Home > G. Tumoral pathology > Molecular pathology of tumors > Paragangliomas (molecular pathology)
Paragangliomas (molecular pathology)
Wednesday 9 September 2015
Until 2000, only 10% of PGLs were considered of genetic origin and linked to hereditary syndromes: von Hippel Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN2) and neurofibromatosis type 1 (NF1), due respectively to a germ line mutation in tumor-suppressor gene VHL, protooncogene RET and tumor-suppressor gene NF1.
In the last years, it has been demonstrated that about 30% of the apparently sporadic PGLs are due to a germ-line mutation in one of the susceptibility genes.
This group of genes includes those encoding the four subunits (A, B, C, and D) of the succinate dehydrogenase (SDH), the recently identified gene SDHAF2, which is responsible for the flavination of the SDHA subunit, and the very recently discovered TMEM127 and MAX, both mainly related to bilateral PCCs.
Germ line mutations in SDHA, SDHB, SDHC, SDHD, and SDHAF2 genes are responsible for the occurrence of syndromes named PGL5, PGL4, PGL3, PGL1, and PGL2, respectively; to note, SDHB-mutations are generally associated with higher morbidity and mortality than mutations in the other SDHx genes [62]. A recent meta-analisis of some studies involving SDHB mutated patients has highlighted that 31% of their tumors were malignant.
Overall, to date, 10 susceptibility PGLs genes have been identified, so that the initial 10% of cases classified as genetically determined has increased to 30%. Nevertheless, the number of the susceptibility genes is likely to increase.
In fact, many young PGL patients, where the mutation frequency is higher, are still classified as sporadic, and some PGLs patients with a positive family history do not show any mutation in the so far known susceptibility genes.
Extensive genetic screening in PGLs has highlighted the correlation between genotype and phenotype thus facilitating a genetic testing algorithm based on clinical features as a guide for a more quick and cost-effective genetic screening.
Genetic analysis has also permitted to predict the malignancy risk which is higher for SDHB mutation carriers.
Furthermore, by studying tumor transcription profile, sporadic as well as hereditary PGLs have been divided in two main clusters linked to two different signalling pathways: the first cluster contains all VHL- and SDHx-mutated tumors and is associated with angiogenesis, hipoxia, and reduced oxidative response, while the second cluster contains all RET- and NF1-mutated tumors and is associated with abnormal activation of kinase-signaling pathways, such as RAS/RAF/MAPK and PI3K/AKT/mTOR; also TMEM127 and MAX mutated tumors have been associated to the activation of mTOR-signaling pathway.
These data have increased overall knowledge on molecular defects in PGLs and could be used for development of new effective molecular-targeted therapies.
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