Copy number alterations determined by single nucleotide polymorphism array testing in the clinical laboratory are indicative of gene fusions in pediatric cancer patients

Abstract

Gene fusions resulting from structural rearrangements are an established mechanism of tumorigenesis in pediatric cancer. In this clinical cohort, 1,350 single nucleotide polymorphism (SNP)-based chromosomal microarrays from 1,211 pediatric cancer patients were evaluated for copy number alterations (CNAs) associated with gene fusions. Karyotype or fluorescence in situ hybridization studies were performed in 42% of the patients. Ten percent of the bone marrow or solid tumor specimens had SNP array-associated CNAs suggestive of a gene fusion. Alterations involving ETV6, ABL1-NUP214, EBF1-PDGFRB, KMT2A(MLL), LMO2-RAG, MYH11-CBFB, NSD1-NUP98, PBX1, STIL-TAL1, ZNF384-TCF3, P2RY8-CRLF2, and RUNX1T1-RUNX1 fusions were detected in the bone marrow samples. The most common alteration among the low-grade gliomas was a 7q34 tandem duplication resulting in a KIAA1549-BRAF fusion. Additional fusions identified in the pediatric brain tumors included FAM131B-BRAF and RAF1-QKI. COL1A1-PDGFB, CRTC1-MAML2, EWSR1, HEY1, PAX3- and PAX7-FOXO1, and PLAG1 fusions were determined in a variety of solid tumors and a novel potential gene fusion, FGFR1-USP6, was detected in an aneurysmal bone cyst. The identification of these gene fusions was instrumental in tumor diagnosis. In contrast to hematologic and solid tumors in adults that are predominantly driven by mutations, the majority of hematologic and solid tumors in children are characterized by CNAs and gene fusions. Chromosomal microarray analysis is therefore a robust platform to identify diagnostic and prognostic markers in the clinical setting.

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

“…The examples include the fusion between the MLLT10 gene in 10p12.3 and KMT2A gene in 11q23 [94], and the fusion between the ETV6 gene in 12p13.2 and the ABL1 gene in 9q34.12 [95]. Generation of such fusions occurs through complex rearrangements with multiple breakpoints and is often accompanied by non-specific abnormalities in the karyotype; CNAs mapping to the breakpoints within the partner genes are frequent in these cases, and can be detected by CMA [26,30,49,91].…”

“…If only one of the derivative chromosomes from a clinically important translocation is present in the karyotype, the abnormality may be difficult to recognize by conventional cytogenetic analysis. However, the resulting copy number imbalance with the breakpoints mapping within the fusion partner-genes make such abnormalities easily recognizable by CMA [91]. Table 1.…”

Effects of the MAML2 genetic variants in glioma susceptibility and prognosis

“…These studies provided some biologic evidence for the role played by MAML2 in possible molecular mechanisms of carcinogenesis. A recent study showed that the CRTC1-MAML2 gene fusion was also identified in the brain tumors [23]. Additionally, MAML2 as a novel gene was abnormal expressed in glioma [14].…”

Making Sense of Genetic Information: The Promising Evolution of Clinical Stratification and Precision Oncology Using Machine Learning

“…In precision medicine, heritable genetic variations of subjects are assessed to determine whether they have a high risk of developing cancer [ 22 ]. Among various genetic variations, SNPs have been relatively well associated with developing breast cancer, glioma, or leukemia along with other forms of cancer [ 22 , 23 , 24 , 25 , 26 ]. The risk of cancer caused by these SNPs is heritable, accounting for approximately 10% of all cancer cases [ 27 , 28 ].…”