September 2013, Vol 2, No 6

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Genomic Sequencing Uncovers the Genetic Landscape of Primary CNS Lymphoma: Will likely lead to new targeted therapies for an incurable malignancy

Dalia Buffery, MA, ABD

Uncategorized

Lugano, Switzerland – The genomic basis of primary central nervous system lymphoma (PCNSL), a very aggressive and incurable type of lymphoma, has not been understood until now. At the 2013 International Conference on Malignant Lymphoma, a team of researchers from the Mayo Clinic and from the University of Virginia presented its recent findings at a poster session involving the most comprehensive study to date of the genomic landscape of PCNSL. Esteban Braggio, PhD, of the Mayo Clinic in Scottsdale, AZ, and colleagues used a variety of tools, including array-based comprehensive genomic hybridization (aCGH), whole-exome sequencing, mate pair whole-genome sequencing, and targeted sequencing, to determine whether PCNSL and systemic diffuse large B-cell lymphoma (DLBCL) are different in their molecular makeup and pathogenesis, and whether there is a CNS-specific genetic signature in PCNSL. The team identified a total of 35 genes with aCGH in the 51 cases of PCNSL that were investigated, and additional molecular sequencing screenings were selected for targeted sequencing in other patients with PCNSL. The large majority of cases – 89% of the patients – had abnormalities of the CDKN2A gene, which can be seen as a unifying characteristic of this disease. In addition, MYD88 mutations were present in 79% of cases, a high prevalence rate. Other genes that were previously identified in DLBCL included inactivated mutations of TNFAIP3 (16%), PRDM1 (16%), GNA13, TMEM­30A, B2M, and CD58 (11% each); activated mutations of CD79B (28%) and CARD11 (19%); and translocations of BCL6 (22%) in patients with PCNSL. By contrast, the following mutations identified in this study (that had not been seen in DLBCL) indicate their unique involvement in PCNSL: 11% of PCNSL cases show biallelic inactivation of TOX and PRKCD and 17% of cases show monoallelic inactivation in these 2 genes. The investigators therefore suggest that TOX, a T-cell development regulator, has a key role in the pathogenesis of PCNSL, based on its high prevalence in abnormalities related to this gene. This study confirms that the genetic signature of PCNSL is associated with post–germinal center DLBCL and is involved in a subset of disease-specific abnormalities. It further shows a large number of genes that are involved in the immune response, lymphocyte differentiation, disease proliferation, and in apoptosis. Furthermore, this new understanding of the genetic makeup of the disease opens the door to the development of new targeted therapies for this type of cancer and potentially improved outcomes.

Reference
Braggio E, O’Neill B, VanWier S, et al. The genomic landscape of primary central nervous system lymphoma (PCNSL). Presented at: 12th International Conference on Malignant Lymphoma; June 19-22, 2013; Lugano, Switzerland. Abstract 168.

Uncategorized - September 23, 2013

Pathways Creating More and More Value

Hollywood, FL – Pathways continue to be refined toward value-based care, adapting to the challenges of a rapidly shifting oncology landscape, as 2 speakers at the Third Annual Conference of the Association for Value-Based Cancer Care described. Michael A. Kolodziej, MD, National Medical Director for Oncology Strategies at Aetna, Hartford, [ Read More ]

Uncategorized - September 23, 2013

Bevacizumab Maintenance Improves Survival in mCRC, but Added Erlotinib Is of No Value

Bevacizumab maintenance therapy following induction with bevacizumab-based chemotherapy significantly increases progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC). However, the addition of erlotinib in the maintenance phase does not increase overall survival (OS) compared with bevacizumab alone. KRAS status was not a predictor of benefit from erlotinib in [ Read More ]