi:10.1634/theoncologist.2012-0218. PMC 3528389. PMID 23086691.