The role of next-generation sequencing in detecting gene FUSIONS with KNOWN and UNKNOWN partners: A single-center experience with methodologies’ integration

Aims: Next-generation sequencing (NGS) is becoming a new gold standard for determining molecular predictive biomarkers. This study aimed to evaluate the reliability of NGS in detecting gene fusions, focusing on comparing gene fusions with known and unknown partners... Conclusions: NGS is a reliable method for detecting gene fusions with known partners, but it is less accurate in identifying gene fusions with unknown partners, for which further analyses (such as FISH) are required. READ ARTICLE

Human Pathology DOI:10.1016/j.humpath.2022.02.005

Authors: Andrea Ambrosini-Spaltro, Anna Farnedi, Daniele Calistri, Claudia Rengucci, Giovanna Prisinzano, Elisa Chiadini, Laura Capelli, Davide Angeli, Chiara Bennati, Mirca Valli, Giovanni De Luca, Dora Caruso, Paola Ulivi, Giulio Rossi

Review PaperKirk SmithFebruary 15, 2022Next-generation sequencing, FISH, IHC, gene fusion, partner, NSCLC

Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules

Receptor tyrosine kinase (RTK)-mediated activation of downstream effector pathways such as the RAS GTPase/MAP kinase (MAPK) signaling cascade is thought to occur exclusively from lipid membrane compartments in mammalian cells. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize RTK/RAS/MAPK signaling in cancer. Chimeric (fusion) oncoproteins involving certain RTKs including ALK and RET undergo de novo higher-order assembly into membraneless cytoplasmic protein granules that actively signal. These pathogenic biomolecular condensates locally concentrate the RAS activating complex GRB2/SOS1 and activate RAS in a lipid membrane-independent manner. RTK protein granule formation is critical for oncogenic RAS/MAPK signaling output in these cells. We identify a set of protein granule components and establish structural rules that define the formation of membraneless protein granules by RTK oncoproteins. Our findings reveal membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform for organizing oncogenic RTK and RAS signaling. READ ARTICLE

Cell DOI:10.1016/j.cell.2021.03.031

Authors: Asmin Tulpule, Juan Guan, Dana S Neel, Hannah R Allegakoen, Yone Phar Lin, David Brown, Yu-Ting Chou, Ann Heslin, Nilanjana Chatterjee, Shriya Perati, Shruti Menon, Tan A Nguyen, Jayanta Debnath, Alejandro D Ramirez, Xiaoyu Shi, Bin Yang, Siyu Feng, Suraj Makhija, Bo Huang, Trever G Bivona

Spindle cell neoplasm with EML4-ALK gene fusion presenting as an intraosseous vertebral mass

In this article, we describe a spindle cell neoplasm harboring an EML4-ALK gene fusion presenting as an intraosseous vertebral mass with extension into the adjacent soft tissue in a 65-year-old man. Histologically, the lesion was characterized by the presence of monotonous, cytologically bland spindle cells with loose myxoedematous stroma and interspersed areas of amianthoid-like collagen fiber deposition. Immunohistochemistry demonstrated strong diffuse staining for CD34 and S100, with absent immunoreactivity for SOX10. At 1 year of follow-up after resection, there is no evidence of local recurrence or metastatic disease. This case adds to the clinical and pathologic spectrum of the recently described group of kinase fusion-positive spindle cell neoplasms and represents the first reported intra-osseous example. The presence of ALK rearrangement in this lesion represents a potential therapeutic target, if clinically indicated. READ ARTICLE

Genes, Chromosomes & Cancer DOI:10.1002/gcc.22917

Authors: Jose G Mantilla, Hoiwan Cheung, Alice S Ha, Benjamin L Hoch, Yajuan J Liu, Robert W Ricciotti

Case StudyKirk SmithNovember 19, 2020EML4-ALK, gene fusion, sarcoma, soft tissue pathology

SPECC1L-ALK: A novel gene fusion response to ALK inhibitors in non-small cell lung cancer

There was a case report showed that a novel pleckstrin homology and RUN domain containing M2 (PLEKHM2)- anaplastic lymphoma kinase (ALK) gene rearrangement in small cell lung cancer (SCLC) patient had long-term benefit from ALK inhibitors [ [1] ]. Actually, the case report demonstrated that next generation sequence (NGS) maybe a very useful method for detecting a new subtype of ALK fusion and it may provide a better understanding of ALK- tyrosine kinase inhibitors (TKIs) treatment. Here, we identified a novel type of ALK rearrangement responding to ALK inhibitors in non-small cell lung cancer (NSCLC) by NGS. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.03.017

Authors: Li Ma, Quan Zhang, Yujie Dong, Haoyang Li, Jinghui Wang

Case StudyKirk SmithMay 1, 2020SPECC1L-ALK, gene fusion, ALK, inhibitors, non-small cell lung cancer