Lois M. Mulligan

Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma

BACKGROUND AND OBJECTIVES Medullary thyroid carcinoma (MTC) occurs both sporadically and In the autosomal domlnantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes. The distinction between true sporadic MTC and a new mutation familial case is important for future clinical managment of both the patient and family. The susceptibility gene for MEN 2 is theRET proto‐oncogene. Systematic analysis for germ‐line mutations of theRET proto‐oncogene was performed in a series of 67 patients with apparently sporadic MTC to determine whether they were true sporadic cases or unsuspected de novo MEN 2 cases.

A novel polymorphism in the coding sequence of the human RET proto-oncogene.

A novel polymorphism in the coding sequence of the human RET proto-oncogene is described. The RET proto-oncogene maps to chromosome 10q11.2, and is involved in multiple endocrine neoplasia (MEN 2A, MEN 2B), familial medullary thyroid carcinoma and Hirschsprungs disease.

Presymptomatic genetic screening in families with multiple endocrine neoplasia type 2

Medullary thyroid carcinoma occurs sporadically or as a part of the inherited cancer syndrome multiple endocrine neoplasia (MEN) type 2. The MEN 2 gene has been identified as the RET proto-oncogene on chromosome 10. In MEN 2A, RET mutations are detectable in one of five cysteine codons within exons 10 and 11 and in MEN 2B in codon 918 (exon 16). Direct DNA testing for RET proto-oncogene mutations is the method of first choice in presymptomatic screening of MEN 2 families. Gene carriers should be offered prophylactic thyroidectomy. The process of DNA analysis for RET proto-oncogene mutations is demonstrated in one family with hereditary medullary thyroid carcinoma. RET mutations were detectable in five of the nine family members at risk.

A multiple interval physical map of the pericentromeric region of human chromosome 10

Five intervals in the pericentromeric region of human chromosome 10 have been defined using a panel of somatic cell hybrids carrying portions of the chromosome. The map positions of twelve markers, consisting of four genes and eight anonymous DNA segments, have been localized by assignment to one of the five intervals. Several other markers could be placed in specific intervals by genetic linkage to assigned loci. When previously published data are incorporated, the summary map of the pericentromeric region encompasses thirty-two loci in bands 10p11.2-q11.2.

Complementary physical and genetic techniques map the vinculin (VCL) gene on chromosome 10q

Vinculin is a cytoskeletal protein component of adherens type cell junctions. The gene had been mapped to 10q11.2-qter. We have used a combination of physical and genetic mapping techniques to refine this localization. Hybridization of the vinculin cDNA probe, HV1, to a human-rodent somatic hybrid panel initially suggested a position of either 10q11.2 or 10q22.1-10q23. Genetic recombination mapping in three-generation families with multiple endocrine neoplasia type 2 (MEN2) indicated a position distal to D10S22 (10q21.1) in 10q22.1-10q23. This was confirmed by hybridization of the vinculin cDNA to flow-sorted translocation derivative chromosomes containing the q21-qter portion of chromosome 10. We conclude that the vinculin locus maps in 10q22.1-q23, distal to D10S22.

Spezifische ret proto-onkogen Mutationen bei verschiedenen hereditären Formen des C-Zell-Karzinoms

Das C-Zell-Karzinom der Schilddruse (medullares Karzinom [MTC]) manifestiert sich in einer sporadischen und in einer familiaren, autosomal dominant vererbbaren Form. Die familiare Form zeichnet sich durch gleichzeitiges oder zeitlich versetztes Auftreten weiterer Adenopathien aus (multiple endokrine Neoplasie [MEN]). Neben dem C-Zell-Karzinom gehoren zum Erscheinungsbild des MEN 2A Syndroms der primare Hyperparathyreoidismus und das Phaochromozytom. Patienten mit einem MEN 2B Syndrom fallen durch einen marfanoiden Habitus, Schleim- hautneurinome und Gangliomatose des Darmes auf. In einigen Familien tritt nur das C-Zell-Karzinom, ohne weitere Beteiligung von endokrinen Drusen auf (FMTC). Der hereditaren Tumorform liegen Keimbahnmutationen des RET Proto-Onkogens auf dem Chromosom 10 zugrunde [1,2, 3]. Wahrend die Mutationen beim MEN 2A und FMTC einen der funf Codons fur Cystein im Exon 10 und 11 der extrazellularen RET Domane betreffen, tritt beim MEN 2B eine Punktmutation im Codon 918 der intrazellularen RET Tyrosin-Kinase Domane auf. Die vorliegende Studie hatte zum Ziel spezifische RET Proto-Onkogen Mutationen bei verschiedenen hereditaren Formen des C-Zell-Karzinoms nachzuweisen.