Publications by authors named "You Jeong Heo"

14 Publications

  • Page 1 of 1

PD-L1 expression in paired biopsies and surgical specimens in gastric adenocarcinoma: A digital image analysis study.

Pathol Res Pract 2021 Feb 2;218:153338. Epub 2021 Jan 2.

Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Center of Companion Diagnostics, Samsung Medical Center, Seoul, Republic of Korea; Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea. Electronic address:

Programmed death-ligand 1 (PD-L1) expression in biopsies of gastric carcinoma may predict the results in corresponding surgical specimens. We compared PD-L1 immunohistochemistry (IHC) 22C3 pharmDx expression in paired biopsy and resection specimens. We also characterized the validity of a new PD-L1 assay using digital image analysis. PD-L1 IHC with 22C3 pharmDx and clone 73-10 was performed in 224 gastric cancer tissues (112 biopsies and paired surgical tissues) and the specimens were analyzed with the Leica Aperio Imagescope. For statistical analyses, the area under the receiver operating characteristic curve and R package were used. With 22C3 pharmDx, a PD-L1 combined positive score of ≥1 was found in 36 biopsied (32.14 %) and 53 surgical (47.32 %) samples. PD-L1 expression results were concordant in 71 cases (63.4 %) and discordant in 41 (36.6 %). The overall discordance rate was 36.61 % (95 % confidence interval 2.101-8.983) and the κ value was 0.254 with fair agreement. The sensitivity and specificity of biopsy PD-L1 to predict the results of the surgical specimen was 62 % and 73 %, respectively. The correlation of 22C3 pharmDx and clone 73-10 was high (correlation coefficient = 0.88). When only tumor cell staining was compared, this correlation was increased (correlation coefficient = 0.95). Our results indicated moderate association of PD-L1 expression between gastric biopsies and corresponding resected tumors. Results of PD-L1 assay with 73-10 are comparable to 22C3 pharmDx results.
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http://dx.doi.org/10.1016/j.prp.2020.153338DOI Listing
February 2021

Digital image analysis in pathologist-selected regions of interest predicts survival more accurately than whole-slide analysis: a direct comparison study in 153 gastric carcinomas.

J Pathol Clin Res 2021 01 4;7(1):42-51. Epub 2020 Sep 4.

The Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Automatic quantification of biomarkers such as tumor-infiltrating lymphocytes and PD-L1 is one of the most studied topics in digital pathology image analysis (DIA). However, direct comparison between the DIA of a whole-slide image (WSI) and that of regions of interest (ROIs) chosen by pathologists has not been performed. In this study, we aimed to compare the prognostic value of tumor microenvironment markers CD8 and PD-L1, measured by DIA of WSIs and ROIs. We selected 153 primary gastric cancer tissues and stained them with CD8 and PD-L1. All IHC slides were scanned at ×200 magnification and ratios of CD8 and PD-L1 were measured in WSIs and ROIs from the invasive front, within the tumor, and the mucosa. Patients with high CD8 and PD-L1 ratios showed more favorable outcomes compared to those with low ratios. Pathologist-aided DIA predicted the survival of patients more accurately than WSI analysis (CD8, p = 0.025 versus p = 0.068; PD-L1, p = 0.008 versus p = 0.2). Although a high density of CD8+ T cells at the invasive front correlated best with patient survival, CD8 ratio in the mucosa could also predict patient outcome. In conclusion, CD8 and PD-L1 ratios measured by pathologist-aided DIA predicted survival more accurately than WSI analyses and ROIs at the invasive front correlated best with patient outcome.
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http://dx.doi.org/10.1002/cjp2.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737754PMC
January 2021

PTEN Protein Loss and Loss-of-Function Mutations in Gastric Cancers: The Relationship with Microsatellite Instability, EBV, HER2, and PD-L1 Expression.

Cancers (Basel) 2020 Jun 29;12(7). Epub 2020 Jun 29.

Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.

Inactivation of phosphatase and tensin homolog (PTEN) is caused by multiple mechanisms, and loss of PTEN activity is related to the progression of various cancers. In gastric cancer (GC), the relationship between the loss of PTEN protein expression and various genetic alterations remains unclear. The effects of microsatellite instability (MSI), Epstein-Barr virus (EBV), HER2 overexpression, and PD-L1 expression on mutation have not been fully explored. We performed comprehensive cancer panel tests with a cohort of 322 tumor samples from patients with advanced GC. Immunohistochemistry for PTEN protein was performed in all cases, and the loss of protein expression was defined as a complete absence of nuclear staining. In total, 34 cases (10.6%) had pathogenic mutations, of which 19 (55.9%) showed PTEN protein loss. The most common variants associated with protein loss were p.R130 ( = 4) followed by p.R335, p.L265fs, and deletions ( = 2). All the ten nonsense mutations identified in the samples resulted in PTEN inactivation. In the remaining 288 GC cases with wild-type , protein loss was found in 35 cases (12.2%). Thus, mutations were significantly associated with PTEN protein loss ( = 5.232 × 10), high MSI ( = 3.936 × 10), and EBV-positivity ( = 0.0071). In conclusion, our results demonstrate that loss-of-function mutations in are a frequent genetic mechanism of PTEN inactivation in GC.
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http://dx.doi.org/10.3390/cancers12071724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407887PMC
June 2020

Dysregulated miRNA in a cancer-prone environment: A study of gastric non-neoplastic mucosa.

Sci Rep 2020 04 20;10(1):6600. Epub 2020 Apr 20.

Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Understanding cancer-prone environments is important to efficiently detect and prevent cancers. The associations between miRNA and cancer-prone environments are still largely unknown in gastric cancer (GC). Six miRNAs that are differentially expressed during gastric carcinogenesis were selected, and quantitative real-time PCR was performed in an independent training set (fresh non-tumor and tumor samples from 18 GC patients) and validation sets (set 1 with formalin-fixed paraffin-embedded non-tumor and tumor samples from 19 solitary GC and set 2 with 37 multiple GC patients). The results were compared with those of 37 gastric mucosa from 20 healthy volunteers. The expression levels of miR-26a, miR-375, and miR-1260 in gastric mucosa from healthy volunteers were statistically higher than that of non-tumorous gastric mucosa located 3 cm apart from the GC in the training set (miR-26a, P < 0.0001; miR-375, P = 0.0049; miR-1260, P = 0.0172), validation set 1 (miR-26a and miR-375, P < 0.0001; miR-1260, P = 0.0008), and validation set 2 (miR-26a, miR-375, and miR-1260, P < 0.0001). And a combination of miR-26a and miR-1260 showed the highest area under the curve value of 0.89. miRNAs are differentially expressed in non-neoplastic gastric mucosa and can be used as a biomarker to predict cancer-prone environments.
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http://dx.doi.org/10.1038/s41598-020-63230-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171080PMC
April 2020

CDH1 mutations in gastric cancers are not associated with family history.

Pathol Res Pract 2020 May 28;216(5):152941. Epub 2020 Mar 28.

Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea. Electronic address:

CDH1 mutation is the most frequent genetic alteration in hereditary diffuse gastric cancer (GC) and early onset diffuse GC patients. However, the incidence of CDH1 mutations in sporadic GC with or without family history has not been studied. This retrospective study includes a total of 993 Korean patients with primary advanced GC who underwent surgery and received palliative chemotherapy. Targeted deep sequencing was performed in all cases and family history of GC was searched with survival analysis. We found CDH1 alterations in 146 of 993 patients (14.7 %) and 8 were germline (0.8 %). Out of 146 patients with CDH1 mutations, 25 (17.1 %) had a family history of GC in one of their first relatives, and 12 patients (8.2 %) were diagnosed with familial GC (FGC). All cases with FGC were diffuse type by Lauren classification, and only one harbored a previously reported germline mutation of CDH1 (c.2638 G > A) and the remaining 11 harbored known somatic CDH1 mutations. Among all patients with CDH1 mutation, there was no significant survival difference between patients with family history or FGC. In the 847 patients without CDH1 mutation, 189 (22.3 %) had a family history of GC and 92 patients (10.9 %) were FGC. CDH1 mutations were more frequent in patients with early onset (<45 years) GC (45.5 %) compared with patients with late onset GC (10.9 %) (p = 0.001), but were not significantly associated with the family history of GC (p > 0.05). CDH1 mutations are mostly somatic and typically are not associated with family history.
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http://dx.doi.org/10.1016/j.prp.2020.152941DOI Listing
May 2020

Tumor Mutational Burden Determined by Panel Sequencing Predicts Survival After Immunotherapy in Patients With Advanced Gastric Cancer.

Front Oncol 2020 13;10:314. Epub 2020 Mar 13.

Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

Panel-based sequencing is widely used to measure tumor mutational burden (TMB) in clinical trials and is ready to enter routine diagnostics. However, cut-off points to distinguish "TMB-high" from "TMB-low" tumors are not consistent and the clinical implications of TMB in predicting responses to immune checkpoint blockade (ICB) in gastric cancer are not clearly defined. We aimed to assess whether TMB is associated with the response to immunotherapy and to examine its relation with other biomarkers of immunotherapy response in advanced gastric cancer. In total, 63 patients with advanced gastric cancer treated with ICB were included in the study. Panel-based TMB in gastric tumor samples, treatment responses to ICB, clinicopathological data, and time to progression were retrospectively analyzed. Microsatellite instability (MSI) status, Epstein-Barr virus (EBV) positivity, and programmed death-ligand 1 (PD-L1) combined positive score (CPS) were also analyzed. TMB ranged from 0 to 446 mutations/megabase (mt/mb) and was significantly associated with MSI ( < 0.001), PD-L1 CPS ( = 0.022), response to ICB ( = 0.04), chemotherapy ( = 0.02) and older patient age (≥65 years; = 0.0014). The cut-off point of 14.31 mt/mb determined by log-rank statistics for progression-free survival divided the tumors into eight (12.7%) TMB-high and 55 (87.3%) TMB-low tumors. The median TMB of the chemo-refractory group was significantly higher (8.43 mt/mb) compared to that of chemo-naïve group (3.42 mt/mb) ( = 0.02). Patients with TMB-high tumors showed prolonged progression-free survival in univariate [HR, 0.32; 95% confidence interval (CI), 0.12-0.90] and multivariate (HR, 0.21; 95% CI, 0.07-0.69) analyses. In area under the receiver operating curve (AUC) analysis of TMB, PD-L1, EBV, MSI, and their combination, the AUC value was the highest for EBV (0.97), followed by MSI (0.96), PD-L1 (0.81), the combination (0.78), and TMB (0.56). In addition to EBV, MSI, and PD-L1 CPS, TMB could be used as a predictive biomarker in patients with advanced gastric cancer treated with ICB and may aid clinical decision making.
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http://dx.doi.org/10.3389/fonc.2020.00314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082319PMC
March 2020

PD-L1 expression in gastric cancer determined by digital image analyses: pitfalls and correlation with pathologist interpretation.

Virchows Arch 2020 Feb 28;476(2):243-250. Epub 2019 Aug 28.

Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, No. 81, Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea.

Programmed death ligand-1 (PD-L1) immunohistochemistry is used to predict response to anti-PD-L1 therapy. However, intra- and inter-observer variability influence the prediction of PD-L1 expression. Unlike evaluations of non-small cell lung cancer according to PD-L1 expression determined by tumor proportion score, gastric cancer is evaluated using combined positive scores. We aimed to compare the results of digital image analysis and pathologists' interpretations for predicting response to pembrolizumab in gastric cancer patients. Gastric cancer tissues from patients enrolled in a clinical trial of pembrolizumab were reviewed, and 39 cases were analyzed. PD-L1 22C3 PharmDx (Dako) immunohistochemistry slides were interpreted by digital image analysis and by the consensus of two pathologists, and the results of interpretations were compared with the eventual clinical responses to pembrolizumab. In direct comparisons of digital image analyses and pathologists' interpretations, 33 (84.6%) out of 39 cases showed concordant results. In 6 (15.4%) cases, weak staining of PD-L1, anthracotic pigment deposits, or decalcification artifacts caused discordant results, and all the cases were challenging. In statistical analyses, PD-L1 expression as interpreted by pathologists and digital image analysis did not differ significantly for predicting responses to pembrolizumab (P = 0.1856). Digital image analyses and pathologists' interpretations showed concordant results for PD-L1 combined positive scores in most cases, and the prediction performances of each were not significantly different.
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http://dx.doi.org/10.1007/s00428-019-02653-2DOI Listing
February 2020

Reproduction of molecular subtypes of gastric adenocarcinoma by transcriptome sequencing of archival tissue.

Sci Rep 2019 07 4;9(1):9675. Epub 2019 Jul 4.

Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Gastric cancer (GC) is a heterogeneous disease, so molecular classification is important for selecting the most appropriate treatment strategies for GC patients. To be applicable in the clinic, there is an urgent need for a platform that will allow screening real-life archival tissue specimens. For this purpose, we performed RNA sequencing of 50 samples from our Asian Cancer Research Group (ACRG) GC cohort to reproduce the molecular subtypes of GC using archival tissues with different platforms. We filtered out genes from the epithelial-to-mesenchymal transition (EMT) and microsatellite instability-high (MSI) signatures (coefficient ≤ 0.4) followed by the ACRG molecular subtype strategy. Overall accuracy of reproduction of ACRG subtype was 66% (33/50). Given the importance of EMT subtype in future clinical trials, we further developed the minimum number of genes (10 genes) for EMT signatures correlating highly with the original EMT signatures (correlation ≥ 0.65). Using our 10-gene model, we could classify EMT subtypes with high sensitivity (0.9576) and specificity (0.811). In conclusion, we reproduced ACRG GC subtypes using different platforms and could predict EMT subtypes with 10 genes and are now planning to use them in our prospective clinical study of precision oncology in GC.
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http://dx.doi.org/10.1038/s41598-019-46216-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609684PMC
July 2019

CCNE1 amplification is associated with liver metastasis in gastric carcinoma.

Pathol Res Pract 2019 Aug 4;215(8):152434. Epub 2019 May 4.

Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address:

With targeted therapies becoming the new standard of care in oncology, next generation sequencing (NGS) is emerging as a valuable method for analyzing the molecular underpinnings of individual tumors. Cyclin E1, encoded by CCNE1 causes activation of E2F mediated transcription and drives cells from G1 into S phase with cyclin-dependent kinase 2 (CDK2). CCNE1 amplification has been found in 11-12% of gastric cancers, but the clinical significance of this amplification remains controversial, and its association with liver metastasis has not been studied. This study included 226 patients diagnosed with advanced gastric adenocarcinoma. We performed multi-gene panel tests containing 143 genes using DNA and RNA obtained from primary (n = 197; 120 endoscopic biopsies and 77 resections) or metastatic cancer tissues (n = 29; 26 biopsies, 2 excisions, and 1 fin. needle aspiration). Among the 226 cases, 28 cases (12.4%) had CCNE1 amplification, almost half of which (n = 13, 46.4%) showed liver metastasis. In patients with CCNE1 amplification (n = 28), TP53 mutations (n = 23, 82.1%) and ERBB2 amplification (n = 8, 28.6%) were the most frequent concurrent genetic alterations. In contrast, 42 (21.2%) of 198 patients without CCNE1 amplification showed liver metastasis. CCNE1 amplification was significantly associated with liver metastasis (p = 0.004; odds ratio, 3.219). Our results show that CCNE1 amplification is significantly associated with liver metastasis in a TP53-mutated gastric cancer subtype. Given the frequent association of CCNE1 amplification with liver metastasis, close follow up for liver metastasis and further clinical trials targeting CDK2 inhibitors are warranted.
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http://dx.doi.org/10.1016/j.prp.2019.152434DOI Listing
August 2019

MET is overexpressed in microsatellite instability-high gastric carcinoma.

Pathol Res Pract 2019 Mar 12;215(3):433-438. Epub 2018 Nov 12.

Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address:

Background: MET is a tyrosine kinase receptor for the hepatocyte growth factor, and its overexpression is a poor prognostic factor in gastric carcinomas. Programmed death-ligand 1 (PD-L1) is an important biomarker of immunotherapy and is frequently positive in microsatellite instability-high (MSI-H) gastric carcinomas. In lung cancers, MET activation up-regulates PD-L1 expression. In this study, we investigated expression of MET and PD-L1 in MSI-H gastric carcinoma and the effects on prognosis.

Methods: MET and PD-L1 (SP142) immunohistochemistry was performed in 73 gastric carcinomas with MSI-H. In cases with MET overexpression, we performed fluorescent in situ hybridization (FISH). PD-L1 expression was calculated from both tumor cells (2+ and 3+ in > 10% of tumor cells was defined as PD-L1) and immune cells (positive in >5% immune cells was PD-L1), and also used a combined positive score (CPS; number of PD-L1 staining cells relative to all viable tumor cells; > 1 was PD-L1).

Results: In 73 MSI-H gastric carcinomas, MET overexpression was observed in 11 cases (15.1%). In all 11 cases with MET overexpression,MET amplification was not found. MET overexpression was not related to any of clinico-pathological variables and PD-L1 expression. However, the PD-L1 CPS tended to be higher in tumors that were MET positive. Although MET overexpression alone was not a prognostic indicator, combined MET overexpression/PD-L1 predictive models showed that patients with MET/PD-L1 showed the best prognosis for overall survival as compared to other groups.

Conclusion: MET overexpression was observed in 15% of MSI-H gastric carcinomas and was associated with high level expression of PD-L1.
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http://dx.doi.org/10.1016/j.prp.2018.11.010DOI Listing
March 2019

Computational measurement of tumor immune microenvironment in gastric adenocarcinomas.

Sci Rep 2018 09 17;8(1):13887. Epub 2018 Sep 17.

Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

The use of four groups of tumor immune microenvironments (TME) based on PD-L1 and tumor-infiltrating T lymphocytes (TIL) is a reliable biomarker for anti-PD-1/PD-L1 inhibitor therapy. We classified the TME in 241 gastric cancers which were subdivided according to 40 EBV+, 76 microsatellite instability-high (MSI-H), and 125 EBV-/microsatellite-stable (MSS) subtypes by quantitative image analysis (QIA) and correlated the results with mRNA expression levels. The mean PD-L1 ratio and CD8 ratio in EBV+, MSI-H, and EBV-/MSS GCs were significantly different (P < 0.006). The PD-L1 ratio and CD8 ratio obtained by QIA correlated well with the RNA levels of PD-L1 (r = 0.63) and CD8 (r = 0.67), respectively. The TME were type I (PD-L1/CD8) in 45, type II (PD-L1/CD8) in 106, type III (PD-L1/CD8) in 8, and type IV (PD-L1/CD8) in 82 cases. The type I TME was significantly associated with high TIL (P = 3.0E-11) and EBV+ status (P = 8.55E-08). In conclusion, QIA results correlated well with the mRNA expression levels and classified TME of gastric cancers.
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http://dx.doi.org/10.1038/s41598-018-32299-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141531PMC
September 2018

Factors Associated With Host Immune Response and Number of Lymph Nodes: A Large Retrospective Cohort Study.

Ann Surg Oncol 2018 Nov 4;25(12):3621-3628. Epub 2018 Sep 4.

Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background: The host immune response (HIR) against tumor cells is one of the key players in antitumor activities. However, the relationship between HIR and regional lymph nodes (LN) and their impacts on prognosis have not been studied.

Methods: This study analyzed HIR and clinicopathologic factors for 8819 consecutive gastric cancer patients who underwent gastrectomy and D2 LN dissection. The findings confirmed Epstein-Barr virus (EBV) with Epstein-Barr encoding region in situ hybridization, HIR grading (G1, G2, and G3), LN numbers classified into seven groups, and performed ordinal regression analysis.

Results: The mean number of LNs was 41. A higher degree of HIR was significantly associated with male sex, EBV+, non-intestinal histology by Lauren classification, earlier American Joint Committee on Cancer (AJCC) stage, and greater number of LNs (P < 0.001). Female gender, younger age (< 60 years), EBV+, non-intestinal histology, higher HIR grade (G2 and G3), larger tumor size, and deeper invasion depth were significantly related to a higher number of LNs, with an odds ratio greater than 1. In cancer-specific survival analyses, EBV+, younger age, higher HIR grade (G3), and increased number of LNs were independent prognostic factors in addition to AJCC stage.

Conclusions: The HIR was associated with increased number of LNs was a significant favorable prognosticator.
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http://dx.doi.org/10.1245/s10434-018-6731-zDOI Listing
November 2018

Four distinct immune microenvironment subtypes in gastric adenocarcinoma with special reference to microsatellite instability.

ESMO Open 2018 15;3(3):e000326. Epub 2018 Mar 15.

Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Introduction: Programmed death-ligand 1 (PD-L1) can be overexpressed in tumours other than Epstein-Barr virus (EBV)-positive (EBV) or microsatellite instability-high (MSI-H) gastric cancer (GC) subtypes. We aimed to determine the tumour immune microenvironment (TME) classification of GC to better understand tumour-immune interactions and help patient selection for future immunotherapy with special reference to MSI-H.

Methods: Immunohistochemistry (IHC) for PD-L1 and CD8 T cells in three distinct subtypes of GC (43 EBV, 79 MSI-H and 125 EBV/MSS) were performed and analysed. In 66 MSI-H GC, mutation counts were compared with PD-L1 expression and survival of the patients.

Results: GC TME divided by PD-L1 IHC and tumour-infiltrating lymphocytes (TIL) measured by intratumoural CD8 density showed: (1) about 40% of GC are type I (PD-L1/TIL) consisting ~70% of MSI-H or EBV GC, and ~15% of EBV/microsatellite stable (MSS) GC patients show the best survival in both disease-free (HR 2.044) and overall survival (HR 1.993); this type would respond to a checkpoint blockade therapy; (2) almost 30% of GC are type II (PD-L1/TIL) with the worst survival; (3) approximately 10% of GC are type III (PD-L1/TIL); and (4) up to 20% are type IV (PD-L1/TIL) and, unexpectedly, ~25% of EBV or MSI-H GC are within this subtype. In MSI-H GC, frequent frameshift mutations were observed in , , , , , , , and and the numbers of frameshift mutation correlated significantly with PD-L1 expression (P<0.05).

Discussion: GC can be classified into four TME types based on PD-L1 and TIL, and numbers of frameshift mutation correlate well with PD-L1 expression in MSI-H GC.
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http://dx.doi.org/10.1136/esmoopen-2018-000326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890063PMC
March 2018

The HSA21 gene EURL/C21ORF91 controls neurogenesis within the cerebral cortex and is implicated in the pathogenesis of Down Syndrome.

Sci Rep 2016 07 11;6:29514. Epub 2016 Jul 11.

EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.

Copy number variations to chromosome 21 (HSA21) cause intellectual disability and Down Syndrome, but our understanding of the HSA21 genetic factors which contribute to fetal brain development remains incomplete. Here, we focussed on the neurodevelopmental functions for EURL (also known as C21ORF91, Refseq Gene ID:54149), a protein-coding gene at the centromeric boundary of the Down Syndrome Critical Region (DSCR) of HSA21. We report that EURL is expressed during human and mouse cerebral cortex development, and we report that alterations to EURL mRNA levels within the human brain underlie Down Syndrome. Our gene perturbation studies in mice demonstrate that disruptions to Eurl impair progenitor proliferation and neuronal differentiation. Also, we find that disruptions to Eurl impair the long-term positioning and dendritic spine densities of cortical projection neurons. We provide evidence that EURL interacts with the coiled-coil domain-containing protein CCDC85B so as to modulate β-catenin levels in cells. Further, we utilised a fluorescent reporter (8xTOPFLASHd2EGFP) to demonstrate that disruptions to Eurl alter β-catenin signalling in vitro as well as in vivo. Together, these studies highlight EURL as an important new player in neuronal development that is likely to impact on the neuropathogenesis of HSA21-related disorders including Down Syndrome.
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http://dx.doi.org/10.1038/srep29514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941730PMC
July 2016