Characterizing Genetic Transitions of Copy Number Alterations and Allelic Imbalances in Oral Tongue Carcinoma Metastasis

Abstract

Primary tumor (PT) heterogeneity can significantly affect the genetic profile of clones at metastatic sites. To understand the mechanisms underlying metastasis, we compared the genetic profile of paired PT and metastatic lymph node (MLN) samples obtained from patients with oral tongue squamous cell carcinoma (OTSCC). Large-scale genetic profiling was performed on paired PT-MLN samples obtained from 10 OTSCC patients using high-density single-nucleotide polymorphism microarrays. We compared the genetic profile of PT and MLN OTSCC samples to identify common and specific copy number alterations and copy-neutral loss-of-heterozygosity (CN-LOH). Unsupervised hierarchical clustering analysis indicated that 8 of the 10 PT-MLN sample pairs formed clusters, indicating that the primary and metastatic tumors were composed of predominantly genetically similar tumor cells. In 6 of the 10 pairs, 8q11.21, 8q12.2-3, and 8q21.3 gains, and 22q11.23 loss were detected in both the PT and MLN. In addition, 16p11.2 CN-LOH was identified in 9 of the 10 pairs. Conversely, 20q11.2 gain was only observed in the MLNs of 5 of the 10 sample pairs, indicating that genes in this chromosomal region may play a significant role in OTSCC lymph node metastasis. To confirm this, we investigated the expression of two candidate 20q11.2 genes in a separate patient cohort. The expression of one of these genes, E2F1, was significantly increased during the process of metastasis. This study indicates that additional genetic changes, such as 20q11.2 gain, which encodes the E2F1 gene, can be acquired through clonal evolution, and may be required for the metastatic process. © 2016 Wiley Periodicals, Inc.

Gene expression profiles and protein‑protein interaction networks during tongue carcinogenesis in the tumor microenvironment

“…A methylation profile revealed that hypermethylation of microRNA (miRNA/miR)-10b with downregulation of its target gene nuclear receptor subfamily 4 group A member 3 was associated with tongue tumor patient survival ( 17 ). An additional study employed single-nucleotide polymorphism microarrays with human OTSCC samples to indicate that genetic changes, such as 20q11.2 gain encoding the E2F transcription factor 1 gene, may be acquired through clonal evolution and may be responsible for metastasis ( 18 ). miR-424 was reported to be a marker specific for tongue tumorigenesis, which also may function in the development of OTSCC ( 19 ).…”

CKS2 modulates cell‐cycle progression of tongue squamous cell carcinoma cells partly via modulating the cellular distribution of DUTPase

“…Although both CKS2 and DUT were significantly upregulated in TSCC, the mechanisms underlying their dysregulation have not been well understood. Gene‐level amplification was a common mechanism of gene upregulation in TSCC 29,30 . Our analysis based on data from 123 TSCC cases in TCGA indicated that gene‐level amplification might be an important mechanism of upregulated CKS2 and DUT .…”

MiR‐873‐5p modulates progression of tongue squamous cell carcinoma via targeting SEC11A

“…Accumulating evidence has shown that the growth, invasion, and metastasis of malignant tumor are a multilink, multistep progression (Morita et al., 2016). In light of this, we detected the expression of SPC18 and EGFR pathway‐related proteins and found that overexpression of miR‐873‐5p could downregulate the expression of SPC18, p‐EGFR/EGFR, p‐Akt/Akt, and p‐ERK1/2/ERK1/2, while overexpression of SEC11A resulted in the upregulation of these proteins.…”