Abstract
BackgroundIt is suspected that early gastric carcinoma (GC) is a dormant variant that rarely progresses to advanced GC. We demonstrated that the dormant and aggressive variants of tubular adenocarcinomas (TUBs) of the stomach are characterized by loss of MYC and gain of TP53 and gain of MYC and/or loss of TP53, respectively. The aim of this study is to determine whether this is also the case in undifferentiated-type GCs (UGCs) of different genetic lineages: one with a layered structure (LS+), derived from early signet ring cell carcinomas (SIGs), and the other, mostly poorly differentiated adenocarcinomas, without LS but with a minor tubular component (TC), dedifferentiated from TUBs (LS−/TC+).MethodsUsing 29 surgically resected stomachs with 9 intramucosal and 20 invasive UGCs (11 LS+ and 9 LS−/TC+), 63 genomic DNA samples of mucosal and invasive parts and corresponding reference DNAs were prepared from formalin-fixed, paraffin-embedded tissues with laser microdissection, and were subjected to array-based comparative genomic hybridization (aCGH), using 60K microarrays, and subsequent unsupervised, hierarchical clustering. Of 979 cancer-related genes assessed, we selected genes with mean copy numbers significantly different between the two major clusters.ResultsBased on similarity in genomic copy-number profile, the 63 samples were classified into two major clusters. Clusters A and B, which were rich in LS+ UGC and LS−/TC+ UGC, respectively, were discriminated on the basis of 40 genes. The aggressive pattern was more frequently detected in LS−/TC+ UGCs, (20/26; 77%), than in LS+UGCs (17/37; 46%; P = 0.0195), whereas no dormant pattern was detected in any of the UGC samples.ConclusionsIn contrast to TUBs, copy number alterations of MYC and TP53 exhibited an aggressive pattern in LS+ SIG at early and advanced stages, indicating that early LS+ UGCs inevitably progress to an advanced GC. Cluster B (enriched in LS−/TC+) exhibited more frequent gain of driver genes and a more frequent aggressive pattern than cluster A, suggesting potentially worse prognosis in UGCs of cluster B.
Highlights
It is suspected that early gastric carcinoma (GC) is a dormant variant that rarely progresses to advanced GC
Genome wide copy number alterations A plot of the genetic aberration penetrance for all chromosomes is shown for layered structure (LS)+ undifferentiated-type GCs (UGCs) and LS−/tubular component (TC)+ UGCs in Figure 2a and Figure 2b, respectively
Based on chromosomal comparative genomic hybridization (CGH) analysis, we have reported that there are two distinct UGC lineages: the LS+ lineage derived from early signet ring cell carcinomas (SIGs) and LS−/TC+ lineage dedifferentiated from tubular adenocarcinomas (TUBs) [15]
Summary
It is suspected that early gastric carcinoma (GC) is a dormant variant that rarely progresses to advanced GC. The aim of this study is to determine whether this is the case in undifferentiated-type GCs (UGCs) of different genetic lineages: one with a layered structure (LS+), derived from early signet ring cell carcinomas (SIGs), and the other, mostly poorly differentiated adenocarcinomas, without LS but with a minor tubular component (TC), dedifferentiated from TUBs (LS−/TC+). The undifferentiated-type gastric carcinoma (UGC) according to the Japanese classification [3] mostly overlaps poorly differentiated GC, which comprises the Recently it has been proposed that advanced diffusetype GC may derive from either early diffuse-type or intestinal-type GC. Negative and late-presenting (≥1 year) neuroblastomas exhibited near-diploidy with terminal 1p deletion, whereas positive neuroblastomas in infants exhibited near-triploidy without 1p deletion [10,11] To perform such subgrouping, we have classified UGCs based on the continuity of genetic lineages as well as the expression of morphological lineage markers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
