Assessing copy number abnormalities and copy-neutral loss-of-heterozygosity across the genome as best practice in diagnostic evaluation of acute myeloid leukemia: An evidence-based review from the cancer genomics consortium (CGC) myeloid neoplasms working group

Xu, Xinjie; Bryke, Christine R.; Sukhanova, Madina; Huxley, Emma; Dash, Durga Prasad; Dixon‐McIver, Amanda; Fang, Min; Griepp, Patricia; Hodge, Jennelle C.; Iqbal, Anwar; Jeffries, Sally; Kanagal‐Shamanna, Rashmi; Quintero‐Rivera, Fabiola; Shetty, Shashi; Slovak, Marilyn L.; Yenamandra, Ashwini; Lennon, Patrick A.; Raca, Gordana

doi:10.1016/j.cancergen.2018.07.005

Cited by 24 publications

(12 citation statements)

References 120 publications

(163 reference statements)

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“…As expected, patients carried variable lesion loads, with an average of 2.32 abnormalities/patient (range 1-39), harboring some of them more than two cryptic aberrations at same time (n = 15). In our cohort, losses were more frequent than gains or CN-LOH (54%, 27% and 19% respectively) as well as in previous reports 4, [9][10][11]13,16,17 . Losses were distributed virtually across all chromosomes, differently from CN-LOH or gains.…”

Section: Discussionsupporting

confidence: 89%

“…However, no statistically significant differences were found regarding relapse free survival. In previous reports, the presence of abnormal SNP-A detected lesions has an adverse impact on clinical outcome and is associated with disease progression 4,[9][10][11]13,16,17 . Consistent with these results, in this study the number of cryptic abnormalities seemed to have an adverse impact on the final outcome.…”

Section: Discussionmentioning

confidence: 93%

“…We extended our cohort to a total of 252 patients by comparing our data with that of 132 patients previously reported in other studies. To our knowledge, this is one of the few SNP array-based on genomics studies that has been performed using Cytoscan HD (Affymetrix), in which paired germline DNA was used 4,[9][10][11]13,16,17 . Due to the absence of available paired samples from our expanded cohort, after a conversion of hg18 to version hg19, germline alterations were excluded from the analysis by visual inspection and by comparison with the polymorphic variations reported in the Database of Genomic Variants.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of SNP Array Abnormalities in Patients with DE NOVO Acute Myeloid Leukemia with Normal Karyotype

Ibáñez

Such

Onecha

et al. 2020

Sci Rep

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Nearly 50% of patients with de novo acute myeloid leukemia (AML) harbor an apparently normal karyotype (NK) by conventional cytogenetic techniques showing a very heterogeneous prognosis. this could be related to the presence of cryptic cytogenetic abnormalities (ccA) not detectable by conventional methods. The study of copy number alterations (CNA) and loss of heterozygozity (LOH) in hematological malignancies is possible using a high resolution SNP-array. Recently, in clinical practice the karyotype study has been complemented with the identification of point mutations in an increasing number of genes. We analyzed 252 de novo nK-AML patients from Hospital La fe (n = 44) and from previously reported cohorts (n = 208) to identify CCA by SNP-array, and to integrate the analysis of CCA with molecular alterations detected by Next-Generation-sequencing. CCA were detected in 58% of patients. In addition, 49% of them harbored CNA or LOH and point mutations, simultaneously. Patients were grouped in 3 sets by their abnormalities: patients carrying several CCA simultaneously, patients with mutations in FLT3, NPM1 and/or DNMT3A and patients with an amalgam of mutations. We found a negative correlation between the number of CCA and the outcome of the patients. This study outlines that CCA are present in up to 50% of NK-AML patients and have a negative impact on the outcome. CCA may contribute to the heterogeneous prognosis. Acute myeloid leukemia (AML) is a heterogeneous disease that represents the most frequent type of acute leukemia in adults. Conventional cytogenetic studies have shown that cytogenetic alterations are frequent in AML, being useful for diagnosis, classification and prognosis purposes 1. However, almost 50% of the patients present an apparently normal karyotype (NK) by conventional cytogenetic techniques. In addition, the prognosis of these patients is very heterogeneous suggesting that cryptic alterations not detectable with such conventional methods may be able to develop the disease, having different prognostic implications. The high resolution single-nucleotide polymorphism array (SNP-A) is a powerful tool for the study of copy number alterations (CNA), loss of heterozygosity (LOH) and chromothripsis in hematological malignancies 2,3. Moreover, the study of matched germline/tumor tissues allows detecting acquired alterations and, therefore, those involved in the leukemogenesis. During the last decade, several studies have been carried out using SNP-A with

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Analysis of SNP Array Abnormalities in Patients with DE NOVO Acute Myeloid Leukemia with Normal Karyotype

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Such

Onecha

et al. 2020

Sci Rep

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“…However, classical karyotyping techniques are based on evaluation of chromosomal banding patterns under light microscopy, and hence has limited resolution. Although application of high-resolution scanning of the entire genome by chromosomal microarrays for CNV analysis >30kbps has proved to be a useful diagnostic technique, it is ineffective for detection of balanced events such inversions and translocations [8-11]. Lastly, FISH techniques have limited utility due to a targeted approach.…”

Section: Introductionmentioning

confidence: 99%

Application of Optical Genome Mapping For Comprehensive Assessment of Chromosomal Structural Variants for Clinical Evaluation of Myelodysplastic Syndromes

Yang

Rush

Montalban‐Bravo

et al. 2021

Preprint

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Structural chromosomal variants [copy number variants (CNVs): losses/ gains and structural variants (SVs): inversions, balanced and unbalanced fusions/translocations] are important for diagnosis and risk-stratification of myelodysplastic syndromes (MDS). Optical genome mapping (OGM) is a novel single-platform cytogenomic technique that enables high-throughput, accurate and genome-wide detection of all types of clinically important chromosomal variants (CNVs and SVs) at a high resolution, hence superior to current standard-of-care cytogenetic techniques that include conventional karyotyping, FISH and chromosomal microarrays. In this proof-of-principle study, we evaluated the performance of OGM in a series of 12 previously well-characterized MDS cases using clinical BM samples. OGM successfully facilitated detection and detailed characterization of twenty-six of the 28 clonal chromosomal variants (concordance rate: 93% with conventional karyotyping; 100% with chromosomal microarray). These included copy number gains/losses, inversions, inter and intra-chromosomal translocations, dicentric and complex derivative chromosomes; the degree of complexity in latter aberrations was not apparent using standard technologies. The 2 missed aberrations were from a single patient within a composite karyotype, below the limit of detection. Further, OGM uncovered 6 additional clinically relevant sub-microscopic aberrations in 4 (33%) patients that were cryptic by standard-of-care technologies, all of which were subsequently confirmed by alternate platforms. OGM permitted precise gene-level mapping of clinically informative genes such as TP53, TET2 and KMT2A, voiding the need for multiple confirmatory assays. OGM is a potent single-platform assay for high-throughput and accurate identification of clinically important chromosomal variants.

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“…In recent years, the clinical utility of CMA has been well established in the diagnosis of several neoplastic disorders. [1][2][3][4][5][6][7] The American College of Medical Genetics and Genomics (ACMG) technical standards and guidelines for CMA in neoplastic disorders includes a section on CMA results evaluation and interpretation. 8 This document provided the initial framework for interpreting CMA results in neoplastic disorders; however, it describes broad principles.…”

Section: Introductionmentioning

confidence: 99%

Technical laboratory standards for interpretation and reporting of acquired copy-number abnormalities and copy-neutral loss of heterozygosity in neoplastic disorders: a joint consensus recommendation from the American College of Medical Genetics and Genomics (ACMG) and the Cancer Genomics Consortium (CGC)

Mikhail

Biegel

Cooley

et al. 2019

Genetics in Medicine

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Disclaimer: This laboratory standard is designed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to this standard is voluntary and does not necessarily assure a successful medical outcome. This standard should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with this standard. They also are advised to take notice of the date any particular standard was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. The detection of acquired copy-number abnormalities (CNAs) and copy-neutral loss of heterozygosity (CN-LOH) in neoplastic disorders by chromosomal microarray analysis (CMA) has significantly increased over the past few years with respect to both the number of laboratories utilizing this technology and the broader number of tumor types being assayed. This highlights the importance of standardizing the interpretation and reporting of acquired variants among laboratories. To address this need, a clinical laboratoryfocused workgroup was established to draft recommendations for the interpretation and reporting of acquired CNAs and CN-LOH in neoplastic disorders. This project is a collaboration between the American College of Medical Genetics and Genomics (ACMG) and the Cancer Genomics Consortium (CGC). The recommendations put forth by the workgroup are based on literature review, empirical data, and expert consensus of the workgroup members. A four-tier evidence-based categorization system for acquired CNAs and CN-LOH was developed, which is based on the level of available evidence regarding their diagnostic, prognostic, and therapeutic relevance: tier 1, variants with strong clinical significance; tier 2, variants with some clinical significance; tier 3, clonal variants with no documented neoplastic disease association; and tier 4, benign or likely benign variants. These recommendations also provide a list of standardized definitions of terms used in the reporting of CMA findings, as well as a framework for the clinical reporting of acquired CNAs and CN-LOH, and recommendations for how to deal with suspected clinically significant germline variants.

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Assessing copy number abnormalities and copy-neutral loss-of-heterozygosity across the genome as best practice in diagnostic evaluation of acute myeloid leukemia: An evidence-based review from the cancer genomics consortium (CGC) myeloid neoplasms working group

Cited by 24 publications

References 120 publications

Analysis of SNP Array Abnormalities in Patients with DE NOVO Acute Myeloid Leukemia with Normal Karyotype

Analysis of SNP Array Abnormalities in Patients with DE NOVO Acute Myeloid Leukemia with Normal Karyotype

Application of Optical Genome Mapping For Comprehensive Assessment of Chromosomal Structural Variants for Clinical Evaluation of Myelodysplastic Syndromes

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