The global incidence of early-onset colorectal cancer (EOCRC) is increasing. The prognostic impact of EOCRC remains controversial, as it is largely confounded by hereditary syndromes and mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) tumors. We aimed to evaluate the clinicopathological features and stage-adjusted outcomes of sporadic, proficient MMR/microsatellite stable (pMMR/MSS) EOCRC. We retrospectively reviewed 1,600 consecutive patients who underwent primary tumor resection for Stage 0–IV CRC. After excluding patients with known hereditary cancer syndromes or inflammatory bowel disease (IBD)-related CRC, as well as those with dMMR/MSI-H tumors or unknown MMR/MSI status, 1,218 patients with sporadic pMMR/MSS CRC were analyzed. Patients were stratified into EOCRC (< 50 years, n = 86) and late-onset CRC (LOCRC, ≥ 50 years, n = 1,132) cohorts. Cancer-specific survival (CSS) and time to recurrence (TTR) were evaluated. Patients with EOCRC were more often diagnosed at an advanced stage than those with LOCRC (P < 0.001). Unadjusted CSS was worse in the EOCRC group (P = 0.042); however, multivariable analysis showed that EOCRC was not an independent predictor of worse CSS (adjusted hazard ratio [HR] 0.84, 95

Background/Objectives: Evidence on longitudinal changes in nutrition, inflammation, and body composition during adjuvant chemotherapy for Stage II/III colorectal cancer (CRC) remains limited. We therefore evaluated these changes and explored preoperative factors associated with treatment discontinuation and prognosis. Methods: This single-center retrospective study included patients with Stage II/III CRC who underwent curative surgery and adjuvant chemotherapy. Body mass index (BMI), computed tomography (CT)-derived psoas muscle index (PMI), psoas muscle density (PMD), modified intramuscular adipose tissue content (mIMAC), Geriatric Nutritional Risk Index (GNRI), Prognostic Nutritional Index (PNI), hemoglobin–albumin–lymphocyte–platelet (HALP) score, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were assessed preoperatively and 6 months after chemotherapy initiation. Analyses were stratified into oxaliplatin-based doublet therapy (CAPOX/FOLFOX) and fluoropyrimidine monotherapy. Results: Among 142 patients, GNRI, PNI, and HALP score increased, whereas BMI, NLR, and PLR decreased from preoperative assessment to follow-up. Adjuvant therapy was discontinued in 45 patients (31.7%). In the doublet therapy group, discontinuation was associated with lower preoperative GNRI, PNI, and HALP scores and higher NLR and PLR. In the monotherapy group, only older age was associated with discontinuation. Lower preoperative PMD and mIMAC, but not PMI, were associated with poorer overall survival. No other nutritional or inflammatory markers were associated with overall survival. Conclusions: Several nutritional and inflammatory markers improved from preoperative assessment to follow-up. Preoperative nutritional and inflammatory markers were associated with treatment discontinuation, particularly in the doublet therapy group. CT-derived muscle quality markers were associated with overall survival, suggesting prognostic relevance of muscle quality in this setting.

Survival after recurrence in colorectal cancer (CRC) is typically evaluated in adjuvant-treated Stage II–III patients, where therapy may select for resistant subclones and biologically modify recurrent tumors. Conversely, the natural history of recurrence in Stage I or chemo-naïve disease remains poorly characterized. We investigated prognostic determinants of cancer-specific survival after recurrence (CS-SAR) in a strictly chemo-naïve cohort. Among 721 patients with pathological Stage I–III CRC who underwent curative resection without perioperative chemotherapy, we identified and analyzed 69 patients who developed recurrence. CS-SAR was analyzed using the Kaplan-Meier method and univariable and multivariable Cox models. Initial Stage I disease, oligometastasis, and salvage surgery were favorable prognostic factors, whereas early recurrence was associated with poor CS-SAR. In multivariable analysis, salvage surgery was strongly associated with favorable CS-SAR, whereas the association between oligometastatic status and CS-SAR was attenuated after adjustment of salvage surgery. Initial Stage I disease remained an independent favorable factor. Recurrent Stage I CRC may represent a clinically favorable subgroup, characterized by a tendency toward late, oligometastatic recurrence. These recurrence patterns may increase the feasibility of salvage surgery, which was strongly associated with long-term survival. Therefore, careful surveillance and multidisciplinary evaluation for curative-intent salvage strategies upon recurrence should be considered even for early-stage patients.

Introduction:In metastatic colorectal cancer (CRC), achieving complete response (CR) through chemotherapy alone is exceedingly rare. We report a case of metastatic CRC that achieved CR following second-line treatment with FOLFIRI plus ramucirumab after disease progression on first-line FOLFOX plus panitumumab therapy. Case Presentation:A 61-year-old woman was diagnosed with stage IVB rectal cancer with synchronous liver, lung, and lateral lymph node metastasis (KRAS/BRAF wild-type, microsatellite stable, and HER2-negative). Following first-line FOLFOX plus panitumumab, regression was observed in the rectal lesion and liver metastasis, but one pulmonary nodule progressed. The regimen was switched to second-line FOLFIRI plus ramucirumab. Subsequently, a complete radiological response was observed in all lesions, and a biopsy of the rectal scar confirmed no malignancy. Considering the tumor heterogeneity and surgical morbidity, we engaged in shared decision-making with the patient and adopted a watch-and-wait strategy. The patient received consolidation chemotherapy and remains recurrence-free for 6 months after achieving CR. Conclusion:We report a rare case in which second-line FOLFIRI plus ramucirumab led to a CR in metastatic CRC, even after progression on anti-epidermal growth factor receptor therapy. In the present case, a watch-and-wait strategy was selected to prioritize organ preservation. Given the lack of consensus, further investigation is required to define the optimal strategy for patients achieving CR.

BACKGROUND:Claudin-18 isoform 2 (CLDN18.2) is a tight junction protein expressed in gastric mucosa and gastric cancer (GC) cells. Although chemotherapeutic agents are suggested to increase CLDN18.2 expression in GC cells, their impact on GC tissues and their underlying mechanisms remain unclear. METHODS:We examined the effects of chemotherapy on CLDN18.2 expression in human GC tissues and cell lines, and investigated the role of cell-cycle regulation in this process. RESULTS:We found that CLDN18.2 expression was upregulated in GC tissues after chemotherapy. In GC cell lines (SNU-601, NUGC4, GSU), chemotherapeutic agents, including 5-fluorouracil, irinotecan, paclitaxel, and cisplatin, increased CLDN18.2 expression at the transcriptional level, although the response patterns varied among cell lines and agents. Since cell-cycle regulation appeared to be involved, we tested cyclin-dependent kinase (CDK) inhibitors and found that CDK1- and CDK4/6-specific inhibitors similarly enhanced CLDN18.2 expression. Importantly, both chemotherapeutic agents and CDK inhibitors significantly increased zolbetuximab-mediated antibody-dependent cellular cytotoxicity in GC cells. CONCLUSION:These results suggest that chemotherapeutic agents upregulate CLDN18.2 in GC cells at least in part through cell cycle arrest, and support combining zolbetuximab with chemotherapy and/or CDK inhibitors for GC treatment.

Abstract The “mesenchymal” consensus molecular subtype 4 (CMS4) of colorectal cancer (CRC) has the poorest prognosis and shows stromal activation and bulk epithelial-mesenchymal transition (EMT) signatures that largely reflect cancer-associated fibroblast-derived signals, obscuring tumor cell-intrinsic programs. Aberrant glycosylation drives EMT and metastasis, yet the glycosyltransferase landscape intrinsic to CMS4 tumor epithelium remains poorly defined because stromal signals dominate bulk transcriptomes. To overcome this confounding, we analyzed single-cell RNA-sequencing datasets to distinguish CMS4 tumor epithelial cells from CMS1–3 epithelial cells, normal epithelium, and stromal/immune populations. This identified a nine-gene glycosyltransferase signature uniquely upregulated in CMS4 tumor epithelium. Among these, GALNT5 showed consistent transcriptional induction during EMT in CRC cell lines. GALNT5 depletion suppressed proliferation, invasion, and migration, independent of overt changes in canonical EMT markers or AKT/ERK signaling. Immunohistochemical analysis of 431 resected CRC specimens confirmed that GALNT5 protein expression was restricted to cancer cells, particularly at the invasive front. High GALNT5 expression was associated with deeper invasion and advanced stage, and served as an independent prognostic factor for worse overall survival, notably within the microsatellite-stable subgroup. In conclusion, by leveraging single-cell transcriptomics, this study defines a CMS4 epithelial-intrinsic glycosylation program and highlights GALNT5 as a prognostic biomarker and therapeutic candidate.

Exposed constantly to environmental challenges, the stomach undergoes highly reversible cycles of regeneration and recovery. Although abnormal activation of regeneration is known to be associated with cancer, the mechanisms underlying tissue restoration remain unclear. Our single-cell gene expression and chromatin analysis defined cell state dynamics during regeneration and recovery, identifying the Brahma-related gene 1(BRG1)/BRM-associated factor (BAF) chromatin remodeling complex during recovery. Strikingly, deletion of AT-rich interaction domain 1A (Arid1a), a subunit of the BAF complex and the second most frequently mutated gene in gastric cancer, impaired recovery across multiple murine injury models, resulting in a persistent regenerative state. Integrative analyses combining single-cell multiome and chromatin immunoprecipitation sequencing (ChIP-seq) demonstrated that the BAF complex recruits lineage-specific transcription factors such as MIST1 and estrogen related receptor gamma (ERRγ) to regulate enhancers of recovery genes. Notably, deletion of Trp53 in the unresolved regenerative state caused by Arid1a loss is sufficient to drive cancer development and invasion, revealing the epigenetic mechanisms bridging gastric regeneration, recovery, and cancer.

Colorectal cancer with deficient mismatch repair (dMMR)/microsatellite instability (MSI) constitutes a distinct clinicopathologic and immunologic subtype, characterized by high sensitivity to immune checkpoint inhibitors. However, prognosis and therapeutic response vary considerably among dMMR/MSI colorectal cancers, underscoring the need for molecular markers to refine patient stratification. In this study, we systematically investigated cancer cell-intrinsic expression profiles of 188 glycosyltransferase genes by integrating single-cell, bulk, and cell line RNA sequencing datasets. This approach identified five glycosyltransferases, including GALNT7, expression of which differed consistently according to MSI status. The clinical and prognostic relevance of these glycosyltransferases was further analyzed across large-scale transcriptomic, proteomic, and IHC cohorts, comprising 662 dMMR/MSI and 3,483 proficient mismatch-repair (pMMR)/microsatellite-stable (MSS) colorectal cancers. A five-gene glycosyltransferase signature effectively distinguished MSI from MSS colorectal cancers across 18 datasets. Among the five genes, GALNT7 expression was robustly associated with favorable prognosis in four independent transcriptomic and IHC cohorts of dMMR/MSI colorectal cancers while showing little or no prognostic impact in pMMR/MSS colorectal cancers. Notably, GALNT7 expression was inversely correlated with PD-L1 expression at both the mRNA and protein levels in multiple datasets exclusively within dMMR/MSI colorectal cancers, but not in pMMR/MSS CRCs. Functional assays and lectin microarray analysis using MSI colorectal cancer cell lines revealed that GALNT7 knockdown enhanced IFNγ-induced PD-L1 expression without altering cell-surface glycosylation. In conclusion, GALNT7 expression stratified dMMR/MSI colorectal cancers into distinct subsets with differential tumor cell PD-L1 expression and diverse survival outcomes, highlighting its potential as a prognostic biomarker to guide treatment strategies. SIGNIFICANCE:We identified glycosyltransferases with altered expression depending on MMR/MSI status. Our findings indicate the existence of two molecularly defined subtypes within dMMR/MSI colorectal cancers based on GALNT7 expression, characterized by differential tumor cell PD-L1 levels and distinct survival outcomes.

Only 15% of young-onset breast cancers have identifiable hereditary germline pathogenic variants (PVs) in an established breast cancer susceptibility gene. However, it is believed that a significant proportion of these breast cancers have additional monogenic or rare risk variants that require identification. To uncover novel cancer susceptibility genes, we performed germline whole-exome/genome sequencing of samples from 564 patients with young-onset breast cancer (aged <40 years), as well as samples from 4032 female controls. The identified candidate variants were further genotyped in 6,967 independent breast cancer cases across all age groups. We identified two PVs that were significantly associated with the risk of hormone receptor-negative young-onset breast cancer: POLH p.K589T (OR = 3.65, 95% confidence interval [CI] = 1.28-10.4, P = 0.0095) and RAD51 p.M1fs (OR = 2.15, 95% CI = 1.15-4.02, P = 0.014). When BRCA1/2 PV carriers were excluded from the analysis, only RAD51 p.M1fs retained a significant association. Whole-genome sequencing of tumor samples carrying these germline risk variants revealed that they harbored mutational signatures indicative of a deficiency of homologous recombination. These findings suggest that hereditary POLH p.K589T and RAD51 p.M1fs are candidate variants associated with an increased risk of hormone receptor-negative breast cancer.

Integration of bulk, cell line, and single-cell RNA-seq for 188 glycosyltransferase genes identified five genes that were differentially expressed between MSI and MSS colorectal cancers. A, Heatmap depicting the upregulation of GALNT7, GALNT1, and HPSE and the downregulation of GALNT6 and ST6GAL1 in MSI colorectal cancer bulk tissues (TCGA cohort), cell lines (CCLE cohort), and single epithelial cancer cells (SMC cohort), compared with those of MSS. Dot size corresponds to the percentage of cells expressing the gene. B, Heatmap depicting the performance of Glyco-MSI score based on the expression of five genes to distinguish MSI from MSS colorectal cancers using 19 transcriptomic and proteomic cohorts of colorectal cancer. C, Forest plot demonstrating Cox HRs and 95% CIs of each five gene and the Glyco-MSI score for OS in TCGA cohort, PFS in the AC-ICAM cohort, and RFS in the GSE39582 cohort. D–F, Kaplan–Meier curves according to the expression of GALNT7 in TCGA (D), AC-ICAM (E), and GSE39582 (F). Log-rank P values, Cox HRs, and 95% CIs are indicated. For survival analysis, patients were dichotomized as high or low based on the median expression of GALNT7.

BackgroundIntratumoral Fusobacterium nucleatum (Fn) infection is closely associated with poor prognosis in esophageal cancer (EC) due to its impact on the tumor microenvironment (TME). The tumor cell-intrinsic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is critical for regulating immune cell activation in the TME. However, the link between intratumoral Fn infection and the activation of the cGAS-STING pathway in tumor cells, as well as its effects on EC progression, remains largely unknown.MethodsIn the present study, we investigated the impact of intratumoral Fn infection on the activation of the tumor cell-intrinsic cGAS-STING pathway and EC progression by analyzing our own EC cohort and performing in vitro experiments using co-cultures of EC-cell lines and Fn.ResultsThe expression of tumor cell-intrinsic STING was significantly associated with worse prognosis in Fn-high EC patients. Exposure to Fn significantly activated the STING pathway in EC cells. RNA-seq analysis revealed that exposure to Fn markedly activated cytokine-chemokine-related signaling pathways and induced the expression of several cytokines and chemokines in STING-expressing EC cells. Among the differentially expressed cytokine and chemokine genes in EC cells co-cultured with Fn, analysis of TCGA datasets demonstrated that the expression of CCL20, CXCL10, and CSF2 may be associated with poor prognosis in EC patients.ConclusionWe revealed that the activation of the STING signaling pathway and the subsequent expression of cytokines and chemokines in EC cells induced by Fn infection may be closely associated with poor prognosis in EC patients.

Background: Anti-programmed death 1 receptor (PD-1) therapy is a promising treatment strategy for patients with unresectable advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer. However, its response rate and survival benefits are still limited; an immunological analysis of the residual tumor after anti-PD-1 therapy would be important. Methods: We evaluated the clinical efficacy of tumor resection (TR) after chemotherapy or anti-PD-1 therapy in patients with unresectable advanced or recurrent G/GEJ cancer and analyzed the immune status of tumor microenvironment (TME) by immunohistochemistry using their surgically resected specimens. Results: Patients treated with TR after anti-PD-1 therapy had significantly longer survival compared to those treated with chemotherapy and anti-PD-1 therapy alone. Expression of human leukocyte antigen (HLA) class I and major histocompatibility complex (MHC) class II on tumor cells was markedly downregulated after anti-PD-1 therapy compared to chemotherapy. Furthermore, the downregulation of HLA class I may be associated with the activation of transforming growth factor-β signaling pathway in the TME. Conclusions: Immune escape from cytotoxic T lymphocytes may be induced in the TME in patients with unresectable advanced or recurrent G/GEJ cancer after anti-PD-1 therapy due to the downregulation of HLA class I and MHC class II expression on tumor cells. TR may be a promising treatment strategy for these patients when TR is feasible after anti-PD-1 therapy.

BackgroundFibroblast growth factor receptor (FGFR) 4 is overexpressed in gastric cancer (GC) and is a potential therapeutic target for GC. Since the FGF/FGFR signaling is involved in tumor microenvironment inducing the formation of an immunosuppression, lenvatinib is expected to inhibit FGFR4 leading to reduced tumor PD-L1 levels and regulatory T cell (Treg) infiltration, improving pembrolizumab efficacy. This study explored the background of the molecular mechanisms underlying the therapeutic efficacy of lenvatinib plus pembrolizumab.MethodsExpression of FGFR4 and its specific ligand FGF19 was assessed by immunohistochemical staining and clinicopathological relevance was also examined. The effect of lenvatinib on FGF19-FGFR4 signaling was evaluated using cellular experiments. Lastly, the expression of FGFR4 on Treg cells was evaluated by immunostaining and flow cytometry. The Cancer Genome Atlas cBioPortal and Gene Expression Omnibus microarray databases were accessed to support these results.ResultsHigh FGFR4 expression was associated with histological type and venous invasion and predominantly detected in human epidermal growth factor receptor 2 and Epstein-Barr virus-positive GC. Bioinformatics data suggested that FGF19-FGFR4 signaling was activated in GC, and cellular experiments showed that lenvatinib reduced FGFR4 and PD-L1 expression in GC cells. Results of integrating various analyses suggested that FGFR4 did not seem to be enough expressed on Treg cells in GC.ConclusionsThe FGF19-FGFR4 signaling has a pivotal role in gastric tumorigenesis and may be involved in immunosuppression through PD-L1 modification. But, lenvatinib may not regulate immune editing by directly inhibiting FGFR4 on Treg cells.

INTRODUCTION:Up to 54% of all lung adenocarcinoma (LADC) cases in Asian populations occur in never-smoking women, suggesting that the impact of smoking and other environmental factors on the risk of early-onset LADC is minimal. Genetic factors may play a crucial role in disease development. METHODS:The prevalence of germline pathogenic variants (GPVs) of 454 hereditary cancer and DNA repair genes was evaluated by whole-exome and whole-genome sequencing of 348 early-onset LADC (aged ≤ 40 y) and 1425 later-onset LADC (aged ≥ 41 y) cases. A case-control study comprising 10,302 LADC cases and 7898 healthy controls was performed to identify moderate-risk genetic factors for the disease. Analysis of somatic mutations in 1278 patients with LADC, including 31 patients with GPVs, was also performed. RESULTS:The frequency of GPVs of TP53 and BRCA2 was significantly higher in those with early-onset LADC than in those with later-onset LADC. The detection rates for TP53 and BRCA2 GPVs were 2.9% and 1.7%, respectively, in patients with early-onset LADC, and 0.14% and 0.21%, respectively, in patients with later-onset LADC. Patients with BRCA1 GPVs exhibited a high incidence of concurrent TP53 somatic mutations. Patients with BRCA2 GPVs exhibited deficient homologous recombination in tumors by means of loss of the wild-type allele. A germline ALKBH2 variant, p.Glu35Alafs∗54, was associated with the risk of early-onset LADC, and patients with a deleterious variant exhibited a correlation between SBS4-related somatic mutations and the Brinkman index. CONCLUSION:TP53 and BRCA2 GPVs and the ALKBH2 novel variant are associated with early-onset LADC in Asians.

INTRODUCTION:Desmoid tumors are locally aggressive, non-metastatic neoplasms that develop in up to 20% of patients with familial adenomatous polyposis (FAP). While active surveillance is the initial approach, surgery may be indicated for symptomatic or progressive disease; however, the optimal surgical strategy remains debated. CASE PRESENTATION:We present the case of a 48-year-old man with FAP and a history of two previous laparotomies. He developed a progressive and symptomatic abdominal wall desmoid tumor refractory to non-operative management, including medical therapy. He underwent a surgical resection without pursuing wide negative margins. Intraoperatively, the tumor was adherent to the prior midline incision scar and anterior rectus sheath. After resection, the resulting 100 × 50 mm fascial defect was repaired with a synthetic mesh. Histopathology confirmed the desmoid tumor with microscopically negative (R0) resection margins, and no evidence of recurrence was observed at the 9-month follow-up. CONCLUSIONS:Surgical resection without pursuing wide negative margins, previously described in sporadic desmoids, may be considered a feasible option for selected FAP-associated abdominal wall tumors, balancing local control with no apparent postoperative abdominal wall functional deficit.

ABSTRACT Despite the importance of genetic testing for risk assessment and treatment in breast cancer, the prognostic impact of germline pathogenic variants (PVs), especially in Asian populations, is unclear. We assessed the impact of germline PVs in patients with early‐stage breast cancer. This study included 7278 Japanese multihospital registry patients. PVs of ATM , BRCA1 , BRCA2 , CDH1 , CHEK2 , NBN , NF1 , PALB2 , PTEN , STK11 , and TP53 were evaluated. PV and non‐PV carriers were matched by age, histology, and stage. Associations between PVs and survival were assessed. The primary outcome was invasive disease‐free survival (IDFS). Secondary outcomes included relapse‐free survival (RFS), overall survival, and breast cancer‐specific survival. We identified 320 (4.4%) patients with BRCA1/2 PVs and 79 (1.1%) with PVs other than BRCA1/2 (non‐ BRCA1/2 ). A total of 360 patients ( BRCA1/2 , n = 289; non‐ BRCA1/2 , n = 71) were matched to 720 noncarriers. Patients with BRCA1/2 PVs had significantly shorter 10‐year IDFS (adjusted hazard ratio (aHR) = 2.15; 95% confidence interval (CI), 1.61–2.86; p < 0.001); and RFS (aHR = 1.74; 95% CI, 1.25–2.44; p = 0.001) than noncarriers. Among patients with hormone receptor‐positive HER2‐negative breast cancer, BRCA1/2 PV carriers exhibited significantly shorter 10‐year IDFS than noncarriers, even those with stage I/II disease (total, aHR = 2.23; 95% CI, 1.55–3.23; p < 0.001, Stage I/II, aHR = 2.22; 95% CI, 1.43–3.44; p < 0.001). There was no significant difference in 10‐year IDFS between the non‐ BRCA1/2 PV carrier and noncarrier groups (aHR = 1.40; 95% CI, 0.67–2.93; p = 0.37). Asian patients with breast cancer carrying germline BRCA1/2 PV, even those with a low recurrence risk, have significantly shorter 10‐year IDFS than noncarriers.