YB-1 (Y-box binding protein 1) is a multifunctional cold-shock protein that has been implicated in all hallmarks of cancer. Elevated YB-1 protein level was associated with poor prognosis in several types of cancers, including breast cancer (BC), where it is a marker of decreased overall survival (OS) and distant metastasis-free survival across all subtypes. YB-1 is also secreted by different cell types and may act as an extracellular mitogen; however the pathological implications of the secreted form of YB-1 (sYB-1) are unknown. Our purpose was to retrospectively evaluate the association between YB-1 measured by ELISA in serum and disease characteristics and outcomes in patients with BC and bone metastases (BM). In our cohort, sYB-1 was detected in the serum of 22 (50%) patients, and was associated with the presence of extra-bone metastases (p=0.044). Positive sYB-1 was also associated with faster bone disease progression (HR 3.1, 95% CI 1.09–8.95, P=0.033), but no significant differences were observed concerning OS, and time to development of skeletal-related events. Moreover, patients with positive sYB-1 also had higher levels of IL-6, a known osteoclastogenic inducer. Therefore, detection of sYB-1 in patients with BC and BM may indicate a higher tumor burden, in bone and extra-bone locations, and is a biomarker of faster bone disease progression.

Colorectal cancer (CRC) is one of the most lethal malignancies. The extreme heterogeneity in survival rate is driving the need for new prognostic biomarkers. Human endogenous retroviruses (hERVs) have been suggested to influence tumor progression, oncogenesis and elicit an immune response. We examined multiple next-generation sequencing (NGS)-derived biomarkers in 114 CRC patients with paired whole-exome and whole-transcriptome sequencing (WES and WTS, respectively). First, we demonstrate that the median expression of hERVs can serve as a potential biomarker for prognosis, relapse, and resistance to chemotherapy in stage II and III CRC. We show that hERV expression and CD8+ tumor-infiltrating T-lymphocytes (TILs) synergistically stratify overall and relapse-free survival (OS and RFS): the median OS of the CD8-/hERV+ subgroup was 29.8 months compared with 37.5 months for other subgroups (HR = 4.4, log-rank P < 0.001). Combing NGS-based biomarkers (hERV/CD8 status) with clinicopathological factors provided a better prediction of patient survival compared to clinicopathological factors alone. Moreover, we explored the association between genomic and transcriptomic features of tumors with high hERV expression and establish this subtype as distinct from previously described consensus molecular subtypes of CRC. Overall, our results underscore a previously unknown role for hERVs in leading to a more aggressive subtype of CRC.

Colorectal cancer (CRC) is a highly diverse disease, where different genomic instability pathways shape genetic clonal diversity and tumor microenvironment. Although intra-tumor heterogeneity has been characterized in primary tumors, its origin and consequences in CRC outcome is not fully understood. Therefore, we assessed intra- and inter-tumor heterogeneity of a prospective cohort of 136 CRC samples. We demonstrate that CRC diversity is forged by asynchronous forms of molecular alterations, where mutational and chromosomal instability collectively boost CRC genetic and microenvironment intra-tumor heterogeneity. We were able to depict predictor signatures of cancer-related genes that can foresee heterogeneity levels across the different tumor consensus molecular subtypes (CMS) and primary tumor location. Finally, we show that high genetic and microenvironment heterogeneity are associated with lower metastatic potential, whereas late-emerging copy number variations favor metastasis development and polyclonal seeding. This study provides an exhaustive portrait of the interplay between genetic and microenvironment intra-tumor heterogeneity across CMS subtypes, depicting molecular events with predictive value of CRC progression and metastasis development.