Characterization of 1q Duplication by Array Comparative Genomic Hybridization in Acute Myeloid Leukemia Patients with t(8;16)(p11.2;p13.3) CURRENT STATUS: REVIEW

Background: Acute myeloid leukemia (AML) is a complex hematological disease characterized by genetic and clinical heterogeneity. The identification and understanding of chromosomal abnormalities are important for the diagnosis and management of AML patients. Compared to recurrent chromosomal translocations in AML, t(8;16)(p11.2;p13.3) can be found in any age group, but is very rare and typically associated with poor prognosis. Methods: Cytogenetic studies were performed among 1,824 AML patients from our oncology database in the last 20 years by karyotype analysis. Fluorescence in situ hybridization (FISH) was used to further confirm the chromosomal translocation fusion. Array comparative genome hybridization (aCGH) was carried out to characterize the additional chromosomal segments in patients with t(8;16)(p11.2;p13.3). Results: Three patients with t(8;16)(p11.2;p13.3) were identified. One patient was pure t(8;16) (p11.2;p13.3), and the other two had an additional chromosomal anomaly of 1q duplication. Interestingly, the molecular size and position of this 1q duplication were similar in both patients, showing as 46.7 Mb and 49.9 Mb, respectively. Conclusion: 1q duplication is a recurrent event in AML patients with t(8;16)(p11.2;p13.3), indicating it could also play a role of an unfavorable prognostic factor. duplication Based on the published studies of combining with our investigation, we found that 1q duplication is common in AML patients with t(8;16)(p11.2;p13.3). We also suggest that 1q duplication may be an adverse prognostic factor in AML patients with these anomalies. The understandings of molecular cytogenetic data would contribute to the diagnosis and treatment evaluation of AML.


Data of patients
The information and routine cytogenetic findings of patients were listed in Table.1 (Fig. 1b).
Additionally, the t(8;16)(p11.2;p13.3) and a similar additional chromosomal material attached to the long arm of chromosome 3 were found in patient No.3 (Fig. 1c) 16p13.3, resulting in the fusion of these two genes. In order to confirm the translocation between chromosome 8 and 16 on patient No.2 and No.3, we set up FISH studies using home-brewed probes corresponding to the KAT6A gene and the CREBBP gene. As we expected, the analyzed metaphase cells of these two patients exhibited the same abnormal hybridization pattern on these two patients: two yellow abnormal fusion signals involving one on the derivative chromosome 8 and another on the derivative chromosome 16 ( Fig. 2a and b). In addition, we performed FISH analysis in patients No.2 and No.3 using WCP 1 and 14, WCP 1 and 3 FISH probes, respectively. Metaphase cells were observed and manifested that the extra chromosomal materials on chromosome 14 chromosome 3 were both from chromosome 1 (Fig. 2c and 2d). Moreover, we used the sub-telomere specific FISH probes on aberrations in AML also exist [12]. The identification of fusion transcripts such as t(8;21) (q22;q22)/RUNX1-RUNX1T1, inv(16)(p13.1;q22)/CBFB-MYH11 or t(15;17)(q24;q21)/PML-RARA is important for the diagnosis and disease progression monitoring of patients with AML [21]. In this study, using karyotyping, FISH and aCGH, three patients with t(8;16)(p11.2;p13.3) were typically analyzed. It is found that one male patient is pure t(8;16)(p11.2;p13.3), and two female patients have a similar additional chromosomal anomaly of 1q duplication. To the best of our knowledge, this is the first study of delineation of 1q duplication by aCGH in AML patients with t(8;16)(p11.2;p13. 3).
Different methods are applied to detect common balanced translocations and the loss or gain of large chromosomal segments in AML. As an example, FISH is a targeted method that enhances analytical resolution to 300-800 kb and allows the analysis of interphase nuclei as well as metaphases [23].
Compared to the conventional cytogenetic analysis and FISH method, aCGH is an attractive method for the investigation of cancer genomes [30]. aCGH has higher resolution, simplicity, high reproducibility, shorter turnaround time and precise mapping of aberrations. Most importantly, it avoids the need for cell culture and dividing cells [31][32][33]. Furthermore, aCGH chromosomal analysis facilitates rapid detection of cytogenetic abnormalities previously undetectable by conventional cytogenetics [23]. aCGH analysis adds to the prognostic stratification of patients with AML. Compared to conventional detection method karyotyping, aCGH shows a higher sensitivity, and detects loss of 17p in AML patients [23]. Recurrent deletions of 5q, 17q11.2 (NF1 gene) and 20q were observed in 30 elderly patients [34]. aCGH detected the chromosome 7 origin of the marker chromosome with deletions of 7p and 7q in children, adolescent and adult AML [35,36]. In our investigation, we applied aCGH to characterize the origin of the additional chromosomal materials in two patients with t(8;16) (p11.2;p13.3). Therefore, we found the segments were both from chromosome 1q at similar cytobands.
Gain of chromosome 1q is often involved in chromosomal translocations. Patients with 1q duplication have demonstrated a wide range of multiple malformations such as mental retardation, macrocephaly, large fontanels, prominent forehead, broad flat nasal bridge, high-arched palate, retrognathia, low-set ears, and cardiac defects [37,38]. More recent studies manifest that 1q gain is also related to a slice of solid tumors. For instance, the gain of 1q is well known as a poor prognostic biomarker of Wilms tumor [39], it plays an important role in predicting poor clinical outcome in patients with thyroid carcinoma as well [40]. Besides, patients with 1q duplication showed worse survival and high risk in acute lymphoid leukemia, Burkitt lymphoma, and myeloproliferative neoplasms [41][42][43][44]. Moreover, previous studies suggest that partial trisomy for the 1q impacts the prognosis of AML, the 1q duplication portends the evolution of disease progression in hematological malignancies as a sole anomaly or associated with other changes [45][46][47]. As

Availability of data and materials
All data generated or analyzed during this study are included in this published article.

Competing interests
The authors declare that they have no competing interests.

Funding
This study has received no funding support.