The genomic landscape of phaeochromocytoma

Abstract

Phaeochromocytomas (PCCs) and paragangliomas (PGLs) are rare neural crest-derived tumours originating from adrenal chromaffin cells or extra-adrenal sympathetic and parasympathetic tissues. More than a third of PCC/PGL cases are associated with heritable syndromes involving 13 or more known genes. These genes have been broadly partitioned into two groups based on pseudo-hypoxic and receptor tyrosine kinase (RTK) signalling pathways. Many of these genes can also become somatically mutated, although up to one third of sporadic cases have no known genetic driver. Furthermore, little is known of the genes that co-operate with known driver genes to initiate and drive tumourigenesis. To explore the genomic landscape of PCC/PGL, we applied exome sequencing, high-density SNP-array analysis, and RNA sequencing to 36 PCCs and four functional PGL tumours. All tumours displayed low mutation frequency, in contrast to frequent large segmental copy-number alterations, aneuploidy, and evidence for chromothripsis in one case. Multi-region sampling of one benign familial PCC tumour provided evidence for the timing of mutations during tumourigenesis and ongoing clonal evolution. Thirty-one of 40 (77.5%) cases could be explained by germline or somatic mutations or structural alterations affecting known PCC/PGL genes. Deleterious somatic mutations were also identified in known tumour-suppressor genes associated with genome maintenance and epigenetic modulation. A multitude of other genes were also found mutated that are likely important for normal neuroendocrine cell function. We revisited the gene-expression subtyping of PCC/PGL by integrating published microarray data with our RNA-seq data, enabling the identification of six robust gene-expression subtypes. The majority of cases in our cohort with no identifiable driver mutation were classified into a gene-expression subtype bearing similarity to MAX mutant PCC/PGL. Our data suggest there are yet unknown PCC/PGL cancer genes that can phenocopy MAX mutant PCC/PGL tumours. This study provides new insight into the molecular diversity and genetic origins of PCC/PGL tumours.

Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis

“…Instead the ubiquitous status of driver mutations emphasizes their potential to serve as prognostic and predictive markers as well as identifiers of druggable targets in PPGL. The ultimate implications of genetic heterogeneity in PPGL need to be clarified in future studies using genome-wide single-nucleotide resolution (44). (Continued. )…”

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

“…Somatic mutations in TSC2 occur frequently in pancreatic NETs (80). Overview of mutational burden in NETs merged from raw data in (80,85,86,87,98,99,100,104,117,120,121,122,128,136,137). Each dot represents a unique tumor, and the line shows the median number of mutations of each category.…”

“…Whether this gene acts as a disease driver or modifier remains to be identified (120). The genomic landscape of PCC and PGL is associated with relatively low degree of genomic instability having an average of 19 nonsynonymous mutations per tumor (117,121,122). Clinical criteria have classified these tumors accordingly to location into PCCs (adrenal medulla) and PGLs (extra adrenal).…”

Genetic Alterations in Pheochromocytoma and Paraganglioma

“…Two additional new studies reported whole-exome sequencing of 40 and 31 additional pheochromocytomas and paragangliomas, respectively 250,251 . These studies confirmed the involvement of ATRX, but also reported other potential novel driver alterations including recurrent mutations in FMR1, TP53, MET and CDKN2A, though neither of the studies identified the FGFR1 gene.…”