PMID- 30348671 OWN - NLM STAT- MEDLINE DCOM- 20190904 LR - 20190904 IS - 2473-9537 (Electronic) IS - 2473-9529 (Print) IS - 2473-9529 (Linking) VI - 2 IP - 20 DP - 2018 Oct 23 TI - High-resolution architecture and partner genes of MYC rearrangements in lymphoma with DLBCL morphology. PG - 2755-2765 LID - 10.1182/bloodadvances.2018023572 [doi] AB - Genomic rearrangements in the MYC locus occur in approximately 12% of lymphomas with diffuse large B-cell lymphoma (DLBCL) morphology and are associated with inferior outcome. Previous studies exploring MYC rearrangements have primarily used fluorescence in situ hybridization (FISH) assays to characterize break-apart status but have rarely examined breakpoint location, and in some cases have not examined partner identity. We performed targeted sequencing of MYC, BCL2, BCL6, and the immunoglobulin (IG) loci in 112 tumors with DLBCL morphology harboring MYC rearrangement. We characterized the location of the MYC rearrangement at base pair resolution and identified the partner in 88 cases. We observed a cluster of breakpoints upstream of the MYC coding region and in intron 1 (the "genic cluster"). Genic cluster rearrangements were enriched for translocations involving IGH (80%), whereas nongenic rearrangements occurred mostly downstream of the MYC gene with a variety of partners, including IGL and IGK Other recurrent partners included BCL6, ZCCHC7, and RFTN1, which has not previously been described as a MYC partner. We compared 2 commercially available FISH break-apart assays for the MYC locus and observed discordant results in 32% of cases examined, including some with MYC-IGL and MYC-IGK rearrangements. In cases of high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement (HGBL-DH), so-called "double-hit" lymphomas, the majority of MYC rearrangements had non-IG partners (65%), with breakpoints outside the genic cluster (72%). In patients with de novo HGBL-DH of DLBCL morphology, MYC-IG rearrangements showed a trend toward inferior time to progression and overall survival compared with MYC-non-IG rearrangements. Our data reveal clinically relevant architecture of MYC rearrangements in lymphomas with DLBCL morphology. CI - (c) 2018 by The American Society of Hematology. FAU - Chong, Lauren C AU - Chong LC AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Ben-Neriah, Susana AU - Ben-Neriah S AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Slack, Graham W AU - Slack GW AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Freeman, Ciara AU - Freeman C AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Ennishi, Daisuke AU - Ennishi D AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Mottok, Anja AU - Mottok A AD - Institute of Human Genetics, University of Ulm and Ulm University Medical Center, Ulm, Germany. FAU - Collinge, Brett AU - Collinge B AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Abrisqueta, Pau AU - Abrisqueta P AD - Department of Hematology, Vall d'Hebron Institute of Oncology (VHIO), University Hospital Vall d'Hebron, Barcelona, Spain. FAU - Farinha, Pedro AU - Farinha P AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Boyle, Merrill AU - Boyle M AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Meissner, Barbara AU - Meissner B AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Kridel, Robert AU - Kridel R AD - Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada. FAU - Gerrie, Alina S AU - Gerrie AS AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Villa, Diego AU - Villa D AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Savage, Kerry J AU - Savage KJ AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Sehn, Laurie H AU - Sehn LH AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Siebert, Reiner AU - Siebert R AD - Institute of Human Genetics, University of Ulm and Ulm University Medical Center, Ulm, Germany. FAU - Morin, Ryan D AU - Morin RD AD - Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada; and. AD - Canada's Michael Smith Genome Sciences Centre, Vancouver, BC, Canada. FAU - Gascoyne, Randy D AU - Gascoyne RD AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Marra, Marco A AU - Marra MA AD - Canada's Michael Smith Genome Sciences Centre, Vancouver, BC, Canada. FAU - Connors, Joseph M AU - Connors JM AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Mungall, Andrew J AU - Mungall AJ AD - Canada's Michael Smith Genome Sciences Centre, Vancouver, BC, Canada. FAU - Steidl, Christian AU - Steidl C AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. FAU - Scott, David W AU - Scott DW AD - Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada. LA - eng GR - GPH-129347/CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood Adv JT - Blood advances JID - 101698425 RN - 0 (Proto-Oncogene Proteins c-myc) SB - IM MH - Aged MH - Female MH - Gene Rearrangement/*genetics MH - Humans MH - Lymphoma, Large B-Cell, Diffuse/*genetics/pathology MH - Male MH - Middle Aged MH - Proto-Oncogene Proteins c-myc/*genetics PMC - PMC6199666 COIS- Conflict-of-interest disclosure: C.F. receives research funding from Roche/Genentech and honoraria from AbbVie, Seattle Genetics, and Roche/Genentech. The remaining authors declare no competing financial interests. EDAT- 2018/10/24 06:00 MHDA- 2019/09/05 06:00 PMCR- 2018/10/22 CRDT- 2018/10/24 06:00 PHST- 2018/07/12 00:00 [received] PHST- 2018/09/24 00:00 [accepted] PHST- 2018/10/24 06:00 [entrez] PHST- 2018/10/24 06:00 [pubmed] PHST- 2019/09/05 06:00 [medline] PHST- 2018/10/22 00:00 [pmc-release] AID - bloodadvances.2018023572 [pii] AID - 2018/023572 [pii] AID - 10.1182/bloodadvances.2018023572 [doi] PST - ppublish SO - Blood Adv. 2018 Oct 23;2(20):2755-2765. doi: 10.1182/bloodadvances.2018023572.