| Autor: |
Rosenbaum, Jason N, Bloom, Ryan, Forys, Jason T, Hiken, Jeff, Armstrong, Jon R, Branson, Julie, McNulty, Samantha, Velu, Priya D, Pepin, Kymberlie, Abel, Haley, Cottrell, Catherine E, Pfeifer, John D, Kulkarni, Shashikant, Govindan, Ramaswamy, Konnick, Eric Q, Lockwood, Christina M, Duncavage, Eric J |
| Zdroj: |
Modern Pathology; May 2018, Vol. 31 Issue: 5 p791-808, 18p |
| Abstrakt: |
In lung adenocarcinoma, canonical EML4-ALKinversion results in a fusion protein with a constitutively active ALK kinase domain. Evidence of ALKrearrangement 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 ALKgenomic rearrangement detected by fluorescence in situhybridization (FISH) of interphase cells in formalin-fixed, paraffin-embedded tissue sections. At the genomic level, however, ALKrearrangements 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-ALKrearrangements, and those without (20.6 months vs5.4 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. |
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