The Clinical Impact of Isolated Trisomy 15 in Myelodysplastic Syndrome Is Governed By Its Clonality

Introduction: Trisomy 15 (+15) presenting as the sole cytogenetic anomaly in myeloid malignancies is a rare finding that lacks universal consensus on its potential indication of a hematological disorder versus an aging effect equivalent to Y chromosome loss. The integration of molecular genetics in these unique cases has been largely uninvestigated and could aid in clarifying this diagnostic ambiguity.

Methods: We screened the clinical cytogenetics laboratory database of hematological disorders at Brigham and Women's Hospital from 2019-2024 for cases with +15 as the sole clonal abnormality. In tandem, we reviewed next generation sequencing (NGS) results for these patients and collected relevant clinicopathological information.

Results: We identified 14 patients with +15 as the sole cytogenetic anomaly in our cohort (0.2%), consistent with prior reports of its rarity. +15 was more frequently observed in males (10/14, 71.4%) and had a median age at diagnosis of 73.3 years (43.5-87.7 years), with 13/14 (92.9%) patients being diagnosed after the age of 60. Patients were initially referred for a variety of myeloid malignancies including idiopathic cytopenia (6/14, 42.9%), myelodysplastic syndrome/neoplasm (MDS) (7/14, 50.0%) and acute myeloid leukemia (AML) (1/14, 7.1%). Three MDS patients (3/7, 42.9%) progressed to AML (times to progression: 0.7, 4.6, and 5.0 years, respectively).

The number of metaphases showing +15 by karyotype ranged from 2-20 (10-100%) and was not significantly associated with the patient's age at diagnosis, sex, or diagnosis. Based on the number of metaphases harboring +15, we classified patients as having high (>75%), intermediate (25-74%), or low (<25%) +15 clonality. Interestingly, all 3 MDS patients that progressed to AML were classified as high +15 clonality (90%-100%), while the 4 remaining MDS had variable levels of +15 clonality (25%-100%). All 6 patients who had unexplained cytopenia had low +15 clonality (<25% metaphases).

In 8 cases, repeat chromosome analysis was performed. This serial analysis showed that when patients initially had low +15 clonality (n=3), it was often reduced (n=1) or lost (n=2) in sequential karyotypes conducted in as little as 3 months after the initial analysis. In contrast, in cases with a high initial clonality (n=2), +15 was retained in the major clone up to 3 years after the initial analysis.

Concurrent NGS was performed on 12/14 (85.7%) patients. The median number of variants detected was 2 (1-9 variants). Patients with high +15 clonality harbored low frequency (<10%) mutations in a variety of genes including spliceosome components (U2AF1 [n=1], 1 SRSF2 [n=1]), and IDH2^p.R140Q [n=2]. In contrast, cases with low or intermediate +15 clonality harbored mutations in genes associated with epigenetic modification (DNMT3A [n=3], TET2 [n=2]) or tumor suppression (PPM1D [n=3], TP53 [n=2]), which can be seen in clonal hematopoiesis or MDS. These events may represent genetic drivers that supplant the minor +15 clone as the likely cause of malignancy.

Conclusion: We describe an unbiased cohort of myeloid proliferations harboring +15 as their sole cytogenetic anomaly. We show that isolated +15 can be associated with MDS, particularly in cases that progressed to AML when present at a high clonality. However, at low clonality, +15 may not be a disease-related finding, but rather a passenger event reflecting clonal hematopoiesis, similar to loss of the Y chromosome.

Hasserjian:Bluebird Bio: Consultancy.