| Cancer and cardiovascular disease are the two leading causes of death in the United States. Although these two complex diseases are seemingly unrelated, our literature searches have led us to the conclusion that they are caused by many of the same biological processes, including proliferation and inflammation. For example, there exist neoplastic and cardiovascular etiologies of hypertension. We therefore wanted to address the hypothesis that tumor suppressor and other cancer-related genes are causative in the development of both cancer and cardiovascular disease. In order to address this hypothesis, we examined the underlying genetic alterations of tumor suppressor and other cancer-related genes in a neuroendocrine neoplasia, pheochromocytoma (PC) and in a specific type of cardiovascular disease, carotid artery atherosclerosis. PCs present in both sporadic and hereditary cases. The syndromic manifestations, including MEN 2, VHL, and PC/PGL syndrome, exhibit strong phenotype-genotype correlations. The causative genes for these syndromes are RET, VHL , and SDHB, SDHC, and SDHD, respectively. Current clinical cancer genetics strives to achieve this correlation in all diseases, for this facilitates genotype-based personalized management of the patients and their families.; Our studies uncovered a number of interesting conclusions. Although it was previously thought that only 10% of PCs were hereditary, we found in a population-based registry of PC cases, that ∼25% of apparently sporadic PC cases are caused by a germline mutation in one of the PC-associated genes. Further examination of the genetics of the remaining mutation-negative PC cases led us to the discovery of novel whole- and partial-gene deletions in SDHB and SDHD. When looking at cases of the Carney triad/dyad, an association of PGL, GIST and pulmonary chondroma, we found that 3/50 (6%) have germline splice-site mutations in either SDHB or SDHC. In addition, up to 1/3-1/2 of apparently sporadic PC cases are associated with a haplotype consisting of RET SNPs, and this haplotype is likely in linkage disequilibrium with a low-penetrance locus in the 5' UTR. Finally, we used three array-based platforms to look for genetic alterations in atherosclerotic carotid artery samples. Chromosomal loci 1q, 3p, 15q, and 16q were found to be altered and previous data indicates that all of these regions are altered in cancers. The data we present has significant implications, including the phenotype-genotype correlations as well as the clinical implications for patients and their physicians. It is our hope that the integration of the genetics of neuroendocrine neoplasms and carotid artery disease will represent the molecular merging of two major disease processes, and allow for common effective genetics-based personalized medical management for both cancer and cardiovascular disease. |
