PMID- 29327716 OWN - NLM STAT- MEDLINE DCOM- 20190415 LR - 20230210 IS - 1530-0285 (Electronic) IS - 0893-3952 (Linking) VI - 31 IP - 5 DP - 2018 May TI - Genomic heterogeneity of ALK fusion breakpoints in non-small-cell lung cancer. PG - 791-808 LID - 10.1038/modpathol.2017.181 [doi] AB - In lung adenocarcinoma, canonical EML4-ALK inversion results in a fusion protein with a constitutively active ALK kinase domain. Evidence of ALK rearrangement occurs in a minority (2-7%) of lung adenocarcinoma, and only ~60% of these patients will respond to targeted ALK inhibition by drugs such as crizotinib and ceritinib. Clinically, targeted anti-ALK therapy is often initiated based on evidence of an ALK genomic rearrangement detected by fluorescence in situ hybridization (FISH) of interphase cells in formalin-fixed, paraffin-embedded tissue sections. At the genomic level, however, ALK rearrangements are heterogeneous, with multiple potential breakpoints in EML4, and alternate fusion partners. Using next-generation sequencing of DNA and RNA together with ALK immunohistochemistry, we comprehensively characterized genomic breakpoints in 33 FISH-positive lung adenocarcinomas. Of these 33 cases, 29 (88%) had detectable DNA level ALK rearrangements involving EML4, KIF5B, or non-canonical partners including ASXL2, ATP6V1B1, PRKAR1A, and SPDYA. A subset of 12 cases had material available for RNA-Seq. Of these, eight of eight (100%) cases with DNA rearrangements showed ALK fusion transcripts from RNA-Seq; three of four cases (75%) without detectable DNA rearrangements were similarly negative by RNA-Seq, and one case was positive by RNA-Seq but negative by DNA next-generation sequencing. By immunohistochemistry, 17 of 19 (89%) tested cases were clearly positive for ALK protein expression; the remaining cases had no detectable DNA level rearrangement or had a non-canonical rearrangement not predicted to form a fusion protein. Survival analysis of patients treated with targeted ALK inhibitors demonstrates a significant difference in mean survival between patients with next-generation sequencing confirmed EML4-ALK rearrangements, and those without (20.6 months vs 5.4 months, P<0.01). Together, these data demonstrate abundant genomic heterogeneity among ALK-rearranged lung adenocarcinoma, which may account for differences in treatment response with targeted ALK inhibitors. FAU - Rosenbaum, Jason N AU - Rosenbaum JN AUID- ORCID: 0000-0002-7969-7423 AD - Department of Pathology and Laboratory Medicine, University of Pennsylvania, The University of Pennsylvania Center for Personalized Diagnostics, Philadelphia, PA, USA. FAU - Bloom, Ryan AU - Bloom R AD - Unum Therapeutics, Cambridge, MA, USA. FAU - Forys, Jason T AU - Forys JT AD - Cofactor Genomics, St Louis, MO, USA. FAU - Hiken, Jeff AU - Hiken J AD - Cofactor Genomics, St Louis, MO, USA. FAU - Armstrong, Jon R AU - Armstrong JR AD - Cofactor Genomics, St Louis, MO, USA. FAU - Branson, Julie AU - Branson J AD - Department of Pathology and Immunology, Division of Anatomic and Molecular Pathology, Washington University School of Medicine, St Louis, MO, USA. FAU - McNulty, Samantha AU - McNulty S AD - Department of Pathology and Immunology, Division of Anatomic and Molecular Pathology, Washington University School of Medicine, St Louis, MO, USA. FAU - Velu, Priya D AU - Velu PD AD - Department of Pathology and Laboratory Medicine, University of Pennsylvania, The University of Pennsylvania Center for Personalized Diagnostics, Philadelphia, PA, USA. FAU - Pepin, Kymberlie AU - Pepin K AD - Department of Internal Medicine, Division of Medical Oncology, Washington University School of Medicine, St Louis, MO, USA. FAU - Abel, Haley AU - Abel H AD - McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA. FAU - Cottrell, Catherine E AU - Cottrell CE AD - Nationwide Children's Hospital, Institute for Genomic Medicine, Columbus, OH, USA. FAU - Pfeifer, John D AU - Pfeifer JD AD - Department of Pathology and Immunology, Division of Anatomic and Molecular Pathology, Washington University School of Medicine, St Louis, MO, USA. FAU - Kulkarni, Shashikant AU - Kulkarni S AD - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. FAU - Govindan, Ramaswamy AU - Govindan R AD - Department of Internal Medicine, Division of Medical Oncology, Washington University School of Medicine, St Louis, MO, USA. FAU - Konnick, Eric Q AU - Konnick EQ AD - Department of Laboratory Medicine, University of Washington, Seattle, WA, USA. FAU - Lockwood, Christina M AU - Lockwood CM AD - Department of Laboratory Medicine, University of Washington, Seattle, WA, USA. FAU - Duncavage, Eric J AU - Duncavage EJ AD - Department of Pathology and Immunology, Division of Anatomic and Molecular Pathology, Washington University School of Medicine, St Louis, MO, USA. LA - eng PT - Journal Article DEP - 20180112 PL - United States TA - Mod Pathol JT - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc JID - 8806605 RN - 0 (EML4-ALK fusion protein, human) RN - 0 (Oncogene Proteins, Fusion) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrimidines) RN - 0 (Sulfones) RN - 53AH36668S (Crizotinib) RN - EC 2.7.10.1 (ALK protein, human) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) RN - K418KG2GET (ceritinib) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Anaplastic Lymphoma Kinase/antagonists & inhibitors/biosynthesis/*genetics MH - Carcinoma, Non-Small-Cell Lung/enzymology/*genetics/pathology MH - *Chromosome Breakpoints MH - Crizotinib/therapeutic use MH - Female MH - Gene Rearrangement MH - High-Throughput Nucleotide Sequencing MH - Humans MH - In Situ Hybridization, Fluorescence MH - Lung Neoplasms/enzymology/*genetics/pathology MH - Male MH - Middle Aged MH - Molecular Targeted Therapy MH - Oncogene Proteins, Fusion/genetics MH - Protein Kinase Inhibitors/therapeutic use MH - Pyrimidines/therapeutic use MH - Sulfones/therapeutic use MH - Survival Analysis EDAT- 2018/01/13 06:00 MHDA- 2019/04/16 06:00 CRDT- 2018/01/13 06:00 PHST- 2017/06/12 00:00 [received] PHST- 2017/10/24 00:00 [revised] PHST- 2017/10/26 00:00 [accepted] PHST- 2018/01/13 06:00 [pubmed] PHST- 2019/04/16 06:00 [medline] PHST- 2018/01/13 06:00 [entrez] AID - S0893-3952(22)01512-5 [pii] AID - 10.1038/modpathol.2017.181 [doi] PST - ppublish SO - Mod Pathol. 2018 May;31(5):791-808. doi: 10.1038/modpathol.2017.181. Epub 2018 Jan 12.