Edelman Saul Eduardo, Urrutia Samuel, Yang Hui, Montalban-Bravo Guillermo, Tang Guilin, Toruner Gokce, Patel Keyur, Luthra Rajyalakshmi, Bueso-Ramos Carlos, Wang Sa A, Chien Kelly, Sasaki Koji, Atluri Himachandana, Goulart Hannah, Thakral Beenu, Garcia-Manero Guillermo, Kanagal-Shamanna Rashmi
1Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
2Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
J Natl Compr Canc Netw. 2025 May 9;23(6):e257015. doi: 10.6004/jnccn.2025.7015.
Accurate and timely detection of clinically relevant genetic abnormalities, such as CBFB::MYH11 or inversion(16) [inv(16)], is critical for the diagnosis and management of patients with acute myeloid leukemia (AML). Notably, CBFB::MYH11 is a disease-defining mutation in AML and is associated with a favorable prognosis. The current standard-of-care workup, which includes a combination of conventional G-banding karyotyping, fluorescence in situ hybridization (FISH), and/or reverse-transcriptase PCR, poses challenges in detecting variant CBFB::MYH11 translocations. High-resolution, genome-wide technologies capable of accurate and unbiased detection of chromosomal structural aberrations at the gene/exon level, such as optical genome mapping (OGM), will be helpful for the timely detection of clinically actionable abnormalities. This case report presents a patient initially diagnosed with therapy-related myelodysplastic syndrome (MDS) following cytotoxic therapy and treated with a hypomethylating agent, who later experienced progression to AML with CBFB::MYH11. Retrospective analysis of the initial diagnostic sample using OGM revealed a cryptic CBFB::MYH11 abnormality at the time of the first presentation. Furthermore, OGM enabled comprehensive characterization of this novel CBFB::MYH11 transcript with noncanonical breakpoints, which were not detected by standard molecular techniques. This case highlights a critical diagnostic blind spot in the detection of CBF::MYH11 AML, representing a missed opportunity to offer effective frontline therapy to a patient with potentially curable AML-an aberration not recognized by conventional karyotype or FISH at the time of initial diagnosis. The implementation of genome-wide technologies such as OGM as a first-tier diagnostic tool in clinical laboratories for the workup of MDS/AML is essential for detecting clinically impactful cryptic genomic alterations. The discovery of this novel alternate CBFB::MYH11 transcript with noncanonical breakpoints underscores a major limitation in current standard-of-care techniques, warranting further prospective studies to evaluate its clinical actionability in guiding personalized therapies.
准确及时地检测临床相关的基因异常，如CBFB::MYH11或16号染色体倒位[inv(16)]，对于急性髓系白血病（AML）患者的诊断和管理至关重要。值得注意的是，CBFB::MYH11是AML的一种疾病定义性突变，与良好的预后相关。当前的标准治疗检查方法，包括传统的G显带核型分析、荧光原位杂交（FISH）和/或逆转录聚合酶链反应，在检测变异型CBFB::MYH11易位方面存在挑战。能够在基因/外显子水平准确、无偏倚地检测染色体结构畸变的高分辨率全基因组技术，如光学基因组图谱（OGM），将有助于及时检测出具有临床可操作性的异常情况。本病例报告介绍了一名患者，最初在接受细胞毒性治疗后被诊断为治疗相关的骨髓增生异常综合征（MDS），并接受了低甲基化药物治疗，后来进展为伴有CBFB::MYH11的AML。使用OGM对初始诊断样本进行回顾性分析发现，首次就诊时存在隐匿性CBFB::MYH11异常。此外，OGM能够全面表征这种具有非典型断点的新型CBFB::MYH11转录本，而标准分子技术未检测到这些断点。该病例突出了CBF::MYH11 AML检测中的一个关键诊断盲点，这代表着错失了为一名可能治愈的AML患者提供有效一线治疗的机会——这种畸变在初始诊断时未被传统核型分析或FISH识别。在临床实验室中，将OGM等全基因组技术作为MDS/AML检查的一线诊断工具，对于检测具有临床影响的隐匿性基因组改变至关重要。这种具有非典型断点的新型替代CBFB::MYH11转录本的发现凸显了当前标准治疗技术的一个主要局限性，需要进一步进行前瞻性研究，以评估其在指导个性化治疗中的临床可操作性。
