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Carney Complex and Related Syndromes and their Genetic Loci—Author’s Response

Head, Unit on Genetics & Endocrinology (UGEN) Developmental Endocrinology Branch, NICHD, NIH Bethesda, Maryland 20892

The data presented by Cetta et al. support our hypothesis that tissue-specific conditions may determine the need for loss-of-heterozygosity (LOH) of tumor-suppressor genes in the process of oncogenesis (1). Mechanisms that may make LOH unnecessary include inactivating mutations of the normal allele and other genomic rearrangements [which would not be identifiable by simple polymerase chain reaction (PCR)-allelotyping] and tissue-specific imprinting, which has recently been demonstrated to occur in such genes as Gsa, IGF-II, and KVLQT-1 (2, 3, 4). In addition, the classic separation between oncogenes and tumor-suppressor genes may not apply in complex pathways leading to oncogenesis (5). Finally, as we pointed out and Cetta et al. underlined, a particular mutation in a tumor-suppressor gene may act in a dominant manner. This is certainly true for dominant negative effects (6) and, perhaps, for the presence of modifier genes, whose expression is tissue-dependent.

Thus, we agree with Cetta et al. that their (and, perhaps, our) findings support this hypothesis. However, one should be cautious in interpreting LOH data from various tissues. Normal cells are almost always there to "contaminate" tumor DNA, unless methods such as laser-guided microdissection and single-cell PCR have been used. This is particularly important for lesions in which only a small proportion of tumor cells may demonstrate LOH. With this caveat in mind, we thank Dr. Cetta and his coworkers for supporting our hypothesis; clearly more work needs to be done in the clarification of the processes of endocrine oncogenesis.

Footnotes

Address correspondence to: Constantine A. Stratakis, M.D., D.Sc., Head, Unit on Genetics & Endocrinology (UGEN), Developmental Endocrinology Branch, National Institute on Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, MSC-1862, Bethesda, Maryland 20892-1862.

Received January 8, 1999.

References

1. Stratakis CA, Kirschner LS, Taymans SE, et al. 1998 Carney complex, Peutz-Jeghers syndrome, Cowden disease, and Bannayan-Zonana syndrome share cutaneous and endocrine manifestations, but not genetic loci. J Clin Endocrinol Metab. 83:2972–2976.[Abstract/Free Full Text]
2. Yu S, Yu D, Lee E, et al. 1998 Variable and tissue-specific hormone resistance in heterotrimeric Gs protein alpha-subunit (Gs) knockout mice is due to tissue-specific imprinting of the gsalpha gene. Proc Natl Acad Sci USA. 95:8715–8720.[Abstract/Free Full Text]
3. Wu HK, Squire JA, Song Q, Weksberg R. 1997 Promoter-dependent tissue-specific expressive nature of imprinting gene, insulin-like growth factor II, in human tissues. Biochem Biophys Res Commun. 233:221–226.[CrossRef][Medline]
4. Lee MP, Hu RJ, Johnson LA, Feinberg AP. 1997 Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements. Nat Genet. 15:181–185.[CrossRef][Medline]
5. He TC, Sparks AB, Rago C, et al. 1998 Identification of c-MYC as a target of the APC pathway. Science. 281:1509–1512.[Abstract/Free Full Text]
6. Brachmann RK, Vidal M, Boeke JD. 1996 Dominant-negative p53 mutations selected in yeast hit cancer hot spots. Proc Natl Acad Sci USA. 93:4091–4095.[Abstract/Free Full Text]

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