LAUSR

T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive lymphoid neoplasm occurring predominantly in children and young adults. T-LBL is characterized by a proliferation of T lymphoblasts arrested at an early stage of maturation and accounts for less than 2% of all the non-Hodgkin lymphomas. Currently, the molecular pathogenetic mechanisms of T-LBL are largely unknown. Previous studies have identified recurring genetic alterations in NOTCH, PI3K/AKT and RAS signaling pathways in T-LBL patients; however, the genome-wide mutational landscape of T-LBL patients remains elusive. To address this question, we performed whole-exome sequencing in a cohort of 96 patients with T-LBL in the present study. All patients (nine pediatric and 87 adult T-LBL patients) were reviewed and interpreted independently by three experienced pathologists. Diagnoses were made according to the current World Health Organization classification criteria. The clinical characteristics of the patient cohort are summarized in the Online Supplementary Table S1, and the experimental design is depicted in the Online Supplementary Figure S1. The study was conducted in accordance with the Declaration of Helsinki and with the approval of the Institutional Review Board of the First Affiliated Hospital of Zhengzhou University. Wholeexome sequencing was performed using DNA extracted from 96 T-LBL patient tumor samples and 41 paired normal tissue samples. Detailed descriptions of wholeexome sequencing and bioinformatics analysis are provided in the Online Supplementary Materials and Methods. The 41 patients with paired normal tissue were deemed a “discovery cohort,” and the remaining patients were considered a “validation cohort.” In the discovery cohort, the mean sequencing depth was 217×, and a mean of 96.6% of the target sequence was covered to a depth of at least 50× after excluding the duplicates (Online Supplementary Table S2). A total of 1,599 nonsilent mutations (median 33, range 4-124) were identified (Online Supplementary Figure S2A and Table S3). We further evaluated the relationship between the somatic nonsilent mutation burden and the clinical features of T-LBL patients. The results showed that the somatic nonsilent mutation burden was associated with age (R=0.16, P=0.010; Online Supplementary Figure S2B) but not with other clinical features of these patients (sex, stage, or LDH). The predominant type of substitution was the C to T transition at NpCpG sites in T-LBL (Online Supplementary Figure S3A). Combined nonnegative matrix factorization clustering and correlation with the 30 curated mutational signatures defined by the Catalog of