Hepatocellular carcinoma (HCC) is a highly heterogeneous and malignant cancer with poor overall survival. The application of sorafenib is a major breakthrough in the treatment of HCC. In our study, FOXQ1 was significantly overexpressed in sorafenib-resistant HCC cells and suppressed sorafenib-induced ferroptosis. We found that phosphorylation of FOXQ1 at serine 248 is critical for the suppression of sorafenib-induced ferroptosis. Furthermore, as the upstream phosphorylation kinase of FOXQ1, JNK1, which is activated by sorafenib, can directly phosphorylate the serine 248 site of FOXQ1. Then, the phosphorylated FOXQ1 got a high affinity for the promoter of ETHE1 and activates its transcription. Further flow cytometry results showed that ETHE1 reduced intracellular lipid peroxidation and iron levels. Collectively, our study implicated the JNK1-FOXQ1-ETHE1 axis in HCC ferroptosis induced by sorafenib, providing mechanistic insight into sensitivity to sorafenib therapy of HCC.

Hepatocellular carcinoma (HCC) is among the most prevalent and lethal cancers worldwide. The NDC80 kinetochore complex component NUF2 has been previously identified as up-regulating in HCC and associated with patient prognosis. However, the pathophysiological effects and molecular mechanisms of NUF2 in tumorigenesis remain unclear. In this study, we confirmed a significant increase in NUF2 expression in HCC tissues and established a correlation between high NUF2 expression and adverse outcomes in HCC patients. Through in vitro and in vivo experiments, we demonstrated that genetic inhibition of NUF2 suppressed the proliferation of HCC cells and disrupted the cell cycle. Further investigation into the molecular mechanisms revealed that NUF2 interacted with ERBB3, inhibiting its ubiquitination degradation, thus activating the PI3K/AKT signaling pathway and influencing cell cycle regulation. Overall, this study revealed the crucial role of NUF2 in promoting the malignant progression of HCC, suggesting its potential as both a prognostic biomarker and a therapeutic target for HCC.

Neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC). Mucinous adenocarcinoma (MAC) is a potential poor prognosis subgroup of rectal cancer. However, the predictive value of MAC in NCRT treatment of LARC is controversial. A comprehensive literature search of PubMed, Embase, and the Cochrane Library was performed. All studies examining the effect of MAC on CRT response in LARC were included. Outcomes of MAC were compared with non-specific adenocarcinoma (AC) by using random-effects methods. Data were presented as odds ratios (ORs) with 95

BackgroundCholangiocarcinoma (CCA), a primary hepatobiliary malignancy, is characterized by a poor prognosis and a lack of effective treatments. Therefore, the need to explore novel therapeutic approaches is urgent. While the role of Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1 (PIN1) has been extensively studied in various tumor types, its involvement in CCA remains poorly understood.MethodsIn this study, we employed tissue microarray (TMA), reverse transcription-polymerase chain reaction (RT-PCR), and The Cancer Genome Atlas (TCGA) database to assess the expression of PIN1. Through in vitro and in vivo functional experiments, we investigated the impact of PIN1 on the adhesion and metastasis of CCA. Additionally, we explored downstream molecular pathways using RNA-seq, western blotting, co-immunoprecipitation, immunofluorescence, and mass spectrometry techniques.ResultsOur findings revealed a negative correlation between PIN1 overexpression and prognosis in CCA tissues. Furthermore, high PIN1 expression promoted CCA cell proliferation and migration. Mechanistically, PIN1 functioned as an oncogene by regulating ANXA2 phosphorylation, thereby promoting CCA adhesion. Notably, the interaction between PIN1 and ANXA2 was facilitated by RACK1. Importantly, pharmacological inhibition of PIN1 using the FDA-approved drug all-trans retinoic acid (ATRA) effectively suppressed the metastatic potential of CCA cells in a nude mouse lung metastasis model.ConclusionOverall, our study emphasizes the critical role of the PIN1/RACK1/ANXA2 complex in CCA growth and functionality, highlighting the potential of targeting PIN1 as a promising therapeutic strategy for CCA.

Background & Aims:Immunotherapy is an option for the treatment of advanced biliary tract cancer (BTC), although it has a low response rate. In this post hoc analysis, we investigated the predictive value of an immuno-genomic-radiomics (IGR) analysis for patients with BTC treated with camrelizumab plus gemcitabine and oxaliplatin (GEMOX) therapy. Methods:Thirty-two patients with BTC treated with camrelizumab plus GEMOX were prospectively enrolled. The relationship between high-throughput computed tomography (CT) radiomics features with immuno-genomic expression was tested and scaled with a full correlation matrix analysis. Odds ratio (OR) of IGR expression for objective response to camrelizumab plus GEMOX was tested with logistic regression analysis. Association of IGR expression with progression-free survival (PFS) and overall survival (OS) was analysed with a Cox proportional hazard regression. Results:CT radiomics correlated with CD8+ T cells (r = -0.72-0.71, p = 0.004-0.047), tumour mutation burden (TMB) (r = 0.59, p = 0.039), and ARID1A mutation (r = -0.58-0.57, p = 0.020-0.034). There was no significant correlation between radiomics and programmed cell death protein ligand 1 expression (p >0.96). Among all IGR biomarkers, only four radiomics features were independent predictors of objective response (OR = 0.09-3.81; p = 0.011-0.044). Combining independent radiomics features into an objective response prediction model achieved an area under the curve of 0.869. In a Cox analysis, radiomics signature [hazard ratio (HR) = 6.90, p <0.001], ARID1A (HR = 3.31, p = 0.013), and blood TMB (HR = 1.13, p = 0.023) were independent predictors of PFS. Radiomics signature (HR = 6.58, p <0.001) and CD8+ T cells (HR = 0.22, p = 0.004) were independent predictors of OS. Prognostic models integrating these features achieved concordance indexes of 0.677 and 0.681 for PFS and OS, respectively. Conclusions:Radiomics could act as a non-invasive immuno-genomic surrogate of BTC, which could further aid in response prediction for patients with BTC treated with immunotherapy. However, multicenter and larger sample studies are required to validate these results. Impact and implications:Immunotherapy is an alternative for the treatment of advanced BTC, whereas tumour response is heterogeneous. In a post hoc analysis of the single-arm phase II clinical trial (NCT03486678), we found that CT radiomics features were associated with the tumour microenvironment and that IGR expression was a promising marker for tumour response and long-term survival. Clinical trial number:Post hoc analysis of NCT03486678.

BACKGROUND:ATP7A is an important copper transporter that regulates numerous cellular biological processes. However, the role of ATP7A in immunotherapy and targeted therapy, especially for hepatocellular carcinoma (HCC), remains unknown.METHODS:We analyzed ATP7A expression and its effect on digestive system tumor prognoses, assessed its expression in tissue microarrays from 319 HCC patients, and investigated the relationship between ATP7A expression and tumor immunity. Specifically, we evaluated the possible association between ATP7A and programmed death ligand 1 (PD-L1) expression in human HCC tissues. Finally, we analyzed the effect of ATP7A on sorafenib efficacy in HCC.RESULTS:ATP7A is generally highly expressed in digestive system tumors but related to poor prognosis only in HCC. ATP7A levels are positively associated with immune cell infiltration and immune checkpoint expression (especially PD-L1). HCC patients coexpressing APT7A and PD-L1 demonstrate poor prognoses. Moreover, HCC patients with high ATP7A levels were more sensitive to sorafenib and demonstrated higher survival rates after sorafenib treatment.CONCLUSIONS:This study provides insights into the correlation between ATP7A levels and tumor immune infiltration and immune checkpoint function in HCC, sheds light on the significance of ATP7A in cancer progression, and provides guidance for more effective and general therapeutic strategies.

Summary Background Immune checkpoint inhibitor (ICI) combination therapy offers a new option for treatment of unresectable intrahepatic cholangiocarcinoma (uICC). Aim To compare the effect of different anti‐PD‐1 combination therapies as the first‐line treatments for uICC. Methods This study included 318 patients who received chemotherapy alone (Chemo), anti‐PD‐1 plus chemotherapy (ICI‐chemo), anti‐PD‐1 plus targeted therapy (ICI‐target) or anti‐PD‐1 plus targeted therapy and chemotherapy (ICI‐target‐chemo) as first line for uICC from 22 centres in China. The primary endpoint was progression‐free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. Results Patients with ICI‐chemo (median PFS [mPFS], 6.3 months; HR: 0.61, 95% CI: 0.42–0.88; p = 0.008; median OS [mOS], 10.7 months; HR: 0.61, 95% CI: 0.39–0.94; p = 0.026), ICI‐target (7.2 months; HR: 0.54, 95% CI: 0.36–0.80; p = 0.002; 15.8 months; HR: 0.54, 95% CI: 0.35–0.84; p = 0.006) or ICI‐target‐chemo (6.9 months; HR: 0.65, 95% CI: 0.47–0.90; p = 0.009; 14.4 months; HR: 0.47, 95% CI: 0.31–0.70; p < 0.001) achieved better clinical outcomes than those with Chemo (3.8 months; 9.3 months). ICI‐target was not inferior to ICI‐chemo in survival outcomes (HR for PFS: 0.88, 95% CI: 0.55–1.42; p = 0.614; HR for OS: 0.89, 95% CI: 0.51–1.55; p = 0.680). ICI‐target‐chemo yielded similar prognoses as ICI‐chemo (HR for PFS: 1.07, 95% CI: 0.70–1.62; p = 0.764; HR for OS: 0.77, 95% CI: 0.45–1.31; p = 0.328) and ICI‐target (HR for PFS: 1.20, 95% CI: 0.77–1.88; p = 0.413; HR for OS: 0.86, 95% CI: 0.51–1.47; p = 0.583) but resulted in more adverse events ( p < 0.001; p = 0.010). Multivariable and propensity score analyses supported these findings. Conclusions Among patients with uICC, ICI‐chemo or ICI‐target provided more survival benefits than Chemo while achieving comparable prognoses and fewer adverse events than ICI‐target‐chemo.

新辅助化疗(NACT)是指针对潜在可根治切除的肿瘤患者,以消除微转移、降低肿瘤分期和手术难度、改善术后局部复发和远处转移等为目的,在肿瘤手术切除或放疗之前,先予以全身化疗,待手术或放疗之后继续完成全程化疗的综合方案.结肠癌是最常见的癌症之一,肿瘤根治性切除联合术后辅助化疗是临床潜在可根治切除结肠癌的主要治疗方式.虽然这种治疗模式较前显著改善了患者的预后,但术后局部复发和远处转移仍是患者最主要的致死因素.近年来NACT方案开始被引入局部进展期结肠癌和原发灶可切除的肝转移患者等潜在可根治切除结肠癌患者的治疗.然而,结肠癌患者是否适合NACT及其方案的选择还存在较大的争议.笔者就局部进展期结肠癌、可切除结肠癌肝转移等在NACT中的进展与争议,以及影像学检查对NACT的作用作一综述.

Abstract Background: Up to 30% colorectal carcinoma (CRC) are inherited tendency. Lynch syndrome (LS) which is caused by mismatch repair (MMR) genes germline mutation, is the most prevalent form of hereditary CRC. Ethnical and regional differences would lead to diverse characteristics of LS. However, Studies of LS from China are few and with relatively small sample sizes. Method: Immunohistochemistry (IHC) testing for MMR deficiency (dMMR) is advocated to preliminarily screen LS in recent guidelines. This single center retrospective study from central China performed IHC to prescreen dMMR and analyze the patterns and characteristics of dMMR CRCs. Results: 12.0% (180/1505) CRCs had dMMR status in this study, they had the universal features such as younger diagnostic age, more proximal colon location, more poorly differentiated with an excess of mucinous type, advanced pT stage and lower pN stage (all P ＜ 0.05), but had larger tumor size and less perineural invasion (all P ＜ 0.05) compared with proficiency MMR CRCs, which were not reported before. Moreover, PMS2 deficiency (8.7%) was common in this study which was different from studies in Western. MLH1/PMS2, isolated PMS2, MSH2/MSH6 and isolated MSH6 were the most common deficiency patterns, and the MSH2/MSH6 subtype had the most often family history. Conclusion: This study demonstrated dMMR CRCs from central China had the similar general characteristics as reported studies, but had larger tumor size and less perineural invasion which were not reported before. What’s more, PMS2 deficiency (8.7%) was common in this study which was different from studies in Western.

Clinical and Translational MedicineVolume 13, Issue 4 e1246 LETTER TO THE EDITOROpen Access Colorectal mucinous adenocarcinoma indicates a meaningful subtype: A whole genome sequencing study Yunhua Xu, Yunhua Xu The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorXiguang Chen, Xiguang Chen The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorYuqiao Chen, Yuqiao Chen Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, P. R. ChinaSearch for more papers by this authorXiaofeng Wu, Xiaofeng Wu The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorQing Fang, Qing Fang The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorXiangwen Tan, Xiangwen Tan The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorShuxiang Li, Shuxiang Li The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorQiulin Huang, Qiulin Huang The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorXuyu Zu, Corresponding Author Xuyu Zu [email protected] The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. China Correspondence Shuai Xiao, The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected] Kai Fu, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P. R. China. Email: [email protected] Xuyu Zu, The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected]Search for more papers by this authorKai Fu, Corresponding Author Kai Fu [email protected] Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, P. R. China Correspondence Shuai Xiao, The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected] Kai Fu, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P. R. China. Email: [email protected] Xuyu Zu, The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected]Search for more papers by this authorShuai Xiao, Corresponding Author Shuai Xiao [email protected] orcid.org/0000-0003-0830-2188 The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. China Correspondence Shuai Xiao, The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected] Kai Fu, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P. R. China. Email: [email protected] Xuyu Zu, The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected]Search for more papers by this author Yunhua Xu, Yunhua Xu The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorXiguang Chen, Xiguang Chen The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorYuqiao Chen, Yuqiao Chen Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, P. R. ChinaSearch for more papers by this authorXiaofeng Wu, Xiaofeng Wu The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorQing Fang, Qing Fang The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorXiangwen Tan, Xiangwen Tan The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorShuxiang Li, Shuxiang Li The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorQiulin Huang, Qiulin Huang The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorXuyu Zu, Corresponding Author Xuyu Zu [email protected] The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. China Correspondence Shuai Xiao, The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected] Kai Fu, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P. R. China. Email: [email protected] Xuyu Zu, The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected]Search for more papers by this authorKai Fu, Corresponding Author Kai Fu [email protected] Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, P. R. China Correspondence Shuai Xiao, The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected] Kai Fu, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P. R. China. Email: [email protected] Xuyu Zu, The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected]Search for more papers by this authorShuai Xiao, Corresponding Author Shuai Xiao [email protected] orcid.org/0000-0003-0830-2188 The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. China Correspondence Shuai Xiao, The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected] Kai Fu, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P. R. China. Email: [email protected] Xuyu Zu, The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected]Search for more papers by this author First published: 26 April 2023 https://doi.org/10.1002/ctm2.1246 Yunhua Xu Xiguang Chen contributed equally to this work. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Dear Editor, Colorectal cancer (CRC) is a common lethal gastrointestinal tumour. Mucinous adenocarcinoma (MAC) is a special histological subtype of CRC, which characterized by abundant extracellular mucin.1 MAC has distinct characteristics compared with the commonest subtype, non-specific adenocarcinoma (AC), including clinicopathologic factors, molecular features, therapy response, and prognosis.2-5 However, since the molecular mechanisms differences between the MAC and AC are still unclear, all of the current treatment guidelines rarely notice their distinction.6, 7 To illustrate these issues, we firstly performed RNA-sequencing on 40 samples comprising 15 MACs, 15 ACs, and 10 normal colorectal tissues, which were collected from our central (hereinafter referred as USC set). The baseline feature of CRC cases is appeared in Table S1. Through the clinicopathological features analysis, we found MAC had a more proximal colon location (p < .05) and larger tumour size (p < .05). In addition, MAC showed a higher pT stage and more frequent dMMR tendency (Table 1). Then, the TCGA-COAD transcriptome and clinical data (referred as TCGA set) were also downloaded and analyzed. Through analyzing TCGA clinical data, we got a similar result: no significant difference in other items except dMMR (Table S2). TABLE 1. The baseline characteristics of MAC and AC patients. AC (cases) MAC (cases) p Value Sex Female 12 8 Male 3 7 .245 Age (years) 62.00 ± 8.08 61.00 ± 13.62 .809 Location Proximal 4 11 Distal 8 2 Rectal 3 2 .029 Size (cm) 5.10 ± 1.64 7.07 ± 2.27 .011 pT stage 0-2 4 1 3-4 11 14 .330 pN stage N0 13 12 N+ 2 3 1.000 MMR status pMMR 12 10 dMMR 1 3 NA 2 2 .541 MVI/PNI status Absent 14 13 Present 1 2 1.000 Abbreviations: AC, adenocarcinoma; dMMR, deficient of MMR; EMT, epithelial-mesenchymal transition; GEO, Gene Expression Omnibus; GSEA, Gene Set Enrichment Analysis; MAC, mucinous adenocarcinoma; MMR, mismatch repair gene; MSI, microsatellite instability; MSS, microsatellite stable; MVI/PNI, microvascular invasion/perineural invasion; MYC, MYC Proto-Oncogene; NA, not available; pMMR, proficient of MMR; SM, supplementary material; TCGA, The Cancer Genome Atlas; TGF, transforming growth factor; TTN, Titin; USC, University Of South China. To elucidate the genome characteristic between MAC and AC, we analyzed the TCGA-COAD mutation data. Results showed that the mutation atlas of them was notably different. In the AC group, APC (74.6%) had the highest mutation frequency followed by TP53 (59.0%), TTN (49.4%) (Figure 1A). While in the MAC group, TTN (72.4%), APC (65.5%), and KRAS (46.6%) are the most mutated genes (Figure 1B). Additionally, we observed a high mutation frequency of BRAF, whereas TP53 was rare in MAC (Figure 1A, B). Additionally, comparing the common 10 mutant genes, we found only the mutation rate of TTN, RYR2, and OBSCN were distinctly different (Figure 1C). In addition, we observed that the integral genome alteration frequency of MAC is higher than AC (Figure 1D). Finally, we compared the fraction genome alteration of the above three genes. Although the mutation rate of these genes was higher in MAC, the fraction genome alteration was lower in MAC, and each gene had a unique mutational feature (Figure 1E). FIGURE 1Open in figure viewerPowerPoint The mutation signature of adenocarcinoma (AC) and mucinous adenocarcinoma (MAC). (A and B) The genomic landscape shows the top 15 mutated genes among AC, MAC. (C) The comparison of common 10 genes mutations in AC and MAC. The values in brackets indicate the statistical value in the mutation frequency of each gene between the two groups. Each column denotes an individual tumour, and each row represents the individual genes. The mutation rate of each gene in all samples was shown in right. (D) The comparison of the integral genome alteration frequency among AC, MAC. (E) The fraction genome altered of TTN, RYR2, and OBSCN. Colours indicate the type of genetic alterations as indicated in the legend. To study the transcriptomics features of MAC and AC, we performed differentially expressed genes (DEGs) analysis in TCGA and USC sets, respectively. In the TCGA set, we found thousands of DEGs between tumour and normal tissue (Figure 2A,B), and hundreds of DEGs between MAC and AC (Figure 2C). In the USC set, we got similar results (Figure 2D–F). The distribution of DEGs was shown as the ternary plot. The variation was apparent among transcriptional properties of different subtypes (Figure 2G,H). Finally, differences and similarities of DEGs for the TCGA and USC datasets are summarized in Figure 2I. Furthermore, we synthesize intersection DEGs of MAC versus AC in USC and TCGA set and performed functional enrichment analysis to uncover the potential gene functions. Through GO, KEGG, cancer hallmarks, and Reactome analysis, we found the gene functions of these DEGs were correlated with symporter activity, and metabolism-related molecules and pathways (SM1, Figure S1). FIGURE 2Open in figure viewerPowerPoint The analysis of differentially expressed genes (DEGs) among adenocarcinoma (AC), mucinous adenocarcinoma (MAC), and normal samples in TCGA and USC datasets. (A–C) The volcano plot of DEGs in AC versus Normal, MAC versus Normal, MAC versus AC samples in TCGA datasets. (D–F) The volcano plots of DEGs in AC versus Normal, MAC versus Normal, MAC versus AC samples in USC datasets. Red triangles indicate up-regulated genes, and green triangles indicate down-regulated genes as the legend. (G and H) The ternary plot of DEGs among AC, MAC, and Normal samples in TCGA and USC datasets. Genes more inclined to normal samples were marked in red, genes tend to AC samples were labeled in blue, and genes prone to MAC samples were tagged in yellow. (I) The 9-quadrant diagram of the distribution of common DEGs between TCGA and USC datasets. In 2011, Weinberg et al. summarized 10 cancer hallmarks, which become the cornerstone of tumour characteristic study.8 Thus, we analyzed the 10 hallmarks differences between AC and MAC. Results showed that evading growth suppressors and inducing angiogenesis appeared a marked weak activity. Nevertheless, reprogramming energy metabolism and tumour-promoting inflammation were highly expressed. Unfortunately, we didn't observe a hallmark that was significantly different between MAC and AC (SM1, Figure S2A,C). In addition, we found some genes played an important role in multiple hallmarks, while others played the exclusive roles in single hallmark (SM1, Figure S2B,D). According to Sadanandam et al. reported that CRCs could be classified into five cell phenotypes, which had distinct therapy response.9 We analyzed the cell subtype differences of MAC and AC both in TCGA and USC sets. Result showed that the samples of two datasets were well classified into five cell subtypes (Figure S3A,C), and the proportion of each subtype was different (Figure S3B,D). The Goblet-like group accounted for the largest proportion in the MAC, followed by Stem-like, and Ta was the least. On the contrary, the predominant cell subtype of AC was the Ta group, and the other four subtypes are relatively evenly distributed (Figure S3). The consensus molecular subtype (CMS) is a new and important classification system for CRC.10 We also explored the association between CMS and MAC, and results showed that there was good consistency between subtype prediction and template features of TCGA and USC set (Figure 3A, D). The signal feature of each subtype was also studied. Results showed that the CMS1 group has obvious MSI characteristics, and the CMS2 group has distinct MSS, MYC, and cell cycle features, and differentiation signal was visible in CMS3, while TGF-Beta and EMT signal was prominent in CMS4 (Figure 3B, E). Our results showed that AC group was enriched in CMS2 and CMS4 subtypes, and MAC group was enriched in CMS3 and CMS4 subtypes, especially in CMS3 (Figure 3C, F). FIGURE 3Open in figure viewerPowerPoint The consensus molecular subtype (CMS) subtype comparative analysis between mucinous adenocarcinoma (MAC) and adenocarcinoma (AC). (A and D) The CMS heatmap of top differentially expressed genes (DEGs) with shades of blue for down-regulation and red for up-regulation in TCGA and USC datasets. (B and E) The heatmap of pathways activity of each CMS subtype with shades of blue for low and red for high activity in TCGA and USC datasets. (C and F) The pie chart for each CMS subtype of AC and MAC samples in TCGA and USC datasets, respectively. Previous studies indicated MAC was correlated with poor chemotherapy response and prognosis. To better understand the underlying molecular mechanisms, we analyzed GEO dataset of CRC drug resistance (GSE83129). GSEA was carried out to acquire the enriched pathway by our sequencing results and drug resistance dataset. Six shared GOBP pathways were enriched in MAC and chemotherapy non-responder group (Figure 4A,B). The common genes interaction among these six GOBP pathways are shown in Figure 4C. We further found six intersection genes in GOBP①/GOBP③(Figure 4D), and 15 intersection genes in GOBP④/GOBP⑤ (Figure 4E). These 21 evolved drug-resistant gene clusters might confer chemotherapy resistance to MAC. FIGURE 4Open in figure viewerPowerPoint GSEA analysis of USC dataset and colorectal cancer (CRC) drug resistance dataset GSE83129. GSEA analysis showed the differentially enriched pathway in the mucinous adenocarcinoma (MAC)/adenocarcinoma (AC) samples and OXA_Responder/Non-responder samples. (A) The upset plot showed the intersection pathways of MAC/AC samples and OXA_Responder/Non-responder samples. (B) Shared enriched GO pathway by GSEA analysis. (C–E) Venn plots of the intersection of genes enriched in GO pathways. OXA, oxaliplatin. In conclusion, this whole genome sequencing study preliminarily revealed the molecular and functional characteristics of MAC, as well as potential clinical value, which indicated that MAC tend to metabolic and mesenchymal phenotypes, contributing to worse prognosis and chemotherapy resistance. ACKNOWLEDGEMENTS This work was supported by the Clinical Medical Technology Innovation Project of Hunan Province (grant number: 2020SK51815), the Scientific Research Fund Project of Hunan Provincial Health Commission (grant numbers: 20201919 and 202104010105), and Natural Science Foundation of Hunan Province (grant number: 2022JJ30538). CONFLICT OF INTEREST STATEMENT The authors declare no conflicts of interest. Supporting Information Filename Description ctm21246-sup-0001-SuppMat.docx22.1 KB Supporting Information ctm21246-sup-0002-SuppMat.docx25.5 KB Supporting Information ctm21246-sup-0003-SuppMat.doc2.2 MB Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Hugen N, Brown G, Glynne-Jones R, de Wilt JHW, Nagtegaal ID. Advances in the care of patients with mucinous colorectal cancer. Nat Rev Clin Oncol. 2016; 13(6): 361- 369. doi:10.1038/nrclinonc.2015.140 2Luo C, Cen S, Ding G, Wu W. Mucinous colorectal adenocarcinoma: clinical pathology and treatment options. Cancer Commun (Lond). 2019; 39(1): 13. doi:10.1186/s40880-019-0361-0 3Bong J-W, Gim J-A, Ju Y, et al. Prognosis and sensitivity of adjuvant chemotherapy in mucinous colorectal adenocarcinoma without distant metastasis. Cancers (basel). 2022; 14(5): 1297. doi:10.3390/cancers14051297 4Zhang Y, Chen Y, Huang J, et al. Mucinous histology is associated with poor prognosis in locally advanced colorectal adenocarcinoma treated with postoperative first-line adjuvant chemotherapy: a systematic review and meta-analysis. Eur J Surg Oncol. 2022; 48(10): 2075- 2081. doi:10.1016/j.ejso.2022.06.024 5Zhang J, Xie X, Wu Z, et al. Mucinous adenocarcinoma predicts poor response and prognosis in patients with locally advanced rectal cancer: a pooled analysis of individual participant data from 3 prospective studies. Clin Colorectal Cancer. 2021; 20(4): e240- e248. doi:10.1016/j.clcc.2021.06.004 6Ott C, Gerken M, Hirsch D, et al. Advanced mucinous colorectal cancer: epidemiology, prognosis and efficacy of chemotherapeutic treatment. Digestion. 2018; 98(3): 143- 152. doi:10.1159/000487710 7Benson AB, Venook AP, Al-Hawary MM, et al. NCCN guidelines insights: colon cancer, version 2.2018. J Natl Compr Canc Netw. 2018; 16(4): 359- 369. doi:10.6004/jnccn.2018.0021 8Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144(5): 646- 674. doi:10.1016/j.cell.2011.02.013 9Sadanandam A, Lyssiotis CA, Homicsko K, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. 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Purpose: Postoperative adjuvant chemotherapy followed surgery is the standard management for localized advanced colorectal carcinoma (CRC). Mucinous adenocarcinoma (MAC) is a peculiar histological subtype of CRC, but the prognosis of MAC patients is controversial. The objective of this study is to assess the implication of MAC in survival of patients treated with surgery and firs-line adjuvant chemotherapy. Methods: Studies describing outcomes for advanced MAC and non-specific adenocarcinoma (AC) of CRC patients treated with first-line postoperative adjuvant chemotherapy followed surgery were searched in PubMed, Embase, Medline, EBSCO, Wiley, and Cochrane Library (January 1963eAugust 2021). Hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS) and cancer-specific survival (CSS) for MAC to AC were extracted. Random-effects model was used for calculating the pooled HRs and 95% confidence interval (CI). Results: This meta-analysis is comprised of 8 studies involving a total of 124,303 CRC patients treated with first-line adjuvant chemotherapy followed surgery. The pooled HR for MAC was 1.23 (95% CI, 1.07-1.41, p < 0.01, I-2 = 80%), and the DFS (HR, 2.95, 95% CI, 1.22-7.14) of MAC patients were significantly poorer than AC patients. Similar results were also observed in stage III and FOLFOX regimen subgroups. Conclusion: MAC was a risk factor for prognosis of localized advanced CRC patients treated with postoperative first-line adjuvant chemotherapy. Thus, the role of first-line adjuvant chemotherapy regimens should be further studied in these MAC patients.

目的:通过生物信息学的方法挖掘基因综合表达数据库(GEO)中影响胆管癌(cholangiocarcinoma,CCA)发生发展的核心基因,并分析其生物学功能,为CCA的诊断、治疗和评估预后提供理论依据.方法:分析来自GEO数据库中的3个微阵列数据集(GSE32879、GSE45001和GSE76297).使用GEO2R进行在线差异基因的分析,DAVID进行差异基因的GO和KEGG通路分析.使用STRING和Cytoscape进行蛋白互作网络分析(PPI)和枢纽基因(HUB)的筛选.结果:共筛选出151个上调基因,通过PPI筛选出连接度最高的10个基因,分析发现APOA1、AGXT、F13B、FETUB、FERPINC1、SLC2A2这些枢纽基因过度表达与胆管癌的不良预后相关.结论:通过生物信息学探索的枢纽基因可能在胆管癌的发生发展中起着重要作用,并为进一步研究胆管癌的分子机制提供了一定的理论依据.

RationaleThe recent research found that IGF regulator genes played a pivotal role in multiple biological processes, which may be developed for cancer treatment. However, the characteristics and implication of IGF regulators in cancers, especially in clear cell renal cell carcinoma (ccRCC), remain elusive.MethodsWe systematically analyzed the expression, prognostic valuation, genome variation, and functional implication at pan-cancer level from The Cancer Genome Atlas. According to expression levels of IGF regulator genes, ccRCC could be divided into three different subtypes via unsupervised cluster algorithm: IGF pattern cancer type1 (IPCS1), type2 (IPCS2), and type3 (IPCS3). The immune microenvironment, immunotherapy response, metabolic pattern, and tumor progression signature among the three subgroups were investigated. The clinical characteristics, genomic mutations, and potential drug sensitivity were further analyzed. IGF pattern–related risk model was constructed to predict RCC patients’ outcome. Finally, SHC1, a potential IGF axis target, was comprehensively investigated in ccRCC.ResultsWe found that IGF regulator genes were specifically upregulated in various cancer tissues, which were correlated with copy number variations and dysregulated pathways. IPCS1, IPCS2, and IPCS3 exhibited different clinical profiles and biological characteristics in ccRCC. IPCS3 subtype indicated a higher clinical stage and a worse survival. IPSC3 ccRCC displayed activated metabolic signatures to fuel the cancer progression. IPCS3 subgroup holds a higher tumor mutation burden and lower immune activities, which resulted in a low ICI therapy response and tumor immunity dysfunction state. The genome copy numbers of IPCS2/3, including arm gain and arm loss, were significantly higher than IPCS1. Besides, the drug sensitivity profiles were different among the three subgroups. The prognostic risk model based on subtype’s biomarker exerted a promising performance both in training and validation cohorts. Finally, upregulated expression of SHC1 partly induced poorer immunotherapy response and shorter survival of ccRCC patients.ConclusionTargeting IGF regulators may be functioned as a treatment approach among multi-cancers. IGF regulator–related signature could reshape the tumor immune microenvironment via activating multi-step immune programs. The inhibition of SHC1 may enhance the efficacy of immunotherapy, and SHC1 could be a suitable target for ccRCC therapy.

PurposeImmune checkpoint inhibitors plus antiangiogenic tyrosine kinase inhibitors may offer a first-line treatment for advanced hepatocellular carcinoma (HCC). In this phase 2 trial [registered with clinicaltrials.gov (NCT04052152)], we investigated the safety and efficacy of first-line anti-PD-1 antibody sintilimab plus antiangiogenic TKI anlotinib for advanced HCC.Methods and MaterialsPathologically-proven advanced HCC patients received sintilimab (200 mg) on day 1 and anlotinib (12 mg) once daily on days 1 to 14 every 3 weeks, with a safety run-in for the first six participants to assess dose-limiting toxicities (DLTs). The primary endpoints were safety and objective response rate (ORR) per RECIST v1.1.ResultsTwenty advanced HCC patients were enrolled. No DLTs occurred in the safety run-in. All patients had treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 8 (40.0%) patients, the most common being decreased platelet count (10.0%) and increased γ-glutamyl transferase (10.0%). No grade 4/5 TRAEs occurred. Five (25%) patients developed immune-related AEs. The ORR was 35.0% (95%CI 15.4%-59.2%) per RECIST v1.1 and 55.0% (95%CI 31.5%-76.9%) per modified RECIST. At data cutoff (March 31, 2021), the median progression-free survival was 12.2 months (95%CI, 3.8 to not reached). The median PFS was significantly longer in patients with lower LDH levels (not reached [NR], 95% CI, 8.7 to NR vs. higher LDH levels 5.2 months, 95% CI 3.4 to NR; P=0.020) and a CONUT score ≤2 (NR, 95% CI 5.1 to NR vs. CONUT score >2 6.2 months, 95% CI 1.8 to NR; P=0.020). Furthermore, patients showing tumor response had a significantly higher median proportion of CD16+CD56+ NK cells than patients who had stable or progressive disease (21.6% vs. 14.6%; P=0.026).ConclusionSintilimab plus anlotinib showed promising clinical activities with manageable toxicity as first-line treatment of advanced HCC.

Objective This study aimed to assess the efficacy and safety of camrelizumab plus apatinib in patients with resectable hepatocellular carcinoma (HCC) as neoadjuvant therapy. Methods Initially, 20 patients with HCC were screened and 18 patients with resectable HCC were enrolled in this open-label, single-arm, phase II clinical trial. Patients received three cycles of neoadjuvant therapy including three doses of camrelizumab concurrent with apatinib for 21 days followed by surgery. Four to 8 weeks after surgery, patients received eight cycles of adjuvant therapy with camrelizumab in combination with apatinib. Major pathological reactions (MPR), complete pathological reactions (pCR), objective response rate (ORR), relapse-free survival (RFS), and adverse events (AE) were assessed. In addition, cancer tissue and plasma samples were collected before and after treatment, and genetic differences between responding and non-responding lesions were compared by tumor immune microenvironment (TIME) analysis, circulating tumor DNA (ctDNA) analysis and proteomics analysis. Results In 18 patients with HCC who completed neoadjuvant therapy, 3 (16.7%) and 6 (33.3%) patients with HCC reached ORR based on Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and modified RECIST criteria, respectively. Of the 17 patients with HCC who received surgical resection, 3 (17.6%) patients with HCC reported MPR and 1 (5.9%) patient with HCC achieved pCR. The 1-year RFS rate of the enrolled patients was 53.85% (95% CI: 24.77% to 75.99%). Grade 3/4 AEs were reported in 3 (16.7%) of the 18 patients, with the most common AEs being rash (11.1%), hypertension (5.6%), drug-induced liver damage (5.6%), and neutropenia (5.6%) in the preoperative phase. The 289 NanoString panel RNA sequencing showed that TIME cell infiltration especially dendritic cells (DCs) infiltration was better in responding tumors than in non-responding tumors. Our results of ctDNA revealed a higher positive rate (100%) among patients with HCC with stage IIb–IIIa disease. When comparing patients with pCR/MPR and non-MPR, we observed more mutations in patients who achieved pCR/MPR at baseline (6 mutations vs 2.5 mutations, p=0.025). Patients who were ctDNA positive after adjuvant therapy presented a trend of shorter RFS than those who were ctDNA negative. Proteomic analysis suggested that abnormal glucose metabolism in patients with multifocal HCC might be related to different sensitivity of treatment in different lesions. Conclusion Perioperative camrelizumab plus apatinib displays a promising efficacy and manageable toxicity in patients with resectable HCC. DCs infiltration might be a predictive marker of response to camrelizumab and apatinib as well as patients’ recurrence. ctDNA as a compose biomarker can predict pathological response and relapse. Abnormal glucose metabolism in patients with multifocal HCC may be related to different sensitivity of treatment in different lesions. Trial registration number NCT04297202.

Renal cell carcinoma (RCC) is one of the most prevalent cancers diseases in the worldwide. Long noncoding RNAs (LncRNAs) have been indicated as a mediator acted in tumorigenesis of RCC. LINC00460 has been reported to participate in many kinds of malignancies and promotes cancer progressions. However, the mechanism of LINC00460 on RCC is yet to be investigated. This study aimed to explore the potential function and regulation mechanism of LINC00460 in RCC. We analysed the LINC00460 expression and the prognosis in RCC patients using Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) databases. LINC00460 level in normal renal cell line and RCC cell lines were examined by qRT-PCR. We study the effects of LINC00460 on proliferation, migration, invasion, apoptosis in RCC cells lines using a series of in vivo and in vitro experiments. RNA sequencing (RNA-seq) analysis was applied to searching potential LINC00460 related signal pathway in RCC. We identified the significant up-regulated expression of LINC00460 both in RCC tissues and cell. RCC patients with elevated LINC00460 expression have shorter survival. Up-expression of LINC00460 promoted cell proliferation, invasion and migration, meanwhile down-regulation of LINC00460 exerted inhibitory effect on these activities. We crucially identified that LNC00460 promotes development of RCC by influencing the PI3K/AKT pathway. Knockdown of LNC00460 decreased the phosphorylation of AKT and mTOR. The key finding of our study showed that LINC00460 functions as an oncogene in RCC pathogenesis by mediating the PI3K/AKT.

Mucinous histology is generally considered as a risk factor of prognosis in stage II colon cancer, but there is no appropriate model for prognostic evaluation and treatment decision in patients with stage II colon mucinous adenocarcinoma (C-MAC) Thus, it is urgent to develop a comprehensive, individualized evaluation tool to reflect the heterogeneity of stage II C-MAC. Patients with stage II C-MAC who underwent surgical treatment in the Surveillance, Epidemiology, and End Results Program were enrolled and randomly divided into training cohort (70

Molecular variation between geographical populations and subtypes indicate potential genomic heterogeneity and novel genomic features within CCA. Here, we analyze exome-sequencing data of 87 perihilar cholangiocarcinoma (pCCA) and 261 intrahepatic cholangiocarcinoma (iCCA) cases from 3 Asian centers (including 43 pCCAs and 24 iCCAs from our center). iCCA tumours demonstrate a higher tumor mutation burden and copy number alteration burden (CNAB) than pCCA tumours, and high CNAB indicates a poorer pCCA prognosis. We identify 12 significantly mutated genes and 5 focal CNA regions, and demonstrate common mutations in post-transcriptional modification-related potential driver genes METTL14 and RBM10 in pCCA tumours. Finally we demonstrate the tumour-suppressive role of METTL14, a major RNA N6-adenosine methyltransferase (m6A), and illustrate that its loss-of-function mutation R298H may act through m6A modification on potential driver gene MACF1. Our results may be valuable for better understanding of how post-transcriptional modification can affect CCA development, and highlight both similarities and differences between pCCA and iCCA.

Proteasome 26S subunit ATPase 2 (PSMC2) plays a pathogenic role in various cancers. However, its function and molecular mechanism in hepatocellular carcinoma (HCC) remain unknown. In this study, tissue microarray (TMA) analysis showed that PSMC2 is highly expressed in HCC tumors and correlates with poor overall and disease-free survival in HCC patients. Multivariate Cox regression analysis revealed that PSMC2 is an independent prognostic factor for HCC patients. Furthermore, our results showed that PSMC2 knockdown inhibited cell proliferation and suppressed tumorigenesis in vivo. Knockdown of PSMC2 increased the expression of p21 and therefore decreased the expression of cyclin D1. Dual-luciferase reporter assays indicated that depletion of PSMC2 significantly enhanced the promoter activity of p21. Importantly, PSMC2 knockdown-induced phenotypes were also rescued by downregulation of P21. Taken together, our data suggest that PSMC2 promotes HCC cell proliferation and cell cycle progression through the p21/cyclin D1 signaling pathway and could be a promising diagnostic and therapeutic target for HCC patients.