Beschreibung:
<jats:p>The etiology and pathogenesis of renal cell carcinoma (RCC) are only partially understood. Key findings in hereditary RCC, which may be site specific or a component of a syndrome, have contributed to our current understanding. Important heritable syndromes of RCC are those associated with pheochromocytoma, especially von Hippel–Lindau disease (VHL) associated with germline <jats:italic>VHL</jats:italic> mutations, and pheochromocytoma and paraganglioma syndrome (PGL) associated with mutations in one of the four genes (<jats:italic>SDHA</jats:italic><jats:italic>–</jats:italic><jats:italic>D</jats:italic>) encoding succinate dehydrogenase. A subset of individuals with <jats:italic>SDHB</jats:italic> and <jats:italic>SDHD</jats:italic> germline DNA mutations and variants develop RCC. RCC has never been described as a component of <jats:italic>SDHC</jats:italic>-associated PGL3. The European–American Pheochromocytoma and Paraganglioma Registry comprises 35 registrants with germline <jats:italic>SDHC</jats:italic> mutations. A new registrant had carotid body tumor (CBT) and his mother had CBT and bilateral RCC. Blood DNA, paragangliomas, and RCCs were analyzed for mutations and loss-of-heterozygosity (LOH) in/flanking <jats:italic>SDHC</jats:italic> and <jats:italic>VHL</jats:italic>. The proband with unilateral CBT had a germline <jats:italic>SDHC</jats:italic> c.3G>A (p.M1I) mutation. His mutation-positive mother had CBT at age 42, clear cell RCC (ccRCC) at age 68, and papillary RCC (pRCC) at age 69. Both paraganglial tumors showed somatic LOH of the <jats:italic>SDHC</jats:italic> locus. Both ccRCC and pRCC did not have a somatic <jats:italic>SDHC</jats:italic> mutation but showed LOH for intragenic and flanking markers of the <jats:italic>SDHC</jats:italic> locus. LOH was also present for the <jats:italic>VHL</jats:italic> locus. Our findings suggest that RCC is a component of PGL3. Biallelic inactivation of the <jats:italic>SDHC</jats:italic> gene may represent a new pathway of pathogenesis of syndromic and nonsyndromic RCC, perhaps of both clear cell and papillary histologies.</jats:p>