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By Hartmut PH Neumann, MD, Jörg Schipper, MD, and Charis Eng, MD, PhD, FACP
It is believed that approximately 10% of all pheo-chromocytomas are hereditary, i.e., caused by gene mutations which can be transmitted from generation to generation. To date, causes of heritable pheochromocytomas include von Hippel Lindau disease (VHL), which is characterized by germline (in every cell of the body) mutations in the VHL tumor-suppressor gene;1 multiple endocrine neoplasia type 2 (MEN 2), which is characterized by germline mutations in the RET proto-oncogene;2 and rarely, type 1 neurofibromatosis, which is characterized by germline mutations in the NF1 tumor-suppressor gene.3,4 Despite advances in human cancer genetics, germline mutations in these genes do not account for all possible hereditary pheochromocytomas.
In mid-2000, Baysal and colleagues identified germline mutations in a presumed tumor-suppressor gene called succinate dehydrogenase subunit d (SDHD) in five families that segregated glomus tumors (paragangliomas of the neck).5 SDHD is the small subunit of cytochrome b (cybS) in the succinate-ubiquinone oxireductase pathway, which comprises mitochondrial complex II. Since glomus tumors are located in the carotid body which has oxygen-sensing capabilities, it made teleological sense that a mutation in a component of a mitochondrial oxidation-reduction pathway was associated with glomus tumors. It should be noted, however, that in these original five families, none had pheochromocytomas. Nonetheless, given the common neural crest origin of paragangliomas and pheochromocytomas, SDHD became an excellent novel candidate susceptibility gene for hereditary pheochromocytomas.
A proportion, perhaps one-half, of site-specific familial pheochromocytoma are caused by germline mutations in VHL, i.e., are actually cryptic VHL.6,7 However, the remainder are unaccounted for. Thus, when the five families were examined for the presence of germline SDHD mutations, one family that segregated pheochromocytomas and paraganglioma was found to harbor germline SDHD mutation.8
In a pilot series of 18 unrelated patients with intra-abdominal, catecholamine-secreting pheochromocytomas without VHL, MEN 2, or NF1 by clinical and molecular means or any family history of cancer, two were found to have pathogenic germline SDHD mutations, and one was found to have a germline variant of unknown significance.9 We suspect that the latter germline variant is a pathogenic missense mutation. Thus, the occult germline SDHD mutation frequency ranges from 10% to 17% among all apparently sporadic pheochromocytoma cases.
These observations have implications for the patient as well as his/her family. Harboring a germline SDHD mutation puts an individual at risk for developing pheochromocytomas, as well as extra-adrenal paragangliomas. If our data can be replicated, then it might be prudent to consider subjecting all pheochromocytoma presentations to germline SDHD mutation analysis, because mutation-positive individuals should be subjected to serial surveillance. No gene testing should be performed, however, without the input of clinical cancer geneticists.
While the molecular etiology of heritable pheo- chromocytoma is at least partially known, the somatic (occurring only in the tumor) genetic etiology of sporadic pheochromocytoma is largely unknown. It is not uncommon that if germline mutation in gene X is found in a syndrome segregating a particular tumor, the sporadic counterpart of that tumor harbors a high frequency of somatic mutations in gene X. For instance, germline mutations of VHL cause VHL.
Renal cell carcinoma is an important component tumor in VHL; somatic VHL mutations are found in a high frequency of sporadic clear cell renal cell carcinoma.10 Sporadic pheochromocytomas only rarely have been found to harbor somatic intragenic mutations in VHL (< 5% of cases) or in RET (< 10% of cases).10-12 When SDHD was examined in sporadic pheochromocytomas, only one of 18 was found to carry a somatic intragenic SDHD mutation.9 Thus, the genetic etiology of sporadic pheochromocytoma remains elusive. Clearly, the pathogenesis of sporadic vs. VHL-related pheochromocytoma is different genetically.
Bender and colleagues examined 17 sporadic pheochromocytoma and 36 VHL-related tumors. They found that while more than 91% of VHL tumors had loss of heterozygosity (LOH) of markers (an indication of the presence of a putative tumor suppressor) on chromosome arm 3p in the region of VHL, only 24% of sporadic tumors had LOH in the VHL chromosomal region.13 Instead, LOH of markers on 1p (71%) and 22q (53%) predominated in sporadic pheochromocytomas, as compared to those from VHL cases. Thus, genetic loci that could play a major role in the pathogenesis of sporadic pheochromocytoma could lie on chromosome arms 1p and 22q. Interestingly, MEN 2-related pheochromocytomas may share similar genetic alterations on 1p more akin to sporadic tumors than VHL-related tumors, although these observations were based on relatively small numbers.14
Heritable pheochromocytoma can be caused by germline mutations in RET, VHL, and SDHD. SDHD is particularly important because it might occur with a frequency as high as 10-17% in apparently sporadic cases of pheochromocytomas. Clinicians must be mindful of this and if in doubt, should refer such individuals for clinical cancer genetics consultation. It also is obvious that other susceptibility genes for hereditary pheochromocytomas do exist and need to be identified. Somatic mutations in RET, VHL, and SDHD account for no more than 15-20% of sporadic pheochromocytomas. Much work is required in this area to elucidate comprehensively the genetic etiology of all sporadic pheochromocytomas. (Dr. Neumann is an Associate Professor of Internal Medicine, and Dr. Schipper is an Assistant Professor of Otolaryngology, Albert-Ludwigs University, Frei-burg, Germany; and Dr. Eng is an Associate Professor of Medicine and Human Cancer Genetics and Director, Clinical Cancer Genetics Program, Ohio State University, Comprehensive Cancer Center in Columbus.)
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