This thesis aims to gain insight in the genetics, inheritance and tumor biology of head and neck paragangliomas, with a focus on SDHD and SDHAF2-related tumors. Mutations in SDHD and SDHAF2... Show moreThis thesis aims to gain insight in the genetics, inheritance and tumor biology of head and neck paragangliomas, with a focus on SDHD and SDHAF2-related tumors. Mutations in SDHD and SDHAF2 show a remarkable parent-of-origin dependent tumorigenesis in which tumor formation almost exclusively occurs following paternal transmission of the mutation. The Hensen model is discussed to explain this striking inheritance pattern seen in SDHD and SDHAF2-linked families. Show less
Paragangliomas are rare neoplasms that occur predominantly in the head and neck region. They originate from the neural crest derived cells within paraganglions, and are closely related to the... Show moreParagangliomas are rare neoplasms that occur predominantly in the head and neck region. They originate from the neural crest derived cells within paraganglions, and are closely related to the pheochromocytomas of the adrenal medulla. In contrast to other European countries, the majority of head and neck paraganglioma patients in the Netherlands suffer from hereditary paraganglioma syndrome, even if they present without a positive family history. The vast majority of Dutch patients carry one of only six founder mutations in genes encoding subunits of the mitochondrial succinate dehydrogenase, most notably in SDHD. SDHD-linked patients are characterized by a mean age at onset between 35-40 years, a high risk of multiple paragangliomas (73%), a risk of concurrent pheochromocytomas (13%) and extra-adrenal paragangliomas (8%), and a small risk of metastases (2%). The penetrance upon paternal transmission of SDHD mutations is high (87-100%). Interestingly, maternal transmission of SDHD mutations only rarely results in paraganglioma formation. This inheritance pattern is consistent with maternal imprinting, but there is ample evidence contradicting the imprinting of the SDHD gene itself. In the thesis, a model is discussed that explains this parent-of-origin-dependent inheritance by the involvement of an additional, imprinted tumor suppressor gene located, like SDHD, on chromosome 11. Show less
