Microarray‐based genomic profiling as a diagnostic tool in acute lymphoblastic leukemia

Abstract

In acute lymphoblastic leukemia (ALL) specific genomic abnormalities provide important clinical information. In most routine clinical diagnostic laboratories conventional karyotyping, in conjunction with targeted screens using e.g., fluorescence in situ hybridization (FISH), is currently considered as the gold standard to detect such aberrations. Conventional karyotyping, however, is limited in its resolution and yield, thus hampering the genetic diagnosis of ALL. We explored whether microarray-based genomic profiling would be feasible as an alternative strategy in a routine clinical diagnostic setting. To this end, we compared conventional karyotypes with microarray-deduced copy number aberration (CNA) karyotypes in 60 ALL cases. Microarray-based genomic profiling resulted in a CNA detection rate of 90%, whereas for conventional karyotyping this was 61%. In addition, many small (< 5 Mb) genetic lesions were encountered, frequently harboring clinically relevant ALL-related genes such as CDKN2A/B, ETV6, PAX5, and IKZF1. From our data we conclude that microarray-based genomic profiling serves as a robust tool in the genetic diagnosis of ALL, outreaching conventional karyotyping in CNA detection both in terms of sensitivity and specificity. We also propose a practical workflow for a comprehensive and objective interpretation of CNAs obtained through microarray-based genomic profiling, thereby facilitating its application in a routine clinical diagnostic setting.

Importance of FISH combined with Morphology, Immunophenotype and Cytogenetic Analysis of Childhood/Adult Acute Lymphoblastic Leukemia in Omani Patients

“…In most routine clinical diagnostic laboratories conventional 1 karyotyping, in conjunction with targeted screens using e.g., FISH which is currently considered as the gold standard to detect such aberrations (Simons et al, 2011), plays a critical role in guiding targeted therapies, has evolved to become a vital diagnostic tool for personalized medicine (Linping, 2014) and reveal recurring chromosome abnormalities in approximately 80% of ALL cases, including numerical and structural changes, such as translocations, inversions, or deletions (Harrison et al, 2005;Moorman et al, 2010).…”

Section E6.1–6.4 of the ACMG technical standards and guidelines: chromosome studies of neoplastic blood and bone marrow–acquired chromosomal abnormalities

“…Interphase FISH analysis is optional and could include the following probes: a. BCR-ABL1 fusion probes: for BCR-ABL1 fusion and ABL1 amplification b. KMT2A (MLL) rearrangement probes -In ALL, CMA analysis can be very helpful for detecting cryptic CNCs, with proven relevance to diagnosis, prognosis, and therapeutic response. [14][15][16] Examples include deletions involving PAX5 and IKZF1 genes. It can also help clarify the structure of complex chromosomal rearrangements.…”

Genome-wide arrays in routine diagnostics of hematological malignancies

“…However, the SNP coverage on the combined arrays is lower than on the traditional SNP arrays. Although SNP array analysis has the ability to identify very small CNLOH, the cutoff for a clinical hematology genetic setting is often set at 10-25 Mb Simons et al, 2011], as all commercially available array platforms can reliably detect CNLOH down to 10 Mb.…”

“…Recently, Simons et al (2011) proposed an objective and standardized workflow for practical routine diagnostic use for ALL (see Fig. 4).…”

“…as chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), multiple myeloma (MM), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) [Dougherty et al, 2011;Dunbar et al, 2008;Gunnarsson et al, 2011;Hagenkord et al, 2011;Heinrichs et al, 2009;Shao et al, 2010;Simons et al, 2011;Tiu et al, 2009Tiu et al, , 2011aTiu et al, , 2011b. Consequently, array-based molecular karyotyping is slowly but surely finding its way into the clinical laboratories for acquired cytogenetics.…”