Concomitance of a novel RMDN2-ALK fusion and an EML4-ALK fusion in a lung adenocarcinoma

Here, we present a lung adenocarcinoma with two ALK fusions, a novel RMDN2-ALK fusion accompanied by an EML4-ALK fusion, detected by a targeted next generation sequencing assay. The genomic translocation breakpoints of the RMDN2-ALK fusion were mapped to intron 2 for RMDN2 and exon 15 for ALK, and EML4-ALK breakpoints were mapped to intron 13 for EML4 and intron 19 for ALK. ALK break-apart FISH detected multiple ALK rearrangements, a gene fusion panel (NanoString) test confirmed the EML4-ALK fusion, and RNA-sequencing revealed two ALK fusions. The RMDN2 gene locates at the short arm of chromosome 2 between ALK and EML4 genes. The intact ALK kinase domain fused to RMDN2. Genome-wide copy number variants were found in multiple chromosome arms and the short arm of chromosome 2, suggestive of complex rearrangements. Further detailed analyses of breakpoints and copy number variants may shed light on mechanisms of their formation and pathogenesis in lung malignancies. READ ARTICLE

Cancer Genetics DOI: 10.1016/j.cancergen.2021.06.004

Authors: Liqun Jiang, Suping Chen, Victoria Stinnett, Lisa Haley, Laura Morsberger, Alison Shane, Melanie Hardy, Kirstin Smith, Christopher D. Gocke, Ming-Tseh Lin and Ying S. Zou,

Phase separation of EML4–ALK in firing downstream signaling and promoting lung tumorigenesis

Using two genetically engineered mouse models (GEMMs), we find that EML4–ALK variant 1 can drive lung tumorigenesis and these murine tumors, as well as primary tumor-derived organoids, clearly show the condensates of EML4–ALK protein, further supporting the findings from in vitro study. Mutation of multiple aromatic residues in EML4 region significantly impairs the phase separation of EML4–ALK and dampens the activation of the downstream signaling pathways, especially the STAT3 phosphorylation. Importantly, it also significantly decreases cancer malignant transformation and tumor formation. These data together highlight an important role of phase separation in orchestrating EML4–ALK signaling and promoting tumorigenesis, which might provide new clues for the development of clinical therapeutic strategies in treating lung cancer patients with the EML4–ALK fusion. READ ARTICLE

Cell Discovery DOI: 10.1038/s41421-021-00270-5

Authors: Zhen Qin, Honghua Sun, Meiting Yue, Xinwen Pan, Liang Chen, Xinhua Feng, Xiumin Yan, Xueliang Zhu, Hongbin Ji

Pre-ClinicalKirk SmithMay 5, 2021EML4-ALK fusion, variant 1, STAT3

Spindle cell tumor with CD34 and S100 co-expression and distinctive stromal and perivascular hyalinization showing EML4-ALK fusion

Recently, a novel group of CD34+ and S100+ spindle cell tumors with distinctive stromal and perivascular hyalinization showing recurrent gene fusions involving RAF1, BRAF, NTRK1/2/3, and RET has been identified. ALK rearrangements have been rarely reported in this group of tumors. We report a 24-year-old woman with a 1.5-cm pink mass of the scalp. The tumor was made of spindle cells organized in fascicles or haphazardly arranged in a patternless architecture, with areas of stromal and perivascular hyalinization. The tumor cells diffusely expressed CD34 and S100, without SOX-10 expression. The tumor showed diffuse immunopositivity for ALK. RNA sequencing using next-generation sequencing (NGS) detected an EML4-ALK fusion. This case extends the spectrum of this newly described group of CD34+/S100+ spindle cell tumors at the molecular-genetic level. Dermatopathologists should be aware of this recent entity, as it may fall in the differential diagnosis of many other spindle cell tumors with..... READ ARTICLE

Journal of Cutaneous Pathology DOI:10.1111/cup.13926

Authors: Diane Abs, Samuel Landman, Amélie Osio, Pauline Lepesant, Pierre Schneider, Déborah Obadia, Philippe Moguelet, Cécile Farges, Brigitte Poirot, Jacqueline Lehmann-Che, Céleste Lebbé, Maxime Battistella

Distribution of EML4-ALK fusion variants and clinical outcomes in patients with resected non-small cell lung cancer

Objectives: The molecular profiles and prognosis of anaplastic lymphoma kinase (ALK) fusion and resectable non-small cell lung cancer (NSCLC) remain unclear. This study aimed to explore the distribution of ALK fusion variants and prognostic factors in patients with surgically resected NSCLC. Conclusions: This study illustrated the patterns of EML4-ALK fusion variants and gene profiles in patients with resected NSCLC. Advanced T stage and EML4-ALK variant 3 were associated with worse prognosis. The role of TP53 mutations in prognosis is worthy of further study. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.09.012

Authors: Hong Tao, Liang Shi, Aoxue Zhou, Hongxia Li, Fei Gai, Zhan Huang, Nanying Che, Zhe Liu

Case StudyKirk SmithSeptember 24, 2020Coexisting mutation, EML4-ALK fusion, Prognosis, Resected NSCLC, Variant

Molecular findings reveal possible resistance mechanisms in a patient with ALK-rearranged lung cancer: a case report and literature review

Background: Non-small-cell lung cancer (NSCLC) is recognised as a particularly heterogeneous disease, encompassing a wide spectrum of distinct molecular subtypes. With increased understanding of disease biology and mechanisms of progression, treatment of NSCLC has made remarkable progress in the past two decades. Molecular testing is considered the hallmark for the diagnosis and treatment of NSCLC, with liquid biopsies being more and more often applied in the clinical setting during the recent years. Rearrangement of the ALK gene which results in the generation of fusion oncogenes is a common molecular event in NSCLCs. Among ALK fusion transcripts, EML4-ALK fusion is frequently observed and can be targeted with ALK tyrosine kinase inhibitors (TKI). However, acquired resistance and disease progression in many cases are inevitable. Conclusions: Based on the results, the EML4-ALK fusion initially detected in tumour tissue was preserved throughout the course of the disease. Two additional..... READ ARTICLE

ESMO Open, Cancer Horizons DOI:10.1136/esmoopen-2019-000561

Authors: Anastasia Kougioumtzi, Panagiotis Ntellas, Eirini Papadopoulou, George Nasioulas, Eleftherios Kampletsas, George Pentheroudakis

Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer

Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4–ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC...... READ ARTICLE

Nature DOI:10.1038/nature05945

Authors: Manabu Soda, Young Lim Choi, Munehiro Enomoto, Shuji Takada, Yoshihiro Yamashita, Shunpei Ishikawa, Shin-ichiro Fujiwara, Hideki Watanabe, Kentaro Kurashina, Hisashi Hatanaka, Masashi Bando, Shoji Ohno, Yuichi Ishikawa, Hiroyuki Aburatani, Toshiro Niki, Yasunori Sohara, Yukihiko Sugiyama & Hiroyuki Mano

Pre-ClinicalKirk SmithJuly 11, 2007EML4-ALK fusion, non-small-cell lung cancer (NSCLC)