Tumors of the adrenal glands : genetic and diagnostic aspects

Sammanfattning: Adrenal tumors have varying clinical presentation, malignancy rates and patient morbidity. Adrenal cortical carcinomas (ACCs) are malignant tumors originating from the adrenal cortex. Pheochromocytomas (PCCs) arise from the adrenal medulla and abdominal Paragangliomas (PGLs), a highly related tumor type, arise in paraganglia mostly in the abdominal area. The genetic background of these tumors has been persistently studied, still knowledge is lacking regarding tumor development and genotype-phenotype relation. In Paper I, NF1 protein expression was investigated in an attempt to clarify a possible association between NF1 mutational status and immunohistochemical staining for NF1. The results showed absent NF1 immunoreactivity in most PCCs. A clear majority of the NF1 mutated cases showed no NF1 immunoreactivity, however that was also seen in the NF1 wild-type cases. From this study we conclude that immunohistochemistry is not an efficient screening tool to detect NF1 mutated cases in clinical practice. In Paper II and III, TERT promoter methylation densities were investigated in PPGLs and ACCs. Telomerase activation have been shown in these tumor types, however only some cases with telomerase activation could be explained by TERT promoter mutations. In PPGLs TERT promoter hypermethylation was found in metastatic PGLs. In ACCs hypermethylation of the TERT promoter region was found compared to normal adrenal samples and hypermethylation was associated with worse clinical outcome. Also, TERT copy number gain was observed in ACCs. We concluded that epigenetic alterations of TERT occur in PPGLs and ACCs and are associated with worse clinical outcome. In Paper IV, histological signs of malignant behavior and mRNA expressional profiles were compared in PPGLs. The results pointed out Chromogranin B (CHGB) as the gene most significantly associated to malignant histological patterns and downregulation of CHGB was found in PPGLs with metastatic disease. Immunohistochemistry showed that weak CHGB expression was associated with histologically malignant behavior. Also, plasma levels of CHGB were lower in PPGLs with histologically aggressive disease. We concluded that CHGB is a possible marker for malignant disease in PPGLs. In Paper V, analysis of whole-exome sequencing data from our cohort as well as from the TCGA database revealed several variants in the calcium voltage-gated channel subunit gene CACNA1H. A total of seven variants were detected in the study. CACNA1H expression was found to be lower in tumor tissue as compared to normal adrenal medulla. In the TCGA database a correlation was found between CACNA1H methylation levels and CACNA1H expression. We concluded that variants in CACNA1H are a possible novel genetic event in PPGL and also a possible link between the genetic background of PPGLs and tumors of the adrenal cortex where CACNA1H mutations have also been found. Overall this thesis gives some clarity to the knowledge gaps in the molecular background of tumors of the adrenal glands.