A 23-gene expression signature was built to predict metastasis from primary cSCC tissue, and this findings provide the most detailed molecular portrait of cSCC to date and establish an assay for risk stratification suitable for clinical implementation.
Abstract
Cutaneous squamous cell carcinoma (cSCC) is the second most common form of cancer worldwide. While most cSCCs are not life-threatening, 2-5% of patients develop metastases. To better understand what causes some cSCCs to progress to metastatic disease, we assembled a nationwide cohort of 19,120 patients with clinico-pathologically annotated tumors linked to metastatic outcome. RNA-sequencing was performed on 378 tumors, and whole-exome sequencing on 147, with balanced numbers of tumors that progressed to metastatic disease (cases) and did not (controls). UV radiation was the dominant mutational signature with additional contributions from aging, APOBEC activity, and, in immunosuppressed patients, azathioprine exposure. We identified 38 genes under selection across a core set of signaling pathways. Gene expression clusters were primarily associated with the differentiation state of tumor cells and secondarily with the composition of the tumor microenvironment. Several mutational and transcriptional programs were associated with metastasis, including a dedifferentiated gene expression signature, activating mutations in the RAS signaling pathway, loss-of-function alterations in the SWI/SNF chromatin remodeling complex, and specific arm-level copy number alterations. A 23-gene expression signature was built to predict metastasis from primary cSCC tissue. The signature was validated in two independent cohorts (N=102 and 52), where it predicted metastasis independently of staging systems. Together, these findings provide the most detailed molecular portrait of cSCC to date and establish an assay for risk stratification suitable for clinical implementation.
Progress in the understanding of ATC biology is highlighted, with a focus on driver genetic alterations, metabolic plasticity and microenvironmental interactions that underpin its exceptional aggressiveness, to provide a rationale for the design of multimodal therapeutic strategies urgently needed to improve outcomes for patients with ATC.
Most melanoma-associated mortality occurs during the metastatic phase, yet our understanding of its clinical characteristics and molecular drivers remains limited. A growing body of literature is actively studying metastatic organotropism of melanoma from both basic and clinical perspectives. The active investigation of such phenomenon augments the risk stratification of patients and helps in the development of novel therapeutic approaches. In this investigation, we explore the clinicogenomic profile of pulmonary metastases of melanoma, an understudied challenging clinical entity. In this retrospective study, 1,142 melanoma patients who underwent next-generation sequencing of their tumors were included in the analyses. Patients were categorized based on the presence (n = 460) or absence (n = 682) of lung metastases. A comparative analysis between the study groups in terms of demographics, disease characteristics, and genomic profiles was conducted. The latter comparison utilized candidate genes originating from differential abundance analysis based on lung metastases status and overall survival (OS). Binary and Cox regression models were performed to identify possible associative and prognostic factors, respectively. The lung metastases sub-cohort had a mean age of 63.07 ± 14.3 years and was predominantly male (n = 292, 63.5%). The majority of patients with lung metastases were White, with cutaneous melanoma being the primary source of metastases. The median survival for patients with lung metastases was 38.41 months, and a significant difference in OS was observed between the lung metastases group and those without lung metastases (HR: 1.657, 95% CI: 1.362–2.016, P < .0001). Lung involvement was significantly associated concomitant metastases to the following sites: liver, bone, central nervous system, peripheral nervous system, intra-abdominal region, pleural, and kidneys. In addition, genomic alterations in SETD2 (OR: 2.074, 95% CI: 1.179–3.648, P = .011) and TSC1 (OR: 2.546, 95% CI: 1.225–5.295, P = .012) were significantly associated with lung metastases. Independent prognostic factors for melanoma lung metastases were microsatellite instability (HR: 2.873, 95% CI: 1.121–7.362, P = .028) and co-metastases to liver (HR: 2.184, 95% CI: 1.546–3.085, P < .001), bone (HR: 1.512, 95% CI: 1.091–2.095, P = .013), and central nervous system (HR: 1.904, 95% CI: 1.382–2.623, P < .001). On the other hand, none of the genomic alterations showed prognostic value. Melanoma pulmonary metastases are associated with poor survival and frequently co-occur with metastases to other sites. Genomic alterations in SETD2 and TSC1 might be linked to lung metastases, while microsatellite instability and co-metastases were independent prognostic factors. These findings highlight the need for further in-depth research with larger cohorts to confirm these findings.
R. Jadallah, A. A. Al Sharie, S. Al-Omari et al.· SN Comprehensive Clinical Me...· 0 citations
Abstract Background Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited genomic data in Asian populations. Lymph node metastasis heavily dictates prognosis, yet molecular determinants of progression remain poorly understood. We aimed to characterize the genomic landscape and explore candidate prognostic genomic features using paired primary and metastatic PSCC tumors. Patients and Methods Targeted next-generation sequencing (437 cancer-related genes) was performed on primary tumors and matched lymph node metastases from 20 Chinese patients. Somatic alterations, intralesional heterogeneity, and tumor mutation burden (TMB) were analyzed and correlated with disease-free survival (DFS) and overall survival (OS). Results The most frequent primary tumor mutations included TP53 (45%) and TERT (40%). Notably, CCND1/FGF19 co-amplification (20% of cases) was associated with inferior DFS (P = .027) and showed a trend toward shorter OS (P = .050). Conversely, T-cell receptor (TCR) pathway alterations correlated with markedly improved survival. Comparing paired lesions revealed 59.8% shared alterations. Elevated TMB in metastases relative to matched primary tumors was significantly associated with poorer DFS (P = .008), while higher intralesional heterogeneity showed a trend toward worse OS. Conclusion Paired profiling revealed broadly conserved genomic features together with lesion-specific divergence in PSCC. Recurrent CCND1/FGF19-containing 11q13 amplification, TCR pathway alterations, and elevated metastatic TMB warrant evaluation as potential prognostic features in larger, independently validated cohorts with integrated HPV and immune profiling.
K. Lou, Ling-Hui Liang, Hong-Zhou Cai et al.· The Oncologist· 0 citations
ABSTRACT Background Bulky disease represents a clinically aggressive subset of diffuse large B‐cell lymphoma (DLBCL) associated with adverse clinical outcomes. The aim of this study was to investigate the influence of oncogenic mutations and tumor microenvironment alterations on bulky disease in DLBCL. Methods We analyzed a cohort of 939 patients with newly diagnosed DLBCL. Using DNA (n = 934) and RNA (n = 524) sequencing, we compared oncogenic mutations and tumor microenvironment (TME) alterations based on tumor diameter, with cutoff values at 5.0 cm and 10.0 cm. Further stratification by mutations in key genes (CD58, STAT6, EBF1) correlated with tumor diameter revealed distinct transcriptomic and immunologic profiles. Subsequent single‐cell RNA sequencing, guided by these mutational signatures, resolved the cellular heterogeneity within the TME. Results Integrative analysis revealed that tumor diameter correlated with increased incidence of mutations in CD58, STAT6, and EBF1; adverse genetic subtypes such as EZB‐like MYC+ and TP53 Mut; activation of oncogenic pathways (JAK/STAT, BCR, PI3K, and MYC); and an immunosuppressive tumor microenvironment. Notably, immune checkpoint molecules varied across the bulky stages, with CTLA‐4, TIGIT, ICOS, and CD28 expression inversely correlated with tumor diameter, while CD70 and 4‐1BBL expression positively correlated. Single‐cell RNA sequencing further revealed mutation‐specific tumor microenvironment insights. CD58‐mutated tumor exhibited a profoundly immune‐deserted microenvironment dominated by malignant B cells with minimal immune infiltration, whereas STAT6‐mutated tumor was associated with increased fibroblasts and CD4 + T cells, particularly regulatory T cells (Treg) and Th1‐like cells; EBF1‐mutated tumor was characterized by increased proportions of malignant B cells. Conclusions Collectively, our findings highlight the biological complexity of bulky disease, identifying candidate molecular targets and providing a biological framework for future therapeutic hypothesis generation in this clinically aggressive subset of DLBCL.
Yu-Qing Wang, Yue Wang, Zhi-Shan Du et al.· Cancer Medicine· 0 citations
Introduction Nasopharyngeal carcinoma (NPC) is a common malignancy with a high incidence in Southern China and Southeast Asia. Distant metastasis remains a major cause of poor prognosis. This study aims to explore the genomic and immune microenvironmental changes in primary and metastatic NPC through longitudinal analysis, to provide insights for guiding precision treatment strategies. Methods We analyzed tumor samples from 11 male NPC patients with distant metastasis. Paired primary and metastatic samples underwent targeted whole-exome sequencing (551 genes) and RNA sequencing (289 genes). Multiplex immunohistochemistry was performed to assess immune cell composition and immune response markers. Genomic alterations and immune features were compared between primary and metastatic tumors, and their associations with clinical outcomes were evaluated. Results Metastatic tumors exhibited distinct chromosomal changes, including frequent 1q gain, while 6p gain showed a trend toward prolonged survival. Primary tumors showed stronger immune suppression characterized by increased B-cell and Treg infiltration and elevated CTLA4 and IDO1 expression, whereas metastatic lesions displayed more active immune responses. Liver metastases presented a distinct immune landscape with lower CD8+ T-cell density compared to non-liver metastases. In locoregionally advanced NPC, high expression of oncogenic genes such as EGFR and MYC correlated with shorter disease-free survival, while elevated PANCK expression and enhanced cytotoxicity were linked to better outcomes. These results delineate the molecular and immune evolution of NPC and provide a foundation for developing precision therapeutic strategies. Conclusion This study identifies key molecular and immune features associated with NPC survival. Primary tumors show an immunosuppressive phenotype, suggesting potential benefits from combining CTLA4 or IDO1 inhibitors with PD-1 blockade. Liver metastases exhibit distinct immune features, supporting the need for site-specific precision therapies. These findings contribute to personalized management strategies in NPC, guiding treatment based on molecular and immune profiles.
Ying Lu, T. Han, Li-Hui Wang et al.· Frontiers in Oncology· 0 citations
Carcinoma of unknown primary (CUP) remains a clinically challenging malignancy with limited treatment options and poor prognosis. Although genomic profiling has identified potentially actionable alterations, optimal therapeutic strategies are often unclear. Here, we report the establishment and characterization of a patient-derived tumoroid from an EGFR-amplified CUP and evaluate its utility as a functional model for therapeutic assessment. The patient-derived tumoroid (PDT-CUP#1) was successfully established from resected tumor tissue and maintained in long-term culture. Whole-exome sequencing demonstrated genomic concordance between the PDT-CUP#1 and the original tumor. Quantitative PCR and fluorescence in situ hybridization confirmed EGFR amplification. Xenograft tumors derived from PDT-CUP#1 recapitulated the histopathological features of the original lesion. Functional drug testing demonstrated differential sensitivity among EGFR-targeted agents. Whereas EGFR tyrosine kinase inhibition resulted in modest growth suppression, anti-EGFR monoclonal antibodies exhibited moderate antitumor effects, and an EGFR-targeted antibody–drug conjugate showed the most pronounced growth inhibition. Notably, the therapeutic sensitivity observed in the tumoroids was generally consistent with the patient’s clinical response to platinum-based chemotherapy combined with necitumumab. These findings demonstrate that a CUP-derived tumoroid can be successfully established while preserving the key molecular and pathological features of the original tumor. This model provides a platform for functional evaluation of therapeutic vulnerabilities and offers proof-of-concept for integrating patient-derived tumoroids into therapeutic decision-making in CUP.
Miki Iwai, Etsuko Yokota, T. Yukawa et al.· Human Cell· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
