Genomic Alterations of Histone Modification Genes Are Significantly Less Common in Non-Hodgkin Lymphomas of Adolescents and Young Adults Compared to Older Patients

Background: Non-Hodgkin lymphoma (NHL) is a large group of hematolymphoid malignant neoplasms that can occur at any age. Genomic alterations of histone modifying genes and the NF-kB signaling pathway are characteristic of NHLs. Histone deacetylase and methyltransferase inhibitors including the EZH2 inhibitors E7438, GSK126 and El1 have shown anti-tumor activity in NHLs (PMID: 24217204). Cancers arising in adolescent and young adults (age 15-39, AYA) often exhibit different clinical and biological features than older adults. However, there is very limited information on age-related genomic profiles of NHLs to facilitate clinical investigation of targeted therapies in the AYA population.

Methods: Nucleic acid was extracted from 149 cases of NHLs including diffuse large B-cell lymphoma (DLBCL, 45%), chronic lymphocytic leukemia (CLL, 18%), follicular lymphoma (FL, 9%), mantle cell lymphoma (MCL, 7%), NK/T-cell lymphoma (NKTCL, 5%), anaplastic large cell lymphoma (ALCL, 3%), cutaneous T-cell lymphoma (CTCL, 3%), B-cell lymphoma (3%), Burkitt lymphoma (BL, 2%), T-cell large granular lymphocytic leukemia (T-LGL, 2%) and lymphoblastic lymphoma as well as not otherwise specified NHL (3% in total), and captured using custom baits targeting all exons up to 405 cancer-related genes and 265 frequently rearranged genes (FoundationOne Heme^TM). All captured libraries were sequenced to high uniform depth in a CLIA-certified, CAP-accredited laboratory with an average depth of >500x for DNA and >6M unique pairs for RNA. There were 29 AYA and 120 older adult (>39 years) NHL cases in this study. DLBCL was the most common diagnosis across groups in 34% of AYAs and 47% of older adults, respectively.

Results: The most frequent genomic alterations (GAs) in AYAs were IGH rearrangement (31%), TP53 (28%), MYC (21%), CIITA (16%), DDX3X (16%), ALK (14%), CDKN2A (10%), and TNFAIP3 (10%). Older adults often harbored IGH rearrangements (33%), TP53 (26%), CDKN2A (24%), MLL2 (21%), CREBBP (15%), TNFAIP3 (14%), and MYD88(13%) alterations.

Only 1 MLL2 mutation was identified in our AYA samples (3%). In contrast, MLL2 mutations were found in 25/120 (21%) of adult NHLs, including 30% of DLBCLs and 58% of FLs (two tailed Fisher's exact test p-value=0.03). Ninety-seven percent of the MLL2 mutations were reading frame disruptions or truncations, supporting the concept of MLL2 functioning as a tumor suppressor in NHLs. Patients whose tumors harbored mutant MLL2 frequently contained 2 mutations simultaneously (35%). No additional alteration of histone modification genes was found in AYAs. But 39% of adult NHLs carried alterations of those genes (ASXL1, CREBBP, EP300, EZH2, KDM5A, MLL2, MLL3, SETD2, and WHSC1) across different subtypes, including 92% of FL cases, 46% of DLBCLs, 50% of ALCLs, 33% of CTCLs, 33% of NKTCLs, 27% of MCLs, and 12% of CLLs. The difference in the alteration frequency of histone modification genes between AYA (1/29) and older adult (47/120) is significant (p=0.0001). This observation was also seen when excluding the FL cases (1/27 versus 36/108, p=0.001).

Conclusions: The unique genomic features of AYA NHLs and guarded clinical outcome strongly favor that AYA NHLs exhibit distinct molecular characteristics compared with older adults. Using comprehensive genomic sequencing (FoundationOne Heme), we discovered that the alterations of histone modifying genes are extremely rare in our AYA samples. Further study of the unique genomic profile of AYA NHLs to expand our knowledge of their biology and discover potential new therapeutic targets for AYA patients appears warranted.