Circulating Tumor DNA Analysis in Lymphomas

In recent years, sequencing of circulating tumor DNA(ctDNA)in peripheral blood has emerged as a promising non-invasive approach for diagnosis, genotyping, risk stratification, response monitoring, and the detection of actionable mutations in malignant lymphomas. Current available technologies for ctDNA detection are polymerase chain reaction-based methods and next generation sequencing techniques. They target single nucleotide variants, structural variants, copy number alterations, and immunoglobulin heavy chain gene/T-cell receptor gene rearrangement, which are specific to lymphomas. Non- invasive detection of ctDNA cannot replace conventional tumor tissue biopsies for initial diagnosis of lymphomas because histological architecture is important. However, it may be an effective tool in certain extranodal lymphomas, such as intravascular large B-cell lymphoma(IVLBCL)and primary diffuse large B-cell lymphoma of the nervous system lymphoma(PCNSL). Tumor cells proliferate in lumina of small vessels, and usually do not form obvious mass to biopsy in IVLBCL. Both lymphomas share genetic mutations including MYD88 L265P, CD79B, and genetic aberrations favoring immune escape. Therefore detection of these mutations via ctDNA analysis could be helpful for prompt diagnosis of IVLBCL and PCNSL. In addition to the fact that ctDNA contains spatial tumor heterogeneity, which may allow for more accurate assessment of prognostic factors and tracking of treatment-resistant subclones, liquid biopsy can be considered a timely snapshot of the disease burden because it can be performed continuously. Since the genomic abnormalities frequently observed in hematologic malignancies are different from those in solid tumors, it is necessary to develop a unique gene panel test. In Japan, preparations are underway to establish a system for genomic and precision medicine for hematologic malignancies.