TY - JOUR
T1 - CREBBP and STAT6 co-mutation and 16p13 and 1p36 loss define the t(14;18)-negative diffuse variant of follicular lymphoma
AU - Xian, Rena R.
AU - Xie, Yi
AU - Haley, Lisa M.
AU - Yonescu, Raluca
AU - Pallavajjala, Aparna
AU - Pittaluga, Stefania
AU - Jaffe, Elaine S.
AU - Duffield, Amy S.
AU - McCall, Chad M.
AU - Gheith, Shereen M.F.
AU - Gocke, Christopher D.
N1 - Funding Information:
We would like to thank the patients, and submitting pathologists and clinicians who provided supporting case data and patient samples for the study. This work was supported in part by the Sidney Kimmel Comprehensive Cancer Center Grant from the National Institutes of Health (P30 CA006973; R.R.X., A.S. D., C.D.G.) and by the intramural research program of the Center for Cancer Research, National Cancer Institute (Y.X., S.P., E.S.J.). We would also like to thank the University of California, Los Angeles, Clinical Cytogenetics Laboratory, and Dr. Nagesh Rao for providing usage of the Nexus Copy Number chromosomal analysis software.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/6/1
Y1 - 2020/6/1
N2 - The diffuse variant of follicular lymphoma (dFL) is a rare variant of FL lacking t(14;18) that was first described in 2009. In this study, we use a comprehensive approach to define unifying pathologic and genetic features through gold-standard pathologic review, FISH, SNP-microarray, and next-generation sequencing of 16 cases of dFL. We found unique morphologic features, including interstitial sclerosis, microfollicle formation, and rounded nuclear cytology, confirmed absence of t(14;18) and recurrent deletion of 1p36, and showed a novel association with deletion/CN-LOH of 16p13 (inclusive of CREBBP, CIITA, and SOCS1). Mutational profiling demonstrated near-uniform mutations in CREBBP and STAT6, with clonal dominance of CREBBP, among other mutations typical of germinal-center B-cell lymphomas. Frequent CREBBP and CIITA codeletion/mutation suggested a mechanism for immune evasion, while subclonal STAT6 activating mutations with concurrent SOCS1 loss suggested a mechanism of BCL-xL/BCL2L1 upregulation in the absence of BCL2 rearrangements. A review of the literature showed significant enrichment for 16p13 and 1p36 loss/CN-LOH, STAT6 mutation, and CREBBP and STAT6 comutation in dFL, as compared with conventional FL. With this comprehensive approach, our study demonstrates confirmatory and novel genetic associations that can aid in the diagnosis and subclassification of this rare type of lymphoma.
AB - The diffuse variant of follicular lymphoma (dFL) is a rare variant of FL lacking t(14;18) that was first described in 2009. In this study, we use a comprehensive approach to define unifying pathologic and genetic features through gold-standard pathologic review, FISH, SNP-microarray, and next-generation sequencing of 16 cases of dFL. We found unique morphologic features, including interstitial sclerosis, microfollicle formation, and rounded nuclear cytology, confirmed absence of t(14;18) and recurrent deletion of 1p36, and showed a novel association with deletion/CN-LOH of 16p13 (inclusive of CREBBP, CIITA, and SOCS1). Mutational profiling demonstrated near-uniform mutations in CREBBP and STAT6, with clonal dominance of CREBBP, among other mutations typical of germinal-center B-cell lymphomas. Frequent CREBBP and CIITA codeletion/mutation suggested a mechanism for immune evasion, while subclonal STAT6 activating mutations with concurrent SOCS1 loss suggested a mechanism of BCL-xL/BCL2L1 upregulation in the absence of BCL2 rearrangements. A review of the literature showed significant enrichment for 16p13 and 1p36 loss/CN-LOH, STAT6 mutation, and CREBBP and STAT6 comutation in dFL, as compared with conventional FL. With this comprehensive approach, our study demonstrates confirmatory and novel genetic associations that can aid in the diagnosis and subclassification of this rare type of lymphoma.
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U2 - 10.1038/s41408-020-0335-0
DO - 10.1038/s41408-020-0335-0
M3 - Article
C2 - 32555149
AN - SCOPUS:85086565418
SN - 2044-5385
VL - 10
JO - Blood cancer journal
JF - Blood cancer journal
IS - 6
M1 - 69
ER -