National Cancer Institute®
Last Modified: November 21, 2001
UI - 21385665
AU - Marsh DJ; Theodosopoulos G; Howell V; Richardson AL; Benn DE; Proos AL;
TI - Eng C; Robinson BG Rapid mutation scanning of genes associated with familial cancer syndromes using denaturing high-performance liquid chromatography.
SO - Neoplasia 2001 May-Jun;3(3):236-44
AD - Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia. firstname.lastname@example.org
Germline mutations in tumor suppressor genes, or less frequently oncogenes, have been identified in up to 19 familial cancer syndromes including Li-Fraumeni syndrome, familial paraganglioma, familial adenomatous polyposis coli and breast and ovarian cancers. Multiple genes have been associated with some syndromes as approximately 26 genes have been linked to the development of these familial cancers. With this increased knowledge of the molecular determinants of familial cancer comes an equal expectation for efficient genetic screening programs. We have trialled denaturing high-performance liquid chromatography (dHPLC) as a tool for rapid germline mutation scanning of genes implicated in three familial cancer syndromes -- Cowden syndrome (PTEN mutation), multiple endocrine neoplasia type 2 (RET mutation) and von Hippel-Lindau disease (VHL mutation). Thirty-two mutations, including 21 in PTEN, 9 in RET plus a polymorphism, and 2 in VHL, were analyzed using the WAVE DNA fragment analysis system with 100% detection efficiency. In the case of the tumor suppressor gene PTEN, mutations were scattered along most of the gene. However, mutations in the RET proto-oncogene associated with multiple endocrine neoplasia type 2 were limited to specific clusters or "hot spots." The use of GC-clamped primers to scan for mutations scattered along PTEN exons was shown to greatly enhance the sensitivity of detection of mutant hetero- and homoduplex peaks at a single denaturation temperature compared to fragments generated using non--GC-clamped primers. Thus, when scanning tumor suppressor genes for germline mutation using dHPLC, the incorporation of appropriate GC-clamped primers will likely increase the efficiency of mutation detection.
UI - 21300310
AU - Stratakis CA
TI - Clinical genetics of multiple endocrine neoplasias, Carney complex and related syndromes.
SO - J Endocrinol Invest 2001 May;24(5):370-83
AD - Unit on Genetics and Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1862, USA. email@example.com
The list of multiple endocrine neoplasias (MENs) that have been molecularly elucidated is growing with the most recent addition of Carney complex. MEN type 1 (MEN 1), which affects primarily the pituitary, pancreas, and parathyroid glands, is caused by mutations in the menin gene. MEN type 2 (MEN 2) syndromes, MEN 2A and MEN 2B that affect mainly the thyroid and parathyroid glands and the adrenal medulla, and familial medullary thyroid carcinoma (FMTC), are caused by mutations in the REToncogene. Finally, Carney complex, which affects the adrenal cortex, the pituitary and thyroid glands, and the gonads, is caused by mutations in the gene that codes for regulatory subunit type 1A of protein kinase A (PKA) (PRKAR1A) in at least half of the known patients. Molecular defects have also been identified in syndromes related to the MENs, like Peutz-Jeghers syndrome (PJS) (the STK11/LKB1 gene), and Cowden (CD; the PTEN gene) and von Hippel-Lindau disease (VHLD; the VHL gene). Although recognition of these syndromes at a young age generally improves prognosis, the need for molecular testing in the diagnostic evaluation of the MENs is less clear. This review presents the newest information on the clinical and molecular genetics of the MENs (MEN 1, MEN 2, and Carney complex), including recommendations for genetic screening, and discusses briefly the related syndromes PJS, CD and VHLD.
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