Halling, Kevin

Abstract Introduction: Clinical staging of multifocal non-small cell lung cancer (NSCLC) is facilitated by comparative genomic analysis of separate tumor nodules, but the role of genome-wide copy number profiling for this purpose is uncertain. Methods: We analyzed single nucleotide variants (SNVs), gene fusions, small copy number variants (gene amplifications and homozygous deletions) (sCNVs), and large-scale copy number variants (lCNVs) in a retrospective cohort of 34 patients with >1 lung cancer nodule tested on a previously validated tumor-only 515-gene next generation sequencing (NGS) panel (MayoComplete Solid Tumor Panel). For patients with <2 shared SNVs, a Bayesian approach was formulated to calculate the probability of shared versus independent events occurring in different tumor nodules in the same patient. The prevalence of specific lCNVs in NSCLC was derived from an independent dataset of 100 NSCLC peers tested by the same panel, and the prevalence of SNVs, fusions, and sCNVs in NSCLC was derived from publicly available data. Alterations unique to different tumor nodules and suspected germline alterations were excluded from the Bayesian analysis. Results: There were 54 total comparisons for 34 patients. Eleven of the patients (32.4%) had >=2 shared SNVs along with one or more shared lCNVs also identified in each patient. Eight patients (23.5%) had no shared SNVs, gene fusions, sCNVs, or lCNVs. Using the Bayesian approach for the remaining fifteen (44.1%) patients with at least one shared alteration (SNVs, sCNVs, and lCNVs), the probability of clonal relatedness ranged from 73% for a shared whole arm or whole chromosome lCNV to >99% for tumors with two or more shared alterations including multiple or complex lCNVs and SNVs. Whole chromosome or whole arm lCNVs were sometimes shared between tumor nodules with different driver SNVs. Conclusions: Incorporating lCNVs into comparative genomic analysis provides additional evidence of clonal relatedness in a subset of multifocal NSCLCs. However, differences in bioinformatics pipelines for calling lCNVs, concerns over the imprecision of genome-wide copy number profiling, and uncertainty regarding the temporal relationship between lCNVs and carcinogenesis (including somatic events possibly related to “field cancerization”) create challenges for integrating lCNVs into comparative genomic analysis with standard clinical workflows for tumor-only NGS on paraffin embedded tissue sections. Our simplified approach mitigates some of the uncertainty introduced by incorporating lCNVs into clonality determination. Citation Format: Claire Teigen, Ying-Chun Lo, Sounak Gupta, Stephanie Smoley, Beth Pitel, Hussam Al Kateb, Gopi Sivasankaran, Benjamin Kipp, Ande Rumilla, Gang Zheng, Kevin Halling, Katherine Geiersbach, . A Bayesian framework for evaluating somatic copy number variants into comparative genomic analysis of multifocal non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5423.

ABSTRACT Myxoid liposarcoma (MLS) accounts for 20%–30% of all liposarcomas, with most cases harboring the fusion gene FUS::DDIT3 , while approximately 5% exhibit the EWSR1::DDIT3 fusion. We report the case of a 26‐year‐old male patient with a right upper arm mass. The tumor displayed the classic histological features of MLS, including small spindle/ovoid cells, variable univacuolated lipoblasts, and a prominent myxoid stroma with delicate arborizing vasculature. Despite these characteristic features, fluorescence in situ hybridization (FISH) revealed no apparent rearrangement of the DDIT3 locus. Next‐generation sequencing (NGS) identified a novel fusion transcript in which SMARCA2 exon 4 was fused in‐frame with DDIT3 exon 2. Chromosomal microarray analysis demonstrated the unbalanced nature of the rearrangement, with partial deletions of 0.243 and 0.176 Mb flanking the centromeric end of the DDIT3 locus on 12q13.3 (which also included GLI ) and disrupting the SMARCA2 locus on 9p24, respectively. The resultant chimeric fusion protein is predicted to lack the SMARCA2 DNA‐binding domains while retaining the DDIT3 leucine zipper dimerization domain. These findings indicate an unusual and complex rearrangement, leading to the recruitment of a novel DDIT3 partner gene. Moreover, they emphasize that the functional aspects of myxoid liposarcoma fusion genes depend on the retention of the key DDIT3 domain. Finally, this case illustrates how classic morphology can appropriately trigger reflex molecular analyses, which may, in turn, uncover novel fusion genes or other molecular alterations.

Myoepithelial tumors are typically characterized by distinct molecular profiles that have been shown to correlate with their anatomical locations. EWSR1 or FUS rearrangements are common in cutaneous, soft tissue and bone tumors, whereas salivary gland myoepithelial tumors are frequently associated with PLAG1 and HMGA2 alterations. This apparent molecular divergence led some previous studies to doubt a common pathogenetic relationship between myoepithelial tumors of soft tissue and bone with their salivary gland counterparts. Herein, we present primary intraosseous myoepithelioma harboring HMGA2::WIF1 fusion. This fusion has been previously identified in a range of salivary gland myoepithelial tumors including myoepitheliomas, myoepithelial carcinomas arising from pleomorphic adenomas, and pleomorphic adenomas themselves. Primary myoepithelial tumors of the bone are exceedingly rare, and to our knowledge, HMGA2 rearrangements have not been previously reported in soft tissue or bone myoepithelial neoplasms. Through this report, we aim to enhance the existing literature on myoepithelial neoplasms, while highlighting the importance of recognizing primary bone myoepitheliomas and contributing to a broader understanding of the pathogenetic landscape of myoepithelial tumors across diverse tissue types.