【Nature】Chinese Academy of Medical Sciences Zhan Qimin / Liu Zhihua et al.: Characterizing the genome structure variation of esophageal cancer somatic cells in Chinese cohort cohort

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Written by Lily

Esophageal cancer is one of the most aggressive cancers and the sixth leading cause of
cancer death worldwide.
The new cases of esophageal cancer in China account for 50%
of the global total.
Esophageal squamous cell carcinoma (ESCC) is the main pathological type of esophageal cancer, with a five-year survival rate of about 30.
3%.

Understanding the genetic basis and underlying mutation mechanisms of esophageal squamous cell carcinoma (ESCC) is critical
for drug development and clinical treatment.
Over the past 10 years, researchers have described the genetic landscape of ESCCs from different perspectives, such as from different populations, multi-region sequencing, and omics integrated analysis
.
Based on genome sequencing, these studies explore the driver mutations, mutation processes, and key pathway/cloning dynamics
during ESCC tumorigenesis.
Some recurrent mutated genes (such as NOTCH1, ZNF750 and NFE2L2, etc.
), mutational processes associated with alcohol consumption, and the efficiency of platinum-based therapy were discovered
.
However, although some of these studies have performed whole genome sequencing, analysis of genomic structural variation (SV) and its mechanisms is limited
.

On October 22, researchers such as Zhan Qimin and Liu Zhihua of the Chinese Academy of Medical Sciences and Cui Yongping of Shanxi Medical University published a paper entitled "Characterization of somatic structural variations in 528 Chinese individuals with Esophageal squamous cells" in Nature Communications Carcinoma" article
.
The study performed genome-wide analysis of 528 paired genomes to study the mechanisms and biological functions
of genomic structural variation (SV).

style="margin-bottom: 15px;white-space: normal;box-sizing: border-box;" _msthash="251139" _msttexthash="227179862">SV is genomic rearrangement that leads to duplication, deletion, or reversal
of genomic segments.
In this study, the investigators defined events involving two or more SVs as complex rearrangements; Simple rearrangement involves only one SV.

Each SV consists of two breakpoints, divided into five types: delete (+/-), TD (-/+), head-to-head (+/+), tail-to-tail (--), and translocation
.
The different sizes of TD and deletion appear to come from very different mutation processes, which show variable functional properties
in human cancers.
Many complex rearrangements often result in high levels of amplification of multiple oncogenes or disruption
of tumor suppressors.

Recently, studies have proposed complex rearrangements with templated insertions, which typically consist of
several copies of templates from different genomic regions.
Templated insertion repeatedly activates TERT
in liver cancer.
However, genomic structural variation (SV) patterns and their prevalence in ESCC have not been fully revealed
.
The clinical significance of these patterns in ESCC is unclear, and driver genes formed by different mutation processes remain largely unknown
.

In order to characterize somatic cell rearrangement and its genomic and clinical significance in esophageal squamous cell carcinoma (ESCC), the researchers decoded SV features according to the size and rearrangement pattern of SV, and developed a graph-based method to find and classify complex rearrangements
.
Breakpoints are treated as graph nodes, and two breakpoints of the same SV or two adjacent breakpoints with appropriate orientation are treated as breakpoint edges and sequence edges
, respectively.
Combined with the coverage of breakpoints and edges, potential rearrangement patterns
in ESCC can be extracted.

In this study, 528 paired genomes were analyzed to investigate potential SV patterns and their clinical significance
in ESCC.
The study defines several types of complex rearrangements that are prevalent in ESCCs, with a highlight of a foldback inversion associated with poor outcomes
.
The mutation processes of different SV types were further explored and their association
with genomic markers was revealed.
A hot spot
in the super-enhancer of the PTHLH gene driven by the TD-c2 feature was also identified.
Finally, different models
of TD and ecDNA leading to high levels of amplification of oncogenes are reported.

Different rearrangement features exhibit variable genomic markers, specifically, reentry inversion tends to occur near
the centrosome.
The carcinogenic role of the PTHLH gene and its interaction
with enhancers were confirmed by functional experiments.
Finally, extrachromosomal circular DNA (ecDNA) is present in 14% of ESCCs and has a strong selective advantage
over driver genes.

Structural variation features in ESCCs (Image source: Nature Communications)

Resources:

style="white-space: normal;box-sizing: border-box;">Note: This article is intended to introduce the progress of medical research and cannot be used as a reference
for treatment options.
If you need health guidance, please go to a regular hospital
.