PD-L1 expression and microsatellite instability (MSI) in cancer of unknown primary site.

BACKGROUND: Cancer of unknown primary site (CUP) is a heterogeneous group of tumors for which the origin remains unknown. Clinical outcomes might be influenced by regulatory processes in its microenvironment. Microsatellite instability (MSI) is a predictive biomarker for cancer immunotherapy and its status, as well as co-occurrence with PD-L1 expression, is poorly evaluated. We aim to evaluate the expression of PD-L1 and the status of MSI in CUP and their possible associations with clinical-pathological features. METHODS: The combined positive score (CPS) PD-L1 expression was evaluated by immunohistochemistry. MSI status was assessed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis. RESULTS: Among the 166 cases, MSI analysis was conclusive in 120, with two cases being MSI positive (1.6%). PD-L1 expression was positive in 18.3% of 109 feasible cases. PD-L1 expression was significantly associated with non-visceral metastasis and a dominance of nodal metastasis. The median overall survival (mOS) was 3.7 (95% CI 1.6-5.8) months and patients who expressed PD-L1 achieved a better mOS compared to those who did not express PD-L1 (18.7 versus 3.0 months, p-value: < .001). ECOG-PS equal to or more than two and PD-L1 expression were independent prognostic factors in multivariate analysis (2.37 and 0.42, respectively). CONCLUSION: PD-L1 is expressed in a subset (1/5) of patients with CUP and associated with improved overall survival, while MSI is a rare event. There is a need to explore better the tumor microenvironment as well as the role of immunotherapy to change such a bad clinical outcome.

Expression of Glycolysis-Related Proteins in Cancer of Unknown Primary Origin.

INTRODUCTION: Cancer of unknown primary origin (CUP) is defined as metastatic cancer without identification of the primary site. Considering that only 15-20% of patients with CUP show a favorable outcome, identifying biomarkers may help improve the clinical management of patients who do not respond well to conventional therapies. In this context, the study of the metabolic profile of CUP may pave the way to establish new biomarkers and/or therapeutic targets; therefore, this study aimed to characterize the expression of metabolism-related proteins in CUP. MATERIALS AND METHODS: The expression of monocarboxylate transporters MCT1, MCT2 and MCT4, their chaperone CD147, the glucose transporter GLUT1 and the pH regulator CAIX was evaluated by immunohistochemistry in a series of 118 CUP patients, and the results were associated with the available clinicopathological information. RESULTS: The metabolism-related proteins MCT1, MCT4, CD147, GLUT1 and CAIX were expressed in a critical portion of the CUP (approximately 20 to 70%). MCT1 and CD147 were both more frequently expressed in cases with lymph nodes as metastasis dominant sites (p = 0.001) as well as in samples from lymph nodes (p <0.001 and p = 0.002, respectively), while MCT1 expression was more frequently expressed in squamous cell carcinomas (p = 0.045). A higher overall survival was observed in patients with tumors positive for GLUT1 and CAIX expression (p = 0.011 and p = 0.041, respectively), but none of the proteins was an independent prognostic factor for overall survival in multivariable analysis. CONCLUSION: The results suggest that a portion of CUPs present a hyperglycolytic phenotype, which is associated with higher overall survival.

Somatic Copy Number Alterations and Associated Genes in Clear-Cell Renal-Cell Carcinoma in Brazilian Patients.

Somatic copy number aberrations (CNAs) have been associated with clear-cell renal carcinoma (ccRCC) pathogenesis and are a potential source of new diagnostic, prognostic and therapeutic biomarkers. Recurrent CNAs include loss of chromosome arms 3p, 14q, 9p, and gains of 5q and 8q. Some of these regional CNAs are suspected of altering gene expression and could influence clinical outcomes. Despite many studies of CNAs in RCC, there are currently no descriptions of genomic copy number alterations in a Brazilian ccRCC cohort. This study was designed to evaluate the chromosomal profile of CNAs in Brazilian ccRCC tumors and explore clinical associations. A total of 92 ccRCC Brazilian patients that underwent nephrectomy at Barretos Cancer Hospital were analyzed for CNAs by array comparative genomic hybridization. Most patients in the cohort had early-stage localized disease. The most significant alterations were loss of 3p (87.3%), 14q (35.8%), 6q (29.3%), 9p (28.6%) and 10q (25.0%), and gains of 5q (59.7%), 7p (29.3%) and 16q (20.6%). Bioinformatics analysis revealed 19 genes mapping to CNA significant regions, including SETD2, BAP1, FLT4, PTEN, FGFR4 and NSD1. Moreover, gain of 5q34-q35.3 (FLT4 and NSD1) and loss of 6q23.2-q23.3 (MYB) and 9p21.3 (MLLT3) had gene expression levels that correlated with TCGA data and was also associated with advanced disease features, such as larger tumors, Fuhrman 3, metastasis at diagnosis and death. The loss of region 14q22.1 which encompasses the NIN gene was associated with poor overall survival. Overall, this study provides the first CNA landscape of Brazilian patients and pinpoints genomic regions and specific genes worthy of more detailed investigations. Our results highlight important genes that are associated with copy number changes involving large chromosomal regions that are potentially related to ccRCC tumorigenesis and disease biology for future clinical investigations.