Review Article Outlines Optical Genome Mapping in MDS, Leukemias

A review article published in Cancer Science discussed optical gene mapping (OGM) and its use in the diagnosis and prognosis of myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL).

The authors described OGM as a “promising technique” as it can detect genomic structural variants within one assay, therefore “offering an alternative to conventional cytogenetic methods.”

First, the authors outlined the advantages and limitations of conventional cytogenetic techniques such as karyotyping, fluorescent in situ hybridization (FISH) testing, and chromosomal microarray (CMA) testing.

Karyotyping

Karyotyping, a “rapid and cost-effective technique,” detects numerical and structural abnormalities with light microscopy. However, the authors noted that due to the resolution limitations of karyotyping, cryptic aberrations or subtle chromosome translocations can go undetected.

FISH

FISH, commonly used for detecting aberrant chromosomes with short periods and high sensitivity, is recommended in the diagnosis of ALL, AML, and CML. This technique allows researchers to visualize genomic loci on human chromosomes through “fluorescent probes that hybridize with target genomic molecules through complementary base pairing.” However, this method depends on existing knowledge of target gene sequences, and therefore “can only detect specific genetic abnormalities for which suitable probes have been designed.”

CMA

CMA provides higher resolution than karyotyping, therefore identifying additional genetic abnormalities. This method involves two microarray-based chromosomal analysis techniques: single-nucleotide polymorphism and comparative genomic hybridization (CGH), which “aims to map relative DNA sequence copy numbers between malignant and normal genomes.” However, the resolution of CGH is limited by the complexity of the target genome.

Next, the authors described the principles, benefits, shortcomings, and application of OGM in MDS and leukemias while comparing the novel technique to conventional cytogenetic methods.

OGM

This “cutting-edge technique in high-resolution genome screening” consists of labeling DNA molecules through an enzymatic reaction. Once the labeled molecules are captured by a charged-coupled device camera for imaging, they are analyzed in two ways: the Rare Variant Pipeline (RVP) and de novo assembly. RVP compares the labeled DNA patterns with a reference genome, while de novo assembly collects the molecules into a complete genome and compares it with the reference genomes.

While the sample processing time is longer with OGM compared to conventional cytogenetic techniques, it can process six samples simultaneously, which “enhances the overall efficiency per sample.”

OGM can also detect additional genetic aberrations in MDS, but conventional methods are still important for the diagnosis of MDS in frontline testing, the authors noted.

To further compare OGM with conventional techniques, the authors incorporated recent studies on genomic testing in MDS and leukemias.

In a 2022 study of six patients with MDS, OGM confirmed all aberrations detected by FISH and missed one abnormality under the detection limit. In another 2022 study of 27 patients with MDS, OGM detected complex rearrangements that were unidentified by karyotyping or FISH.

In a study of nine AML cases, OGM, in combination with whole genome sequencing, identified over 97% of the genomic structural variants detected by karyotyping. In ALL, OGM identified 90% of the abnormalities detected by standard methods.

OGM also identified two novel translocations (t[2;8][q37.1;q13.1] and t[Y;15][q11.221;q21.2]) in a study of 18 CLL samples.

“Although not yet widely adopted as a frontline testing technique, OGM shows promise due to its high resolution and ability to screen the entire genome independently of sequence information,” the authors concluded. “Its capacity to uncover novel genetic abnormalities holds significant potential for improving treatment strategies for newly diagnosed leukemia.”

Reference

Lu S, Liu K, Wang D, Ye Y, Jiang Z, Gao Y. Genomic structural variants analysis in leukemia by a novel cytogenetic technique: Optical genome mapping. Cancer Sci. 2024. doi:10.1111/cas.16325