Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.

Multiple endocrine neoplasia type 2B (MEN 2B) is a human cancer syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytomas, mucosal neuromas, ganglioneuromas of the intestinal tract, and skeletal and ophthalmic abnormalities. It appears both as an inherited disorder and as de novo disease. Sequence analysis of germ-line DNA from MEN 2B patients revealed the existence of the same point mutation in the RET

Basic helix-oop-helix transcription factors of the achaete-scute family are instrumental in Drosophl!a neurosensory development and are candidate regulators of development in the mammalian central nervous system and neural crest. We report the isolation and initial characterization of a human achaete-scute homolog that is highly expressed in two neuroendocrine cancers, meduilary thyroid cancer (MTC) and small cell lung cancer (SCLC). The human gene, which we have termed human achaete-scute homolog 1 (hASH1), was cloned from a human MTC cDNA library. It encodes a predicted protein of238 aa that is 95% homologous to mammalian achaete-scute homolog (MASH) 1, a rodent basic helix4oop-helix factor. The 57-residue basic helix-oop-helix domain is identical to that in the rodent gene, and the basic and helical regions, exduding the loop, are 72-80% identical to Drosophila achaete-scute family members. The proximal coding region of the hASHl cDNA contains a striking 14-copy repeat of the triplet CAG that exhibits polymorphism in human genomic DNA. Thus, hASHl is a candidate locus for disease-causing mutations via triplet repeat amplification. Analysis of rodent-human somatic cell hybrids permitted assignment of hASHl to human chromosome 12. Northern blots revealed hASHl transcripts in RNA from a human MTC cell line, two fresh MTC tumors, fetal brain, and three lines of human SCLC. In contrast, cultured lines of non-SCLC lung cancers and a panel of normal adult human tissues showed no detectable hASHl transcripts. Expression of hASHl may provide a useful marker for cancers with neuroendocrine features and may contribute to the differentiation and growth regulation of these cells.Cancers with neuroendocrine features such as small cell lung cancer (SCLC) and the calcitonin-secreting tumor, medullary thyroid carcinoma (MTC), frequently lose their characteristic endocrine phenotype as tumor progression occurs (1-3). To understand the evolution ofendocrine cancers, it is important to define, at a molecular level, both the regulation of neuroendocrine phenotypic features in the normal cellular precursors of these tumors and the alterations in these processes that occur during tumor progression.In the complex regulation of neuroendocrine phenotypic expression at a transcriptional level, there is increasing evidence for involvement of basic helix-loop-helix (bHLH) transcriptional enhancer factors. bHLH proteins may have particular importance in the control of polypeptide hormone synthesis and secretion. Our laboratory (4) and others (5) have demonstrated that bHLH recognition elements form a constitutive enhancer in the human calcitonin gene. Other polypeptide hormones including insulin, gastrin, and secretin also appear to utilize bHLH enhancer factors that are reThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. stricted to their differentiated host tissues (6-8)....

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