The causes of most cancers remain unknown because the biological pathways underlying cancer development are poorly understood. Large-scale plasma proteomics offers a powerful strategy to uncover these pathways, identify biomarkers for cancer early detection, and discover novel therapeutic targets but has rarely been applied in prospective cohorts. Here, we profiled 6,402 plasma proteins using the SomaScan TM 7K Assay in baseline samples from 9,828 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC), including 6,073 incident cancer cases within a case-cohort design. We identified 1,732 protein-cancer associations (FDR P < 0.05) across 25 cancer endpoints in multivariable-adjusted models, including 60 proteins associated with overall cancer risk. Confirmation analyses in the Atherosclerosis Risk in Communities (ARIC) Study cohort showed directional concordance for 78% of associations and statistical replication of 49% of findings. Most proteins were associated with a single cancer type, whereas 284 were associated with multiple cancers, indicating both shared and distinct biological pathways across cancer sites. Stratification by follow-up time revealed 523 protein associations that were restricted to specific time windows after blood collection (<2 years, <5 years, and >5 years), including 447 that were not apparent in primary analyses, highlighting proteins with potential roles as early detection or aetiological biomarkers. Proteins associated with cancer risk were enriched across diverse biological pathways and 315 corresponded to targets of approved cancer and non-cancer medications, while most proteins represent previously unrecognised links to cancer risk. As the most comprehensive prospective investigation of the plasma proteome and cancer risk to date, our study significantly expands our understanding of key biological pathways shaping cancer development and provides a resource for the scientific community to accelerate development of early detection strategies, biomarkers for risk stratification, and novel therapeutic interventions for cancer prevention.

Germline pathogenic variants in BRCA1/2 substantially increase lifetime risks of both breast and ovarian cancers. However, whether specific mutation characteristics predispose carriers to breast-ovarian double primary cancers (DPC) and whether DPC affects ovarian cancer outcomes-particularly in the PARP inhibitor (PARPi) era-remain unclear. We conducted a retrospective analysis of patients with germline BRCA1/2-mutated high-grade serous ovarian cancer in China from 2015 to 2025, including 114 DPC patients and 296 ovarian cancer (OC)-only patients as controls. Clinical characteristics, mutation profiles, and survival outcomes were compared between the two groups. Among 114 DPC patients, 92 were diagnosed with breast cancer first, 12 with ovarian cancer first, 9 had synchronous diagnoses, and 1 was unknown. Compared with the OC-only group, BRCA1/2 mutations in the DPC group were predominantly located outside the Ovarian Cancer Cluster Region (BRCA1: 63.1% vs. 48.9%, p = 0.019; BRCA2: 80.0% vs. 56.2%, p = 0.008). Among BRCA2-mutated patients, DNA-binding domain mutations were enriched in the DPC group (33.3% vs. 17.8%, p = 0.018). Both groups benefited from first-line PARPi maintenance. No significant differences in progression-free or overall survival were observed between DPC and OC-only patients on either univariable or multivariable analysis. A subgroup analysis restricted to the 92 patients whose breast cancer preceded ovarian cancer yielded consistent results. In conclusion, the location of BRCA1/2 mutations influences susceptibility to breast-ovarian DPC. DPC status was not significantly associated with inferior survival in this cohort; however, long-term outcomes warrant validation in larger, prospectively followed populations.

Cutaneous angiosarcoma (cAS) is an aggressive vascular malignancy comprising idiopathic primary cutaneous angiosarcoma (PCAS) and secondary cutaneous angiosarcoma (SCAS) arising after radiation therapy or chronic lymphedema. Comparative genomic analyses delineating these subtypes in Asian populations remain limited. We retrospectively evaluated 15 Japanese cAS patients (10 PCAS, 5 SCAS) who underwent comprehensive genomic profiling (CGP) using FoundationOne CDx or liquid CDx between 2020 and 2026. Variants of unknown significance (VUS) and potential clonal hematopoiesis (CH)-derived mutations were systematically excluded. The cohort demonstrated a uniformly low tumor mutational burden (median 4 mut/Mb) with no MSI-H cases. TP53 was the most frequent driver mutation (47%), followed by CDKN2A (33%), MYC (33%), KDR (27%), CDKN2B (27%), MTAP (27%), KIT (27%), and PDGFRA (27%). A molecular separation was observed between the two clinical subtypes, where focal MYC amplification was confined to SCAS cases (5/5, 100%), whereas PCAS lesions were enriched with cell-cycle pathway alterations via co-deletions of CDKN2A, CDKN2B, and MTAP, alongside variable receptor tyrosine kinase (RTK) gains (KIT/PDGFRA). RAS pathway mutations presented only as three cases of missense variants across both subtypes. Although limited by sample size, these findings suggest subtype-associated genomic patterns in Japanese cAS and may serve as preliminary observations that warrant validation in larger East Asian cohorts.

Dermatomyositis is a recognized paraneoplastic syndrome, with malignancy risk being an important consideration during evaluation. Its association with head and neck squamous cell carcinoma (SCC) is uncommon, and its occurrence with a presumed unknown primary has not been well documented. We report the case of an 80-year-old man who presented with dysphagia, proximal weakness, and a characteristic rash. Serology was negative, but multiple malignancy alarm features (age, dysphagia, leukocytoclastic vasculitis on biopsy) prompted aggressive screening. Fluorodeoxyglucose (FDG)-PET/CT revealed a single hypermetabolic cervical lymph node; biopsy confirmed p16-positive SCC. No mucosal primary was identified despite laryngoscopy, and further biopsies could not be performed due to rapid functional decline. The patient proved refractory to immunosuppression and was unfit for oncologic therapy. He died three months after symptom onset. This case illustrates the utility of clinical alarm features and early PET/CT in seronegative dermatomyositis, while highlighting how quickly the window for diagnosis and treatment can close.

Carcinoma of unknown primary origin (CUP) involving the skeletal system is rare in dogs and may closely mimic primary bone neoplasia or multicentric lymphoma, creating substantial diagnostic challenges. A 15-year-old spayed female Jindo-mix dog was referred for rapidly progressive tetralimb lameness and inability to stand following a 2-week history of worsening forelimb lameness. Computed tomography revealed aggressive multifocal osteolytic and osteoproliferative lesions involving the pelvis, distal femur, and lumbar vertebra, accompanied by generalized lymphadenopathy, raising differential diagnoses including osteosarcoma, lymphoma, and metastatic neoplasia. Serial CT examinations demonstrated rapid progression of the dominant left ischial lesion, which was considered most consistent with a primary bone neoplasm and was surgically excised for definitive diagnosis. MRI failed to identify clinically significant neurologic disease. Histopathologic examination of a surgically excised ischial lesion favored poorly differentiated epithelial malignancy, although lymphoma could not initially be excluded. During hospitalization, serial thromboelastography (TEG) and coagulation testing demonstrated a predominantly hypercoagulable profile despite antithrombotic therapy. Following acute clinical deterioration, contrast-enhanced CT identified thrombosis involving the splenic vein and caudal vena cava, pulmonary thromboembolism (PTE), and concurrent multi-organ infarction. Cytology of an enlarged peripheral lymph node suggested metastatic carcinoma, and postmortem immunohistochemistry supported epithelial differentiation, and in the absence of an identifiable primary tumor despite comprehensive diagnostic evaluation, the case was clinically classified as carcinoma of unknown primary origin. This case highlights an unusual diagnostic presentation of skeletal CUP mimicking osteosarcoma or lymphoma and complicated by fatal cancer-associated thrombosis. Rapidly progressive multifocal bone lesions accompanied by hypercoagulability should prompt consideration of metastatic carcinoma, including carcinoma of unknown origin, even in the absence of an identifiable primary tumor.