Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. Although proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible expression in normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10−17 mol/L) ORF1p concentrations in plasma across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multianalyte panel, provides early therapeutic response monitoring in gastroesophageal cancers, and is prognostic for overall survival in gastroesophageal and colorectal cancers. Together, these observations nominate ORF1p as a multicancer biomarker with potential utility for disease detection and monitoring. Significance: The LINE-1 ORF1p transposon protein is pervasively expressed in many cancers and is a highly specific biomarker of multiple common, lethal carcinomas and their high-risk precursors in tissue and blood. Ultrasensitive ORF1p assays from as little as 25 μL plasma are novel, rapid, cost-effective tools in cancer detection and monitoring. See related commentary by Doucet and Cristofari, p. 2502. This article is featured in Selected Articles from This Issue, p. 2489

Hepatocellular carcinoma (HCC) remains one of the most lethal cancers globally, driven by chronic liver disease and a complex tumor microenvironment (TME). Recent advances in spatial omics, single-cell analyses, and AI-driven digital pathology have shed light on the intricate heterogeneity of HCC, highlighting key roles for immune suppression, angiogenesis, and fibrosis in tumor progression. This review synthesizes current epidemiological trends, noting a shift from viral hepatitis to metabolic syndrome as a primary etiology in Western populations, and elucidates how TME components—such as tumor-associated macrophages, cancer-associated fibroblasts, vascular endothelial cells, and immunosuppressive cytokines—contribute to resistance against conventional therapies. We detail the evolution of immunotherapeutic strategies from monotherapy to combination regimens, including dual immune checkpoint blockade and the integration of antiangiogenic agents. Emerging circulating and tissue-based biomarkers offer promise for enhanced patient stratification and real-time monitoring of treatment responses. Collectively, these innovations herald a paradigm shift toward TME-directed precision oncology in HCC, emphasizing the need for multi-targeted approaches to synergistically modulate interacting cellular constituents and ultimately improve clinical outcomes.

PURPOSE: Colorectal cancer (CRC) incidence in patients younger than 50 years of age, commonly defined as early-onset (EO-CRC), is rising. EO-CRC often presents with distinct clinicopathologic features. However, data on prognosis are conflicting and outcomes with modern treatment approaches for metastatic disease are still limited. MATERIALS AND METHODS: We prospectively enrolled patients with metastatic CRC (mCRC) to a biobanking and clinical data collection protocol from 2014 to 2018. We grouped the cohort based on age at initial diagnosis: < 40 years, 40-49 years, and ≥ 50 years. We used regression models to examine associations among age at initial diagnosis, treatments, clinicopathologic features, and survival. RESULTS: We identified 466 patients with mCRC (45 [10%] age < 40 years, 109 [23%] age 40-49 years, and 312 [67%] age ≥ 50 years). Patients < 40 years of age were more likely to have received multiple metastatic resections (odds ratio [OR], 3.533; P = .0066) than their older counterparts. Patients with EO-CRC were more likely to receive triplet therapy than patients > 50 years of age (age < 40 years: OR, 6.738; P = .0002; age 40-49 years: OR, 2.949; P = .0166). Patients 40-49 years of age were more likely to have received anti-EGFR therapy (OR, 2.633; P = .0016). Despite differences in care patterns, age did not predict overall survival. CONCLUSION: Despite patients with EO-CRC receiving more intensive treatments, survival was similar to the older counterpart. However, EO-CRC had clinical and molecular features associated with worse prognoses. Improved biologic understanding is needed to optimize clinical management of EO-CRC. The cost-benefit ratio of exposing patients with EO-CRC to more intensive treatments has to be carefully evaluated.

High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we showed that LIN28B expression was associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7–independent enrichment of transcripts encoding components of the translational and ribosomal apparatus and depletion of transcripts of neuronal developmental programs. We further observed that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrated that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a posttranscriptional driver of the metastatic phenotype.

PURPOSE: Hepatocellular carcinoma (HCC) has high relapse rates after standard-of-care (SOC) resection or liver transplantation (LT). We evaluated the utility of circulating tumor DNA (ctDNA) to predict relapse/progression risk in patients with HCC. Materials and Methods: This retrospective analysis examined real-world data from ctDNA testing on 125 patients with HCC (721 plasma samples) undergoing curative-intent treatments and SOC management. Patients were divided into four subcohorts: cohort A (n = 64) and B (n = 52) comprised patients under recurrence monitoring after LT or resection, respectively. Cohort C (n = 4) and D (n = 5) comprised patients under treatment response monitoring with known recurrence or inoperable disease, respectively. A personalized, tumor-informed 16-plex polymerase chain reaction next-generation sequencing assay (Signatera, Natera, Inc, Austin, TX) was used for ctDNA testing. The molecular residual disease (MRD) window was defined as 2-12 weeks post-LT/resection (cohorts A/B), before starting adjuvant therapy (AT). Surveillance window was defined as post-MRD window or 2 weeks post-AT (cohort B) or during ongoing treatment (cohorts C/D). RESULTS: The median follow-up was 40 (1.5-60) months. In cohort A, 97.2% (35/36) of patients with ctDNA negativity in the MRD window remained negative during surveillance. In cohort B, ctDNA was detected in 29.4% (10/34) of patients within the MRD window, all of whom experienced clinical recurrence (hazard ratio [HR], 7.2 [95% CI, 2.6 to 20]; P < .0001). In the surveillance window (cohort B), the ctDNA detection rate was 32.3% (10/31), and all experienced recurrence (HR, 18.0 [95% CI, 3.9 to 85]; P < .0001). In cohorts C/D, on-treatment ctDNA dynamics were concordant with treatment response as measured by imaging. Compared with alpha-fetoprotein, ctDNA had higher sensitivity and a significantly longer lead time (7.9 v 2.2 months) for recurrence detection. CONCLUSION: Serial ctDNA testing effectively identified HCC recurrence early, postresection and post-LT. ctDNA was also useful for treatment response monitoring and could help resolve ambiguous imaging results.

Hepatocellular carcinoma (HCC) remains a lethal malignancy and is an increasingly common cause of cancer death worldwide. Curative-intent surgical resection remains the standard of care for eligible patients, yet outcomes remain poor for many patients, with most patients experiencing recurrence in the 5 years after resection. There is currently significant interest in using locoregional and systemic therapies—in both the neoadjuvant and adjuvant settings—to increase the chance of cure. This review article appraises the existing literature and current clinical trial landscape of neoadjuvant therapies in HCC.