Cancer Genomics & Proteomics最新文献

{"title":"G-Protein-coupled Estrogen Receptor 1 (GPER1) Overexpression Affects Aggressiveness of Cervical Carcinoma Cells Depending on Histological Entity.","authors":"Lena Hambach, Julia Gallwas, Carsten Gründker","doi":"10.21873/cgp.20509","DOIUrl":"https://doi.org/10.21873/cgp.20509","url":null,"abstract":"<p><strong>Background/aim: </strong>Cervical cancer (CC) is the fourth most common cancer in women worldwide. There are two main histological subtypes of CC: the more common cervical squamous cell carcinoma (CSCC) and the rarer cervical adenocarcinoma (CAC), which has a poorer prognosis. Unlike estrogen receptor (ER) α and ERβ, G-protein-coupled estrogen receptor 1 (GPER1) is recognized as a rapid mediator of cellular estrogenic action and tends to have tumor suppressive properties in CC. Since a clinical study showed that an elevated GPER1 expression is associated with a worse prognosis, we investigated the effects of stable GPER1 overexpression (GPER1-OE) on SiHa CSCC and HeLa CAC cells.</p><p><strong>Materials and methods: </strong>SiHa CSCC and HeLa CAC cells with stable GPER1-OE were generated. GPER1-OE was tested by RT-qPCR, western blot and fluorescence-activated cell analysis (FACS). The effects of GPER1-OE on proliferation, migration, invasion, apoptosis and stem cell properties (colony and sphere formation) were then examined.</p><p><strong>Results: </strong>Successful GPER1-OE in SiHa CSCC and HeLa CAC cells was confirmed. The cell characterization experiments showed that SiHa CSCC cells with stable GPER1-OE had faster proliferation and migration, and increased stem cell properties with larger and more numerous colonies and larger tumor spheres. In HeLa CAC cells, on the other hand, GPER1-OE resulted in slower cell proliferation, migration and invasion, reduced colony formation and tumor sphere formation. An increased rate of apoptosis was also observed.</p><p><strong>Conclusion: </strong>GPER1-OE resulted in a more aggressive tumor behavior of SiHa CSCC cells and a less aggressive tumor behavior of HeLa CAC cells, due to a different effect of GPER1 overexpression depending on the respective histological subtypes of CC. This underlines the need for personalized medicine and a precise differentiation of subtypes in CC-related research.</p>","PeriodicalId":9516,"journal":{"name":"Cancer Genomics & Proteomics","volume":"22 3","pages":"397-414"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of \"Hallmarks of Cancer\" Genes in Cervical Carcinoma Is Differentially Affected by GPER1 Overexpression Depending on Histologic Entity.","authors":"Lena Hambach, Julia Gallwas, Carsten Gründker","doi":"10.21873/cgp.20510","DOIUrl":"https://doi.org/10.21873/cgp.20510","url":null,"abstract":"<p><strong>Background/aim: </strong>Cervical cancer (CC) remains the fourth most common malignancy in women worldwide. Current treatments primarily consist of surgery and combined radiochemotherapy, while targeted therapies, as seen in other malignancies, remain underdeveloped. The G-protein-coupled estrogen receptor (GPER1) is implicated in various cancers and can differentially influence tumor behavior, though its precise role in CC remains unclear, with both tumor-promoting and tumor-suppressive effects reported. We previously explored the impact of stable GPER1 overexpression (OE) in CC cell lines, SiHa (cervical squamous cell carcinoma, CSCC) and HeLa (cervical adenocarcinoma, CAC), analyzing proliferation, migration, invasion, apoptosis, and stem cell properties. GPER1-OE enhanced tumorigenic properties in CSCC cells but demonstrated tumor-suppressive effects in CAC cells. To investigate the underlying mechanisms, we conducted next-generation sequencing (NGS) analyses, which supported our earlier findings.</p><p><strong>Materials and methods: </strong>SiHa CSCC and HeLa CAC cells with stable GPER1-OE were generated. The effects of GPER1-OE on gene expression were then examined using next-generation sequencing (NGS) analyses.</p><p><strong>Results: </strong>In CSCC cells, GPER1-OE upregulated genes involved in tumorigenic pathways, including epithelial-to-mesenchymal transition (EMT), mTOR-C1, Myc, p53, hypoxia, and angiogenesis signaling. In CAC cells, however, GPER1-OE downregulated these pathways, along with additional pathways such as KRAS, Hedgehog, TNFα (<i>via</i> NFκB), and Wnt/Beta-Catenin signaling.</p><p><strong>Conclusion: </strong>The results highlight the divergent roles of GPER1-OE in CC cells, promoting oncogenesis in CSCC while exerting tumor-suppressive effects in CAC by modulating oncogenic signaling pathways.</p>","PeriodicalId":9516,"journal":{"name":"Cancer Genomics & Proteomics","volume":"22 3","pages":"415-433"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Similar Allele Frequencies of Two Pathogenic <i>NF2</i> variants in Each of Nine Sporadic Vestibular Schwannomas.","authors":"Maria Breun, Tim Schulz, Camelia M Monoranu, Ralf-Ingo Ernestus, Cordula Matthies, Tabea Hartung, Lan Kluwe, Said Farschtschi","doi":"10.21873/cgp.20516","DOIUrl":"https://doi.org/10.21873/cgp.20516","url":null,"abstract":"<p><strong>Background/aim: </strong>Vestibular schwannomas are benign tumors on the vestibular nerve caused by bi-allelic inactivation of the <i>NF2</i> tumor suppressor gene. This study identifies sporadic vestibular schwannomas with two pathogenic <i>NF2</i>-variants in each of them and compares the allele-frequencies of the two variants.</p><p><strong>Patients and methods: </strong>Sporadic vestibular schwannomas were subjected to genetic analysis regarding pathogenic variants in the <i>NF2</i> gene using targeted sequencing. Cases with two different pathogenic <i>NF2</i> variants were identified and the allele-frequencies of the two variants in each tumor were compared.</p><p><strong>Results: </strong>Nine tumors were identified which had two different pathogenic <i>NF2</i> variants in each of them. For all the 9 tumors, the allele-frequencies of the two pathogenic <i>NF2</i> variants in each were nearly identical.</p><p><strong>Conclusion: </strong>This finding may indicate that the two inactivating <i>NF2</i> variants occurred shortly after one another, leaving no room for the Schwann cells with one inactivating <i>NF2</i> variant to expand. Alternatively, the variants occurred in a late development stage whereas Schwann cells do not expand anymore or expand only extremely slowly. In addition, our finding suggests that Schwann cells with one inactivating variant do not gain a growth advantage.</p>","PeriodicalId":9516,"journal":{"name":"Cancer Genomics & Proteomics","volume":"22 3","pages":"491-495"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum Starvation-induced ROS Production Activates the ERK-AP-1-TfR1 Pathway to Up-regulate Survivin to Support Nasopharyngeal Carcinoma Cell Viability.","authors":"Chih-Chun Wang, Tzer-Zen Hwang, Ching-Feng Lien, Yingxiao Li, Yu-Yan Lan","doi":"10.21873/cgp.20513","DOIUrl":"https://doi.org/10.21873/cgp.20513","url":null,"abstract":"<p><strong>Background/aim: </strong>Transferrin receptor 1 (TfR1), a cell surface protein involved in iron transport, has been detected in nasopharyngeal carcinoma (NPC) biopsies and is associated with NPC malignancy. However, the mechanisms regulating TfR1 expression in NPC are not well understood. This study aimed to investigate whether and how serum starvation, a nutrient-deficient model often associated with tumor development, affects TfR1 expression in NPC cells.</p><p><strong>Materials and methods: </strong>Two NPC cell lines, NPC-TW01 and NPC/HK1, were used for this study. Various assays, including MTT, reactive oxygen species (ROS) detection, luciferase reporter, and immunoblotting, were conducted to assess cell viability, ROS production, AP-1 activity, and protein expression, respectively.</p><p><strong>Results: </strong>Serum starvation significantly increased both TfR1 mRNA and protein expression in NPC cells. Activation of the ERK-AP-1 pathway is essential for TfR1 expression during serum starvation. Additionally, serum starvation induced ROS production, which is required for ERK activation. Knockdown of TfR1 using specific siRNAs resulted in decreased survivin expression, and treatment with YM155, a survivin inhibitor, significantly reduced the viability of serum-starved NPC cells.</p><p><strong>Conclusion: </strong>The serum starvation-induced ROS-ERK-AP-1 axis is crucial for the up-regulation of TfR1, which contributes to survivin expression and ultimately sustains the viability of NPC cells.</p>","PeriodicalId":9516,"journal":{"name":"Cancer Genomics & Proteomics","volume":"22 3","pages":"458-466"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of Matrix Metalloproteinase-2 Promoter Genotypes With Leiomyoma Risk.","authors":"Shu-Yu Chang, Wen-Shin Chang, Chia-Wen Tsai, Yun-Chi Wang, Hou-Yu Shih, Chen-Hsien Su, DA-Tian Bau","doi":"10.21873/cgp.20511","DOIUrl":"https://doi.org/10.21873/cgp.20511","url":null,"abstract":"<p><strong>Background/aim: </strong>The role of matrix metalloproteinase-2 (MMP-2) in leiomyoma pathogenesis has been suggested, but the association between <i>MMP-2</i> genotypes and leiomyoma risk remains unexplored. This study investigated the impact of two <i>MMP-2</i> polymorphisms, promoter -1306 (rs243865) and promoter -735 (rs2285053), on leiomyoma susceptibility.</p><p><strong>Materials and methods: </strong><i>MMP-2</i> genotypes were analyzed in a cohort of 216 leiomyoma females and 648 non-leiomyoma controls using PCR-based RFLP.</p><p><strong>Results: </strong>Genotypic distributions of <i>MMP-2</i> rs243865 and rs2285053 in controls adhered to Hardy-Weinberg equilibrium (<i>p</i>=0.6161 and 0.3286, respectively). The heterozygous and homozygous variant genotypes of rs243865 were significantly associated with elevated leiomyoma risk (OR=1.63 and 4.33, 95%CI=1.13-2.35 and 1.67-11.16, <i>p</i>=0.0120 and 0.0027, respectively). The dominant model further revealed increased risk for CT and TT genotypes (OR=1.80, 95%CI=1.27-2.56, <i>p</i>=0.0013). The T allele at rs243865 was also significantly linked to higher risk (OR=1.84, 95%CI=1.35-2.50, <i>p</i>=0.0001). No significant association was found for rs2285053. Stratified analysis showed a significant interaction between rs243865 genotypes and age, with elevated risk in older females (<i>p</i> for trend=0.0003) and a notable association with larger tumors (<i>p</i> for trend=0.0029).</p><p><strong>Conclusion: </strong><i>MMP-2</i> rs243865 CT and TT genotypes significantly contribute to leiomyoma risk, particularly in older women and those with larger tumors.</p>","PeriodicalId":9516,"journal":{"name":"Cancer Genomics & Proteomics","volume":"22 3","pages":"434-443"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Replication Factor C Subunit 4 Plays a Role in Human Breast Cancer Cell Progression.","authors":"Jae Woong Koh, Seon-Joo Park","doi":"10.21873/cgp.20515","DOIUrl":"https://doi.org/10.21873/cgp.20515","url":null,"abstract":"<p><strong>Background/aim: </strong>Breast cancer is a heterogenous disease characterized by complex molecular pathways that drive its progression. Despite advances in treatment strategies, the need for novel therapeutic targets remains critical. Replication factor C subunit 4 (RFC4) is an important component of the DNA replication machinery and repair pathways. Its precise regulation ensures genomic stability and its dysregulation is implicated in various cancers. However, its oncogenic role in breast cancer is unclear. Therefore, this study aimed to elucidate the biological role of RFC4 in breast cancer.</p><p><strong>Materials and methods: </strong>Breast cancer cell lines MCF7, BT-549, and MDA-MB-231 were transfected with control and RFC4 siRNA to investigate biological functions of RFC4 in breast cancer. Cell proliferation was measured using the MTT and colony formation assays. In addition, cell cycle analysis, migration, and invasion assays were performed on RFC4-depleted breast cancer cells.</p><p><strong>Results: </strong>siRNA-mediated RFC4 knockdown inhibited breast cancer cell proliferation and cell cycle arrest, and reduced cell migration and invasion ability.</p><p><strong>Conclusion: </strong>Our findings highlight the critical role of RFC4 in breast cancer progression. The observed decrease in cell proliferation and clonogenic potential following RFC4 knockdown suggests its potential as a therapeutic target for breast cancer.</p>","PeriodicalId":9516,"journal":{"name":"Cancer Genomics & Proteomics","volume":"22 3","pages":"478-490"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR-575 in Exosomes of Vaginal Discharge Is Downregulated in Ovarian Cancer Patients.","authors":"Maho Azumi, Sachiko Inubushi, Yoko Yano, Kenta Obata, Keitaro Yamanaka, Yoshito Terai","doi":"10.21873/cgp.20508","DOIUrl":"https://doi.org/10.21873/cgp.20508","url":null,"abstract":"<p><strong>Background/aim: </strong>Ovarian cancer is asymptomatic in its early stages, and often diagnosed at advanced stages, leading to a high recurrence rate. In recent years, exosomes have been shown to be useful for early-detection, prognosis prediction, and treatment of cancer. Although many studies of cancer-related exosomes using other bodily fluids have been reported, there are few studies examining vaginal discharge, but none related to ovarian cancer. In this study, we investigated a method for early-detection of ovarian cancer using vaginal discharge, which are physically close to the fallopian tubes, where ovarian cancer originates, and can be easily collected from outside the body.</p><p><strong>Materials and methods: </strong>Vaginal discharge was collected from 30 patients with ovarian cancer and 29 patients with benign gynecological diseases, and exosomal miRNAs were extracted. Samples from each group were submitted to miRNA microarray in order to examine miRNAs with significant differences in expression levels. We further narrowed down the list to four miRNAs based on literature and microarray data and examined the expression levels of miRNAs in the malignant and benign groups by RT-qPCR.</p><p><strong>Results: </strong>MiR-575 expression was significantly decreased in the malignant group compared to the benign group (<i>p</i>=0.00861). qPCR results were analyzed for several patient characteristics and no significant differences were found.</p><p><strong>Conclusion: </strong>This is the first study to investigate exosomal miRNAs in vaginal discharge of ovarian cancer. Exosomal miR-575 in vaginal discharge may be used as a biomarker for ovarian cancer.</p>","PeriodicalId":9516,"journal":{"name":"Cancer Genomics & Proteomics","volume":"22 3","pages":"382-396"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KRIBB11 Exerts Anticancer Effects on A172 Glioblastoma Cells <i>via</i> the Cdh1/SKP2/p27 and HSF1/p53/p21 Pathways.","authors":"Kyunghyun Yoo, Hye Hyeon Yun, Soon-Young Jung, Chang-Nim Im, Tae-Ryong Riew, Mun-Yong Lee, Jeong-Hwa Lee","doi":"10.21873/cgp.20514","DOIUrl":"https://doi.org/10.21873/cgp.20514","url":null,"abstract":"<p><strong>Background/aim: </strong>KRIBB11, a heat shock factor1 (HSF1) inhibitor, sensitizes cancer cells to several anticancer drugs. We have previously demonstrated that KRIBB11 alone induced the apoptosis of A172 glioblastoma cells. However, the molecular basis of its anticancer activity remains unclear. Hence, we aimed to examine the alterations in cell cycle regulators and the relevance of HSF1 activity following KRIBB11 treatment in A172 cells.</p><p><strong>Materials and methods: </strong>The expression levels of p21, p27, and p53 were determined using western blotting or real-time PCR. Alterations in p27 levels were induced using small interfering RNA and retroviral transfection. SKP2 degradation was analyzed through a cycloheximide chase assay.</p><p><strong>Results: </strong>p21 and p27 exhibited opposite expression profiles in A172 cells following KRIBB11 treatment, with p21 accumulating and p27 decreasing, respectively. Further experiments revealed that p21 induction could be attributed to HSF1-dependent p53 accumulation, which is responsible for cell cycle arrest and apoptosis. In contrast, p27 reduction was not reproduced by HSF1 silencing; however, further suppression of p27 accelerated poly (ADP-ribose) polymerase cleavage by KRIBB11 treatment, which was partially reversed by p27 overexpression. Thus, the reduction in p27 levels by KRIBB11 appeared favorable for apoptosis, suggesting that p27 functions as an oncogene in A172 cells. Subsequently, we demonstrated that the decrease in p27 levels following KRIBB11 exposure was mediated by the accumulation of the SKP2 protein, accompanied by a reduction in Cdh1 ubiquitin ligase.</p><p><strong>Conclusion: </strong>KRIBB11 induces apoptotic cell death in A172 cells through two axes: HSF1-dependent p53/p21 accumulation and Cdh1/SKP2-dependent reduction of p27.</p>","PeriodicalId":9516,"journal":{"name":"Cancer Genomics & Proteomics","volume":"22 3","pages":"467-477"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of ER Stress and the Unfolded Protein Response in Cancer.","authors":"Rose Ghemrawi, Sedra Kremesh, Walaa K Mousa, Mostafa Khair","doi":"10.21873/cgp.20507","DOIUrl":"https://doi.org/10.21873/cgp.20507","url":null,"abstract":"<p><p>Dysregulation of protein synthesis, folding, and secretion leads to endoplasmic reticulum (ER) stress, triggering the unfolded protein response (UPR). While the UPR is essential for cell survival under stress, its chronic activation in cancer cells supports tumorigenesis, metastasis, and chemoresistance by enabling cellular adaptation to hypoxia, nutrient deprivation, and oxidative stress. This review provides a comprehensive overview of the roles of key UPR mediators - binding immunoglobulin protein (BiP), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6) - in cancer progression and therapy resistance. Furthermore, it discusses strategies to target UPR pathways, including small molecule inhibitors, gene therapies, natural compounds, and combination therapies, while it evaluates their preclinical and clinical relevance. Finally, it explores how modulating UPR signaling can overcome therapeutic resistance, improve immunotherapy outcomes, and reshape the tumor microenvironment. This review emphasizes the promise of UPR-targeted approaches in enhancing the efficacy of current cancer treatments and achieving better patient outcomes.</p>","PeriodicalId":9516,"journal":{"name":"Cancer Genomics & Proteomics","volume":"22 3","pages":"363-381"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of the Neoantigen Profile in a Tumor Mutation Burden-high Melanoma Patient With Multiple Metastases.","authors":"Shusuke Yoshikawa, Chie Maeda, Akira Iizuka, Tomoatsu Ikeya, Kazue Yamashita, Tadashi Ashizawa, Akari Kanematsu, Haruo Miyata, Yasufumi Kikuchi, Kenichi Urakami, Keiichi Ohshima, Takeshi Nagashima, Ken Yamaguchi, Yoshio Kiyohara, Yasuto Akiyama","doi":"10.21873/cgp.20517","DOIUrl":"https://doi.org/10.21873/cgp.20517","url":null,"abstract":"<p><strong>Background/aim: </strong>Recently, neoantigen (NA) profiling has been intensively performed for the development of novel immunotherapy. We previously reported a melanoma case with a high tumor mutation burden that achieved complete remission after anti-programmed death-1 therapy. We herein revisited the same case, characterized the NA profiles of other metastatic lesions using <i>in silico</i> algorithms and <i>in vitro</i> CTL assays, and investigated the immunological status, including tumor-infiltrating lymphocytes and the T cell receptor (TCR) repertoire profile, in metastatic sites.</p><p><strong>Materials and methods: </strong>NA candidates obtained from whole-exome sequencing were applied to the HLA-binding prediction algorithm, NetMHCpan4.1. HLA-A*2402-restricted sequence candidates with a strong binding capacity (<50 nM) and elution affinity (<1%) were selected and evaluated for synthetic peptide candidates. The immunological status in metastatic sites was characterized using gene expression profiling, immunohistochemistry, and a TCR repertoire analysis.</p><p><strong>Results: </strong>The genomic analysis revealed that all metastatic sites, such as costal, intra-muscular, and brain lesions, had >1,500 SNVs, and 12 driver mutations were common to all sites. New driver mutations were identified in intra-muscular (KMT2C: p.P3292S) and brain (JAK1: p.S404P) metastases and a functional analysis of these mutations revealed that JAK1 mutation exhibited a promoting effect on invasion activity. CTL assays using synthetic NA peptides identified more NA epitopes in brain metastasis.</p><p><strong>Conclusion: </strong>These results might suggest that the heterogeneity of driver gene mutations is unremarkable, while immunological response is variable in metastatic sites. As a result, the genomic and immunological investigation has provided a very valuable and informative suggestion regarding better cancer therapy decisions.</p>","PeriodicalId":9516,"journal":{"name":"Cancer Genomics & Proteomics","volume":"22 3","pages":"496-509"},"PeriodicalIF":2.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12041879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}