Abstract
Understanding the evolutionary processes operative in cancer genome may provide insights into clinical outcome and drug-resistance. However, studies focus on genomic signatures, especially for macro-evolutionary events, in esophageal squamous cell carcinoma (ESCC) are limited. Here, we integrated published genomic sequencing data to investigate underlying evolutionary characteristics in ESCC. We found most of ESCC genomes were polyploidy with high genomic instability. Whole genome doubling that acts as one of mechanisms for polyploidy was predicted as a late event in the majority of ESCC genome. Moreover, loss of heterozygosity events were more likely to occur in chromosomes harboring tumor suppressor genes in ESCC. The 40% of neutral loss of heterozygosity events was not a result of genome doubling, suggesting an alternative mechanism for neutral loss of heterozygosity formation. Importantly, deconstruction of copy number alterations extending to telomere revealed that telomere-bounded copy number alterations play a critical role for amplification/deletion of oncogenes/suppressor genes. For well-known genes SOX2, PIK3CA and TERT, nearly all of their amplifications were telomere bounded, which was further confirmed in a Japanese ESCC cohort. Furthermore, we provide evidence that karyotype evolution was mostly punctuated in ESCC. Collectively, our data reveal the potential biological role of whole genome doubling, neutral loss of heterozygosity and telomere-bounded copy number alterations, and highlight mecro-evolution in ESCC tumorigenesis.
Highlights
Genomic studies have revealed an extensive genetic heterogeneity generated through genomic instability between different tumors and intra-tumor [1]
Four types of tumors including colorectal carcinoma (COAD), liver hepatocellular carcinoma (LIHC), pancreatic adenocarcinoma (PAAD) and stomach adenocarcinoma (STAD) were found to be divided into two classes: one class with high somatic copy number alteration (SCNA) shows copy number changes converging to specific chromosomes such as chr8 amplification and 4q deletion; the other class with low SCNAs shows few copy number alterations and may evenly be chromosomal stable
Largely copy number alterations (CNAs) were observed in almost all of esophageal carcinoma (ESCA) and frequent copy-number changes were not clustered in specific chromosome (Figure 1A)
Summary
Genomic studies have revealed an extensive genetic heterogeneity generated through genomic instability between different tumors and intra-tumor [1]. Chromosomal instability (CIN) represents a dynamic state that likely to contribute to intra-tumor heterogeneity by creating a genetically distinct pool of tumor cells. CIN has profound effects on the cell genome and is a common trait of more than 70% of human cancers, is implicated as an initiator of tumorigenesis [3]. CIN may facilitate the adaptation of tumors to environmental or stromal stress and is implicated in determining tumor progression and associated with poor outcome, tumor relapse, and multi-drug resistance across a range of cancer types [5]. Exploiting tumor CIN status and defining how it generate genetic diversity and shape genome evolution may provide insights into clinical outcome, treatment failure and assist prognostic predictions and therapeutic target. The CIN status and how it shapes genome evolution in ESCC have not been fully understood
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