Surendra Dasari

Anaplastic lymphoma kinase–rearranged renal cell carcinoma (ALK-RCC) is a rare and recently recognized molecular subtype of RCC defined by ALK gene fusions. We describe five ALK-RCC and one likely ALK-rearranged epithelioid mesenchymal neoplasm from both pediatric and adult patients. Tumors exhibited diverse morphologic features, including papillary, mucinous, and cribriform patterns. ALK expression was confirmed in all cases by immunohistochemistry. Molecular profiling revealed several fusion partners including ARNT, EML4, NUMA1, TPM3, and VCL. A single patient with a VCL::ALK gene rearrangement had sickle cell trait. Novel gene rearrangements in RCC include NUMA1::ALK and ARNT::ALK. Metastatic disease was documented in three patients, and two died of disease. This series underscores the morphological heterogeneity of ALK-RCC (including frequent papillary and mucinous features), is informative of novel fusion partners such as NUMA1 and ARNT, further highlights the association of the VCL::ALK fusion with sickle cell trait, and is informative of the natural history of disease in a subset of patients.

Cardiac AL and ATTR are potentially fatal cardiomyopathies. Current therapies do not address mechanisms of tissue dysfunction because these remain unknown. Our prior work focused on the amyloid plaque proteome, which may not capture tissue-wide proteomic alterations. To evaluate mechanisms of tissue dysfunction in cardiac AL and ATTR using a full biopsy tissue proteomics approach. We performed proteomics analysis on 76 ATTR and 27 AL diagnostic endomyocardial biopsies. Stage-3 AL patients exhibited increased coagulation, extracellular matrix remodelling (ECM), epithelial-to-mesenchymal transition (EMT), complement activation, hypoxia, and clathrin-mediated endocytosis pathways vs. stages-1/2, with decreased healthy cardiac metabolism. In stages-2 and 3 ATTR, immunoglobulin proteins, complement, and keratinisation pathways were increased compared to stage-1. Unsupervised analyses identified an ATTR group with worse survival characterised by upregulated complement and downregulated metabolic pathways. Compared to ATTR, AL had higher clathrin-mediated endocytosis, mRNA splicing, and ribosomal proteins, while ATTR had higher complement levels. This study identifies known processes dysregulated in heart failure with preserved ejection fraction as well as novel pathways responsible for tissue damage. Our results support an immune-mediated mechanism of tissue toxicity in cardiac amyloidosis, especially among patients with worse outcomes.