Genomic pattern of intratumor heterogeneity predicts the risk of progression in early stage diffuse large B-cell lymphoma.

Abstract

Intratumor heterogeneity (ITH) plays an important role in tumor development, metastases, recurrence and has impact on clinical diagnosis, therapeutic responses. In this study, we used mutant-allele tumor heterogeneity (MATH) through whole-exome sequencing data to evaluate ITH in early stage diffuse large B-cell lymphoma (DLBCL). A discovery set of 22 patients and a validation set of 35 patients with primary DLBCL which staged I or II were chosen from The Cancer Genome Atlas database and The Gene Index Project database, respectively. Then patients were divided into low and high MATH score groups according to the median expression level. As a result, higher MATH score displayed an increasing risk of progression compared with lower MATH score both in the discovery set (P = 0.045) and the validation set (P = 0.025). Further, the genomic pattern according to MATH demonstrated that mutation rates of immunoglobulin lambda locus, B-cell translocation gene and membrane-associated guanylate kinase were the sites with the highest mutation rate. Moreover, Gene enrichment analysis showed that immunoglobulin lambda constant 2 (IGLC2) which belongs to immunoglobulin lambda locus was only enriched in high MATH group. Besides, BTG2 and Caspase recruitment domain-containing protein 11 were cancer driver genes which listed on the top three high rate of mutation. Our study revealed the prognostic value of MATH and relevant genomic pattern in early stage DLBCL. Potential mechanisms on genetic level of how genomic aberration influence the ITH of DLBCL are provided. MATH based on whole genome sequencing may be feasible for deciding clinical treatment of DLBCL patients in the future researches.