Bridging genomics and phenomics of gastric carcinoma

Cho, Junhun,Ahn, Soomin,Son, Dae‐,Soon,Kim, Nayoung KD,Lee, Ki‐,Wook,Kim, Seungtae,Lee, Jeeyun,Park, Se Hoon,Park, Joon Oh,Kang, Won Ki,An, Ji Yeong,Choi, Min Gew,Lee, Jun‐,Ho,Sohn, Alan R. Liss, Inc 2019 International journal of cancer Vol.145 No.9

<P>Genetic alterations are the starting point leading to numerous changes in clinical and pathologic features (phenotypes) of individual cancers; however, their inter‐relationships in gastric cancers (GC) are unclear. We performed massive parallel sequencing of 381 cancer‐related genes and compared the results with clinical and pathologic findings in 330 GC. High tumor mutation burden (TMB) accounted for 11% of GC (<I>n</I> = 37) and all 19 MSI‐H GCs were high TMB. High TMB was significantly more frequent in intestinal‐type by Lauren, tumor with higher host cellular immune response, earlier AJCC stage and favorable prognosis. The most significantly mutated genes were <I>TP53</I> (54%), <I>ARID1A</I> (23%), <I>CDH1</I> (22%), <I>PIK3CA</I> (12%), <I>RNF43</I> (10%) and <I>KRAS</I> (9%). For receptor tyrosine kinases, amplifications detected by immunohistochemistry were higher than sequencing (HER2, 9.1% <I>vs</I>. 5.8%; EGFR, 11.2% <I>vs</I>. 6.1%; FGFR2, 4.6% <I>vs</I>. 3.9%, c‐MET, 3.4% <I>vs</I>. 0.9%). PTEN protein loss (22%) correlated well with underlying <I>PTEN</I> alterations while ATM loss (27%) was not significantly correlated with genetic alterations of <I>ATM</I>. p53 protein expression predicted alterations of <I>TP53</I> with high sensitivity (97.8%) and low (15.9%) specificity. The poorly cohesive histology/<I>CDH1</I>‐mutant GC subgroup showed the worst survival (<I>p</I> < 0.001). PD‐L1 expression was significantly associated with MSI‐H, MLH1 loss, ATM loss, MET positivity, higher host immune response, and genetic alterations of <I>ARID1A</I>, <I>BRD3</I>, <I>PIK3CA</I>, <I>KRAS</I>, <I>MAP3K13</I>, <I>CDH2, PTEN</I> and <I>ESR1</I>. The merged clinical, pathology and genomics of GC provide a better understanding of GC and new insights into the treatment of GC.</P>

Epstein-Barr Virus-Associated Gastric Carcinoma and Specific Features of the Accompanying Immune Response

Cho, Junhun,Kang, Myung-Soo,Kim, Kyoung-Mee The Korean Gastric Cancer Association 2016 Journal of gastric cancer Vol.16 No.1

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is one of the four subtypes of gastric carcinoma (GC), as defined by the novel classification recently proposed by The Cancer Genome Atlas. EBVaGC has several clinicopathological features such as longer survival and higher frequency of lymphoepithelioma-like carcinoma (LELC) and carcinoma with Crohn's disease-like lymphoid reaction that distinguish it from EBV-negative GC. The intensity and pattern of host cellular immune response in GC have been found to significantly correlate with the prognosis of patients with GC, suggesting that immune reaction and tumor microenvironment have critical roles in the progression of GC, and in particular, EBVaGC. Here, we reviewed the cellular and molecular mechanisms underlying prominent immune reactions in patients with EBVaGC. In EBVaGC, deregulation of the expression of immune response-related genes promotes marked intra-or peritumoral immune cell infiltration. The expression of programmed death receptor-ligand 1 is known to be increased in EBVaGC, and therefore, it has been proposed as a favorable prognostic factor for patients with EBVaGC, albeit some data supporting this claim are controversial. Overall, the underlying mechanisms and clinical significance of the host cellular immune response in patients with EBVaGC have not been thoroughly elucidated. Therefore, further research is necessary to better understand the role of tumor microenvironment in EBVaGC.

Basic immunohistochemistry for lymphoma diagnosis

Junhun Cho 대한혈액학회 2022 Blood Research Vol.57 No.-

Immunohistochemistry is a technique that uses antigen-antibody interactions to detect specific proteins in cells. This technique has several essential applications in lymphoma diagnosis, including identifying the cell lineage and phase of maturation, detecting specific genetic alterations, visualizing the degree of cell proliferation, and identifying therapeutic targets. CD3 is a pan T-cell marker expressed on most of the mature T/NK-cell lymphomas, except for anaplastic large cell lymphoma, whereas CD20 is a pan B-cell marker that is expressed on most of the mature B-cell lymphomas. CD79a may be a good alternative to CD20, compensating for its loss owing to the plasmocytic differentiation of tumor cells or history of rituximab administration. CD56, a neuroendocrine marker, is used as an NK cell marker in lymphoma diagnosis. Characteristic translocations occurring in follicular lymphoma (BCL2) and mantle cell lymphoma (CCND1) can be detected by the overexpression of Bcl-2 and cyclin D-1 in immunohistochemistry, respectively. Ki-67 reflects the degree of tumor cell proliferation by indicating cells in cell cycle phases other than G0. With the development of immunotherapy, several antibodies against markers such as programmed death-ligand 1 (PD-L1), CD19, and CD30 have been used as biomarkers to identify therapeutic targets. It is critical to properly fix the specimens to obtain accurate immunohistochemical results. Therefore, all processes, from tissue collection to the final pathological diagnosis, must be performed appropriately for accurate lymphoma diagnosis.

Host immune response index in gastric cancer identified by comprehensive analyses of tumor immunity

Park, Charny,Cho, Junhun,Lee, Jeeyun,Kang, So Young,An, Ji Yeong,Choi, Min Gew,Lee, Jun Ho,Sohn, Tae Sung,Bae, Jae Moon,Kim, Sung,Kim, Seung Tae,Park, Se Hoon,Park, Joon Oh,Kang, Won Ki,Sohn, Insuk,Ju Informa UK (Taylor Francis) 2017 Oncoimmunology Vol.6 No.11

<P>Tumor infiltrating lymphocytes (TIL) in Epstein-Barr virus (EBV)-associated/microsatellite-unstable (MSI) gastric carcinomas (GC) constitute immune-active principal cellular components of tumor microenvironment and contribute to better prognosis. With the remarkable success of cancer immunotherapies, there is an urgent need for a comprehensive understanding of tumor-immune interactions in patients with GC in the context of host immune response. To identify GC subtype-specific immune response gene set, we tested differentially expressed genes for MSI and EBV+ GC subtypes in randomly selected test set (n = 278) in merged ACRG-SMC microarray and TCGA RNA sequencing data set. We identified Host ImmunE Response index (HIERI) consisting of 29 immune genes classifying GC patients into robust 3 groups with prognostic significance. Immune-high cluster 1 was enriched with PD-L1(High)/EBV+/MSI/TILHigh with the best clinical outcome while immune-low cluster 3 displayed worst outcome and exemplified with PD-L1(Low)/EBV-/MSS. The results were validated in the same cohort (n = 279) and independent cohort (n = 181) with RNA from formalin-fixed paraffin-embedded (FFPE) tissue. Unexpectedly, nearly half of GC in cluster 1 were EBV-/MSS and 10% of cluster 3 GC were EBV+/MSI GC patients, suggesting that in addition to EBV+/MSI GC subtypes, EBV-/MSS subtype also constitutes almost half of high immune cluster and would be a good candidate for immune checkpoint inhibitor therapy. In contrary, almost 10% of EBV+/MSI GC patients may not respond to immune checkpoint inhibitor therapy. Thus, our HIERI gene signature demonstrates the potential to subclassify tumor immunity levels, predict prognosis and help immunotherapeutic decisions.</P>

Pyloric Gland Adenoma in Lynch Syndrome

Lee, Seung Eun,Kang, So Young,Cho, Junhun,Lee, Boram,Chang, Dong Kyung,Woo, Hyein,Kim, Jong Won,Park, Ha Young,Do, In Gu,Kim, Young Eun,Kushima, Ryoji,Lauwers, Gregory Y.,Park, Cheol Keun,Kim, Kyoung Raven Press 2014 The American journal of surgical pathology Vol.38 No.6

<P>The prevalence of gastric cancer associated with Lynch syndrome (LS) is highly variable, and the underlying histologic pathway or molecular mechanisms remain unclear. From 1995 to 2012, 15 patients had been treated for both gastric and colonic adenocarcinomas and diagnosed as LS. In all cases, pathologic review, immunohistochemical analysis for mismatch-repair proteins, and microsatellite instability (MSI) tests were performed. To confirm LS, germline mutation tests and multiplex ligation-dependent probe amplification were performed. All gastric and colonic carcinomas were MSI-high and lost expressions of MLH1/PMS2 in 11 (73%) cases and MSH2/MSH6 in 4 (27%) cases. Remarkably, in a patient with LS and germline mutation of <I>MLH1</I> gene, pyloric gland adenoma (PGA) transformed to adenocarcinoma during follow-up. In 2 additional cases, PGA was found adjacent to advanced gastric cancers. All PGAs in LS patients were MSI-high and lost expression of mismatch-repair proteins (MLH1/PMS2 in 2 cases and MSH2/MSH6 in 1 case), whereas none of the 14 sporadic PGAs was MSI-high or had lost expression of mismatch-repair proteins. On the basis of these observations, although very rare, we suggest the possibility that PGA may be a precursor lesion to gastric adenocarcinoma in LS and that the mismatch-repair deficient pathway of carcinogenesis is involved early in the gastric carcinogenesis pathway.</P>

A retrospective analysis of ibrutinib outcomes in relapsed or refractory mantle cell lymphoma

Yong-Pyo Lee,Ye Ji Jung,Junhun Cho,Young Hyeh Ko,Won Seog Kim,Seok Jin Kim,Sang Eun Yoon 대한혈액학회 2023 Blood Research Vol.58 No.4

Background While treatment strategies for mantle cell lymphoma (MCL) have evolved, patients often experience disease progression and require additional treatment therapies. Ibrutinib presents a promising option for relapsed or refractory MCL (RR-MCL). This study investigated real-world treatment outcomes of ibrutinib in patients with RR-MCL. Methods A single-center retrospective analysis investigated clinical characteristics and survival outcomes of patients with RR-MCL, treated with ibrutinib. Results Forty-two patients were included, with 16 received rituximab and bendamustine, and 26 receiving anthracycline-based regimens as front-line treatment. During a median follow- up of 46.0 months, the response rate to ibrutinib was 69%, with 12 CRs and 8 partial responses. Disease progression (54.8%) and adverse events (11.9%) were the primary reasons for discontinuation. Median progression-free survival (PFS) and overall survival (OS) were approximately 16.4 and 50.1 months, respectively. Patients older than 70 years (P =0.044 and P=0.006), those with splenomegaly (P =0.022 and P =0.006), and those with a high-risk simplified Mantle Cell Lymphoma International Prognostic Index (sMIPI) (P <0.001 and P <0.001) exhibited siginificantly inferior PFS and OS. Notably, patients with a high-risk sMIPI relapsed earlier. Post-ibrutinib treatment yilded an OS of 12.2 months, while clinical trial participants demonstrated superior survival compared to those receiving chemotherapy alone. Conclusion This study underscores the importance of considering patient characteristics before administering ibrutinib as salvage therapy. Early relapse was associated with poor outcomes, highlighting the need for novel therapeutic strategies.

Renal Ischemia-Reperfusion Injury in a Diabetic Monkey Model and Therapeutic Testing of Human Bone Marrow-Derived Mesenchymal Stem Cells

Lee, Kyo Won,Kim, Tae Min,Kim, Kyeong Sik,Lee, Seunghwan,Cho, Junhun,Park, Jae Berm,Kwon, Ghee Young,Kim, Sung Joo Hindawi 2018 Journal of diabetes research Vol.2018 No.-

<P>Clinically, acute kidney injury (AKI) episodes in diabetes mellitus (DM) patients are associated with a cumulative risk of developing end-stage renal disease. In this study, we asked whether the severity of AKI induced by renal ischemia-reperfusion injury (IRI) is more prominent in DM than in non-DM control using a cynomolgus monkey (<I>Macaca fascicularis)</I> model. We also investigated whether human bone marrow-derived mesenchymal stem cells (hBM-MSCs) infused via the renal artery could ameliorate renal IRI in DM monkeys. The experimental data, including mortality rate, histologic findings, and urinary albumin secretion indicate that the severity of AKI was greater in DM monkeys than in control animals. Moreover, histological findings and qRT-PCR analysis of <I>Ngal</I> mRNA in renal biopsy tissue showed that hBM-MSC promoted the recovery of tubular damage caused by AKI. Serum analysis also revealed that the level of albumin and ALT was increased 24 and 48 hours after AKI, respectively, suggesting that AKI induced acute liver injury. We suggest that this nonhuman primate model could provide essential information about the renal and nonrenal impairment related to DM and help determine the clinical usefulness of MSCs in AKI.</P>

Hydroa Vacciniforme-Like Lymphoproliferative Disorder in Korea: Prognostic Implication of Clinical Signs and Whole Blood Epstein-Barr Virus DNA

( Se Jin Oh ),( Jongeun Lee ),( Ji-hye Park ),( Jong Hee Lee ),( Junhun Cho ),( Young-hyeh Ko ),( Dongyoun Lee ) 대한피부과학회 2021 Annals of Dermatology Vol.33 No.3

Background: Hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) is rare Epstein-Barr virus (EBV)-associated disease. The classic form of HVLPD is a self-resolving disease, whereas the systemic form can progress to malignant lymphoma, resulting in fatal outcomes. However, the prognostic factors remain unclear. Objective: This study aimed to evaluate the clinical characteristics of HVLPD and the association between whole blood EBV DNA and clinical outcomes. Methods: We retrospectively reviewed our 25-year experience involving 11 patients with HVLPD from a single tertiary center in South Korea and evaluated the clinical characteristics of HVLPD and the correlation between whole blood EBV DNA and clinical outcomes. Results: Of the total 11 patients, 54.5% (6/11) manifested classic HVLPD that resolved with conservative treatment, while 45.5% (5/11) patients had systemic HVLPD, four of whom died of progressive disease or hemophagocytic syndrome. Five patients with systemic HVLPD manifested severe skin lesions such as prominent facial edema, deep ulcers and necrotic skin lesions involving sun-protected areas. Median EBV DNA levels at initial diagnosis were higher in three dead patients than in those alive (2,290 vs. 186.62 copies/μl). Conclusion: When EBV DNA levels were high, patients showed severe skin lesions and when EBV DNA levels were low, skin lesions tended to improve. Thus, patients with high EBV DNA levels showed an increased risk of severe skin lesions and disease progression. (Ann Dermatol 33(3) 222∼227, 2021)