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M.C.J. Ma et al.
mutation in FL, TCF4 copy gain and MYD88 mutation in DLBCL, and ATM mutation and RPL5 deletion in MCL, should therefore be performed to further explore these con- cepts and define their underlying functional relationship. We suggest that combinations of genetic alterations are likely to recapitulate the biology of B-NHL more accurately than are single gene models, and may reveal contextually different functional roles of genetic alterations depending on the co-occurring events.
The caveats regarding this study include the targeted nature of the LymphoSeq platform which may preclude consideration of a subset of important genes, the lack of germline DNA for the majority of samples that may lead to a small number of germ-line variants being falsely assigned as somatic, and the sample size for any given histological subtype being below that required to identify genes that are mutated at low frequency. Nonetheless, these data repre- sent the first broad cross-sectional analysis of multiple his- tological and molecular subtypes of B-NHL using the same methodology and provide a framework of functional hall- marks and co-occurring genetic alterations that are enriched within these subtypes of B-NHL. These functional hall- marks are genetically perturbed in the majority of B-NHL, but our cross-sectional approach enabled us to elucidate subtype-specific preferences for genetic alterations within each functional hallmark. Furthermore, the subtype-spe- cific clusters of co-occurring genetic alterations likely rep- resent cooperative interactions that underpin the biology of different subtypes of B-NHL. These combinations iden- tify opportunities for moving from single-allele to multi- allele designs in cell line or animal models to better under- stand the molecular etiology of B-NHL subtypes. Together,
these hallmarks and clusters of co-associated genetic alter- ations represent processes that are potentially druggable with targeted therapies,63-66 but that are likely influenced in a non-binary fashion by different combinations of genetic alterations. Deciphering the relationships between complex sets of genetic alterations and targetable dependencies will be a next step towards developing new rationally targeted therapeutic strategies in B-NHL.
Disclosures
No conflicts of interest to disclose.
Contributions
MCJM and ST performed experiments, analyzed data and wrote the manuscript. AB analyzed data. TH, HY, QD, DM, KH, NJ, JS, and SG performed experiments. AA, LS, MD, CC, JT, DP, KMV, MAL, ARS, BJC, RB, SN, LN, RED, JW, SP, MG, DS, KB, JI, SR, and AM provided samples and/or clinical data. MRG conceived and supervised the study, per- formed experiments, analyzed the data and wrote the manu- script. All authors reviewed and approved the manuscript.
Funding
This research was supported by NCI R01CA201380 (MRG), the Nebraska Department of Health and Human Services (LB506 2016-17; MRG), and NCI cancer center sup- port grants to the University of Texas MD Anderson Cancer Center (P30 CA016672) and the Fred & Pamela Buffet Cancer Center (P30 CA036727). HY is supported by a Fellow award from the Leukemia and Lymphoma Society. MRG is supported by a Scholar award from the Leukemia and Lymphoma Society and an Andrew Sabin Family Foundation Fellow award.
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