Abstract Recent updates to monocyte count thresholds recognize oligomonocytic chronic myelomonocytic leukemia (OM-CMML) as an early form of CMML. However, the clinical validity of these changes remains uncertain without incorporating biological and genomic factors. In this study, we analyzed a cohort of 911 patients (249 with OM-CMML, 359 with overt CMML, and 303 with myelodysplastic syndromes) using unsupervised clustering to evaluate the role of genomic determinants in refining CMML diagnosis. Our findings show that CMML molecular signatures (biallelic TET2 mutations or SRSF2-TET2 comutations) are linked to a distinct transcriptome, monocytic bias, classical monocytosis, and a higher risk of progression to overt CMML in OM-CMML cases. We developed a weighted genomic model and diagnostic workflow showing that combining genomic signatures with bone marrow monocyte frequencies in OM-CMML more accurately predicts progression to overt CMML. These findings support integrating genomic determinants and our clinic-ready diagnostic workflow into the CMML diagnostic framework to improve accuracy. Significance: Through comprehensive clinical and genomic profiling of a large patient cohort, alongside immunophenotypic and transcriptional cellular analyses, this study provides evidence that incorporating genomic determinants into the diagnostic criteria for OM-CMML improves diagnostic accuracy and refines the identification of early-stage CMML, thereby preventing misclassification.
Conventional Cytogenetic Analysis of Solid Tumor Abnormalities: A 25-Year Review of Proficiency Test Results from the College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee
Background: The joint College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee works to ensure the competency and proficiency of clinical cytogenetic testing laboratories through proficiency testing (PT) programs for various clinical tests offered by such laboratories, including the evaluation of cytogenetic abnormalities in solid tumors. Methods: Review and analyze 25 years (1999–2023) of solid tumor chromosome analysis PT results, utilizing G-banded karyograms. A retrospective review of results from 1999 to 2023 was performed, identifying the challenges addressing solid tumors. The chromosomal abnormalities and overall performance were evaluated. Results: A total of 21 solid tumor challenges were administered during the period 1999–2018. No solid tumor challenges were administered during the period 2019–2023. Challenges consisted of metaphase images and accompanying clinical history for the evaluation of numerical and/or structural abnormalities. All 21 cases reached 80% grading consensus for abnormality recognition. However, five cases (24%) failed to reach consensus for nomenclature reporting by participating laboratories. These cases illustrate errors in reporting chromosomal abnormalities, including whole-arm translocations and those involving sex chromosomes. In addition, they highlight the challenges with differentiation of terminal and interstitial deletions, difficulties in identifying correct breakpoints, and omission of brackets in neoplastic cases. Conclusions: This comprehensive 25-year review demonstrates the exceptional proficiency of cytogenetic laboratories in accurately identifying chromosome abnormalities in solid tumors, while also highlighting the challenges of reporting specific types of chromosomal abnormalities.