Paragangliomas are neuroendocrine tumors originated in paraganglia of the autonomic nervous system. These are rare tumours, but their prevalence in northern Spain, particularly in the region of Asturias, is high. Familial paragangliomas have recently been shown to be associated with germline alterations in SDHD, SDHB and SDHC, which are genes that code for three subunits (SDHD, SDHB and SDHC) of succinate dehydrogenase (SDH). Moreover, some sporadic cases also showed germline alterations in these genes, suggesting an “occult” familial condition. We sought to determine if the higher prevalence of paragangliomas in northern Spain was associated with a high frequency of germline alterations in SDHD and SDHB genes. We analysed the coding region and exon-flanking sequences of SDHD and SDHB in 36 “sporadic” paragangliomas and six familial cases. One family was affected by paraganglioma and pheocromocytoma and the remaining five families displayed exclusively paragangliomas. We observed that 13 out of 36 “sporadic” cases (36%) harbored germline alterations in either SDHD or SHDB or both. Of these 13 cases, nine presented alterations in SDHB, three in SDHD and one in both subunits. The patients with germline alterations exhibited a lower age at diagnosis (p=0.001) and the tumors were preferentially located in the carotid body (p=0.016). Of the six familial cases, three were found associated with SDHD alterations and one with a SDHB alteration. Overall, we disclosed 17 alterations in SDHD and SDHB, 12 of which had not been previously described. While 12 alterations were disease-associated and not found in a series of 92 healthy blood donors, the other 4 alterations were observed in varying percentages among healthy blood donors. Our results show a high frequency (36%) of SDHD and SDHB germline alterations in “sporadic” paragangliomas from Spain and also that a significant proportion of these tumors can be classified as “occult” familial paragangliomas. At variance with previous reports, we observed a higher frequency of alterations in SDHB (eight, seven of which were previously unreported) than in SDHD (four, one of which was previously unreported). These findings suggest that germline alterations in SDHD and particularly in SDHB may be associated with the high incidence of sporadic paragangliomas in northern Spain and that patients who develop paraganglioma sporadically or in a familial context should be examined for germline alterations both in SDHD and in SDHB in order to disclose the familial condition of the disease.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]