Journal of Pathology and Translational Medicine

Review

Immune landscape and biomarkers for immuno-oncology in colorectal cancers: Jeong Mo Bae, Seung-Yeon Yoo, Jung Ho Kim, Gyeong Hoon Kang; J Pathol Transl Med. 2020;54(5):351-360. Published online June 26, 2020; DOI: https://doi.org/10.4132/jptm.2020.05.15

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Recent advances in immuno-oncology have increased understanding of the tumor immune microenvironment (TIME), and clinical trials for immune checkpoint inhibitor treatment have shown remission and/or durable response in certain proportions of patients stratified by predictive biomarkers. The TIME in colorectal cancer (CRC) was initially evaluated several decades ago. The prognostic value of the immune response to tumors, including tumor-infiltrating lymphocytes, peritumoral lymphoid reaction, and Crohn’s-like lymphoid reaction, has been well demonstrated. In this review, we describe the chronology of TIME research and review the up-to-date high-dimensional TIME landscape of CRC. We also summarize the clinical relevance of several biomarkers associated with immunotherapy in CRC, such as microsatellite instability, tumor mutational burden, POLE/POLD mutation, consensus molecular subtype, and programmed death-ligand 1 expression.

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T cell receptor clonotype in tumor microenvironment contributes to intratumoral signaling network in patients with colorectal cancer
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Intratumoral spatial heterogeneity of tumor-infiltrating lymphocytes is a significant factor for precisely stratifying prognostic immune subgroups of microsatellite instability-high colorectal carcinomas
Minsun Jung, Ji Ae Lee, Seung-Yeon Yoo, Jeong Mo Bae, Gyeong Hoon Kang, Jung Ho Kim
Modern Pathology.2022; 35(12): 2011. CrossRef
Association of Tumor-Infiltrating Lymphocytes With Survival in Stages II and III Colorectal Cancer
Marina Vitorino, Inês Eiriz, Tiago C Tomás, Rodrigo Vicente, Ana Mendes, Ana Rita Freitas, Sofia Braga, Catarina Alves-Vale, Paula Borralho, André Ferreira, Luisa Leal da Costa
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Tumor Mutational Burden Predicting the Efficacy of Immune Checkpoint Inhibitors in Colorectal Cancer: A Systematic Review and Meta-Analysis
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Genomic and transcriptomic characterization of heterogeneous immune subgroups of microsatellite instability-high colorectal cancers
Jung Ho Kim, Mi-Kyoung Seo, Ji Ae Lee, Seung-Yeon Yoo, Hyeon Jeong Oh, Hyundeok Kang, Nam-Yun Cho, Jeong Mo Bae, Gyeong Hoon Kang, Sangwoo Kim
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Original Articles

Clinicopathological Characterization and Prognostic Implication of SMAD4 Expression in Colorectal Carcinoma: Seung-Yeon Yoo, Ji-Ae Lee, Yunjoo Shin, Nam-Yun Cho, Jeong Mo Bae, Gyeong Hoon Kang; J Pathol Transl Med. 2019;53(5):289-297. Published online June 24, 2019; DOI: https://doi.org/10.4132/jptm.2019.06.07

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Abstract PDF Supplementary Material

Background
SMAD family member 4 (SMAD4) has gained attention as a promising prognostic factor of colorectal cancer (CRC) as well as a key molecule to understand the tumorigenesis and progression of CRC.
Methods
We retrospectively analyzed 1,281 CRC cases immunohistochemically for their expression status of SMAD4, and correlated this status with clinicopathologic and molecular features of CRCs.
Results
A loss of nuclear SMAD4 was significantly associated with frequent lymphovascular and perineural invasion, tumor budding, fewer tumor-infiltrating lymphocytes, higher pT and pN category, and frequent distant metastasis. In contrast, tumors overexpressing SMAD4 showed a significant association with sporadic microsatellite instability. After adjustment for TNM stage, tumor differentiation, adjuvant chemotherapy, and lymphovascular invasion, the loss of SMAD4 was found to be an independent prognostic factor for worse 5-year progression-free survival (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.01 to 1.60; p=.042) and 7-year cancerspecific survival (HR, 1.45; 95% CI, 1.06 to 1.99; p=.022).
Conclusions
We confirmed the value of determining the loss of SMAD4 immunohistochemically as an independent prognostic factor for CRC in general. In addition, we identified some histologic and molecular features that might be clues to elucidate the role of SMAD4 in colorectal tumorigenesis and progression.

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Mona Hany Emile, Sameh Hany Emile, Amr Awad El-Karef, Mohamed Awad Ebrahim, Ibrahim Eldosoky Mohammed, Dina Abdallah Ibrahim
Updates in Surgery.2024; 76(6): 2181. CrossRef
TGF-β and SMAD2/4 Expression in Nonmetastatic and Metastatic Colorectal Cancer Patients
Ainul Mardiah, Hendra Susanto, Sri Rahayu Lestari, A. Taufiq, H. Susanto, H. Nur, M. Diantoro, M. Aziz, N.A.N.N. Malek
BIO Web of Conferences.2024; 117: 01001. CrossRef
Unraveling Resistance to Immunotherapy in MSI-High Colorectal Cancer
Ronald Heregger, Florian Huemer, Markus Steiner, Alejandra Gonzalez-Martinez, Richard Greil, Lukas Weiss
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Association of β-Catenin, APC, SMAD3/4, Tp53, and Cyclin D1 Genes in Colorectal Cancer: A Systematic Review and Meta-Analysis
Hongfeng Yan, Fuquan Jiang, Jianwu Yang, Ying-Kun Xu
Genetics Research.2022; 2022: 1. CrossRef
Comprehensive genetic features of gastric mixed adenoneuroendocrine carcinomas and pure neuroendocrine carcinomas
Jiwon Koh, Soo Kyung Nam, Yoonjin Kwak, Gilhyang Kim, Ka‐Kyung Kim, Byung‐Chul Lee, Sang‐Hoon Ahn, Do Joong Park, Hyung‐Ho Kim, Kyoung Un Park, Woo Ho Kim, Hye Seung Lee
The Journal of Pathology.2021; 253(1): 94. CrossRef
Alterations of PTEN and SMAD4 methylation in diagnosis of breast cancer: implications of methyl II PCR assay
Menha Swellam, Entsar A. Saad, Shimaa Sabry, Adel Denewer, Camelia Abdel Malak, Amr Abouzid
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Molecular Characterization and Functional Analysis of Two Steroidogenic Genes TSPO and SMAD4 in Yellow Catfish
Fang Chen, Chong-Chao Zhong, Chang-Chun Song, Shu-Wei Chen, Yang He, Xiao-Ying Tan
International Journal of Molecular Sciences.2021; 22(9): 4505. CrossRef
SMAD7 and SMAD4 expression in colorectal cancer progression and therapy response
Jovana Rosic, Sandra Dragicevic, Marko Miladinov, Jovana Despotovic, Aleksandar Bogdanovic, Zoran Krivokapic, Aleksandra Nikolic
Experimental and Molecular Pathology.2021; 123: 104714. CrossRef
Actionable Potentials of Less Frequently Mutated Genes in Colorectal Cancer and Their Roles in Precision Medicine
Ryia Illani Mohd Yunos, Nurul Syakima Ab Mutalib, Francis Yew Fu Tieng, Nadiah Abu, Rahman Jamal
Biomolecules.2020; 10(3): 476. CrossRef

CpG Island Methylation in Sessile Serrated Adenoma/Polyp of the Colorectum: Implications for Differential Diagnosis of Molecularly High-Risk Lesions among Non-dysplastic Sessile Serrated Adenomas/Polyps: Ji Ae Lee, Hye Eun Park, Seung-Yeon Yoo, Seorin Jeong, Nam-Yun Cho, Gyeong Hoon Kang, Jung Ho Kim; J Pathol Transl Med. 2019;53(4):225-235. Published online March 19, 2019; DOI: https://doi.org/10.4132/jptm.2019.03.12

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Abstract PDF Supplementary Material

Background
Although colorectal sessile serrated adenomas/polyps (SSA/Ps) with morphologic dysplasia are regarded as definite high-risk premalignant lesions, no reliable grading or risk-stratifying system exists for non-dysplastic SSA/Ps. The accumulation of CpG island methylation is a molecular hallmark of progression of SSA/Ps. Thus, we decided to classify non-dysplastic SSA/Ps into risk subgroups based on the extent of CpG island methylation.
Methods
The CpG island methylator phenotype (CIMP) status of 132 non-dysplastic SSA/Ps was determined using eight CIMP-specific promoter markers. SSA/Ps with CIMP-high and/or MLH1 promoter methylation were regarded as a high-risk subgroup.
Results
Based on the CIMP analysis results, methylation frequency of each CIMP marker suggested a sequential pattern of CpG island methylation during progression of SSA/P, indicating MLH1 as a late-methylated marker. Among the 132 non-dysplastic SSA/Ps, 34 (26%) were determined to be high-risk lesions (33 CIMP-high and 8 MLH1-methylated cases; seven cases overlapped). All 34 high-risk SSA/Ps were located exclusively in the proximal colon (100%, p = .001) and were significantly associated with older age (≥ 50 years, 100%; p = .003) and a larger histologically measured lesion size (> 5 mm, 100%; p = .004). In addition, the high-risk SSA/Ps were characterized by a relatively higher number of typical base-dilated serrated crypts.
Conclusions
Both CIMP-high and MLH1 methylation are late-step molecular events during progression of SSA/Ps and rarely occur in SSA/Ps of young patients. Comprehensive consideration of age (≥ 50), location (proximal colon), and histologic size (> 5 mm) may be important for the prediction of high-risk lesions among non-dysplastic SSA/Ps.

Citations

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MLH1 Methylation Status and Microsatellite Instability in Patients with Colorectal Cancer
Manuel Alejandro Rico-Méndez, Miguel Angel Trujillo-Rojas, María de la Luz Ayala-Madrigal, Jesús Arturo Hernández-Sandoval, Anahí González-Mercado, Melva Gutiérrez-Angulo, José Geovanni Romero-Quintana, Jesús Alonso Valenzuela-Pérez, Ruth Ramírez-Ramírez,
Genes.2025; 16(2): 182. CrossRef
Immune microenvironmental heterogeneity according to tumor DNA methylation phenotypes in microsatellite instability-high colorectal cancers
Jung Ho Kim, Jiyun Hong, Ji Ae Lee, Minsun Jung, Eunwoo Choi, Nam-Yun Cho, Gyeong Hoon Kang, Sangwoo Kim
Cancer Immunology, Immunotherapy.2024;[Epub] CrossRef
How to "pick up" colorectal serrated lesions and polyps in daily histopathology practice: From terminologies to diagnostic pitfalls
Thai H Tran, Vinh H Nguyen, Diem TN Vo
World Journal of Clinical Oncology.2024; 15(9): 1157. CrossRef
Serrated Colorectal Lesions: An Up-to-Date Review from Histological Pattern to Molecular Pathogenesis
Martino Mezzapesa, Giuseppe Losurdo, Francesca Celiberto, Salvatore Rizzi, Antonio d’Amati, Domenico Piscitelli, Enzo Ierardi, Alfredo Di Leo
International Journal of Molecular Sciences.2022; 23(8): 4461. CrossRef
NTRK oncogenic fusions are exclusively associated with the serrated neoplasia pathway in the colorectum and begin to occur in sessile serrated lesions
Jung Ho Kim, Jeong Hoon Hong, Yoon‐La Choi, Ji Ae Lee, Mi‐kyoung Seo, Mi‐Sook Lee, Sung Bin An, Min Jung Sung, Nam‐Yun Cho, Sung‐Su Kim, Young Kee Shin, Sangwoo Kim, Gyeong Hoon Kang
The Journal of Pathology.2021; 255(4): 399. CrossRef
Evolving pathologic concepts of serrated lesions of the colorectum
Jung Ho Kim, Gyeong Hoon Kang
Journal of Pathology and Translational Medicine.2020; 54(4): 276. CrossRef

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