Abstract
Gastroesophageal junction (GEJ) cancer is a tumor that occurs at the junction of stomach and esophagus anatomically. GEJ cancer frequently metastasizes to lymph nodes, however the heterogeneity and clonal evolution process are unclear. This study is the first of this kind to use single cell DNA sequencing to determine genomic variations and clonal evolution related to lymph node metastasis. Multiple Annealing and Looping Based Amplification Cycles (MALBAC) and bulk exome sequencing were performed to detect single cell copy number variations (CNVs) and single nucleotide variations (SNVs) respectively. Four GEJ cancer patients were enrolled with two (Pt.3, Pt.4) having metastatic lymph nodes. The most common mutation we found happened in the TTN gene, which was reported to be related with the tumor mutation burden in cancers. Significant intra-patient heterogeneity in SNVs and CNVs were found. We identified the SNV subclonal architecture in each tumor. To study the heterogeneity of CNVs, the single cells were sequenced. The number of subclones in the primary tumor was larger than that in lymph nodes, indicating the heterogeneity of primary site was higher. We observed two patterns of multi-station lymph node metastasis: one was skip metastasis and the other was to follow the lymphatic drainage. Taken together, our single cell genomic analysis has revealed the heterogeneity and clonal evolution in GEJ cancer.
Highlights
Cancers of the upper gastrointestinal tract include esophageal cancer (EC), gastroesophageal junction (GEJ) cancer and gastric cancer (GC)
We obtained the primary tumors from all the patients and two lymph nodes from two of the patients (Pt.3, Pt.4) respectively
The mutation spectra in our study revealed that C > T mutations were significantly enriched in the patients whether in the primary site or lymph node site, indicating that C > T mutation played a crucial role in Gastroesophageal junction (GEJ) tumorigenesis and progression
Summary
Cancers of the upper gastrointestinal tract include esophageal cancer (EC), gastroesophageal junction (GEJ) cancer and gastric cancer (GC). Esophageal cancer is classified as squamous cell carcinoma or adenocarcinoma by histopathology [1], while GEJ cancer and GC are mainly adenocarcinoma [2,3,4]. GEJ cancer can be classified as a part of EC or GC, in most cases it is categorized as the latter. GEJ cancer and distal GC show different characteristics in epidemiology, risk factors, origin, and prognosis [5, 6]. GEJ cancer shows stronger penetrability, more prone to lymph node metastasis and worse prognosis, comparing to GC [7]. The incidence of GC has gradually decreased owing to the effective eradication of Helicobacter pylori infection, but the incidence of GEJ cancer is gradually increasing attributed to the major risk factor of reflux diseases [8, 9]
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