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Cancer genetics has for many years focused on mutational events that have their primary effect within the cancer cell. Recently that focus has widened, with evidence of the importance of epigenetic events and of cellular interactions in cancer development. The role of common genetic variation in determining the range of individual susceptibility within the population is increasingly recognized, and will be addressed using information from the Human Genome Project. These new research directions will highlight determinants of cancer that lie outside the cancer cell, suggest new targets for intervention, and inform the design of strategies for prevention in groups at increased risk.

Multiple endocrine neoplasia type 2A (MEN 2A) is a dominantly inherited cancer syndrome that affects tissues derived from neural ectoderm. It is characterized by medullary thyroid carcinoma (MTC) and phaeochromocytoma. The MEN2A gene has recently been localized by a combination of genetic and physical mapping techniques to a 480-kilobase region in chromosome 10q11.2 (refs 2,3). The DNA segment encompasses the RET proto-oncogene, a receptor tyrosine kinase gene expressed in MTC and phaeochromocytoma and at lower levels in normal human thyroid. This suggested RET as a candidate for the MEN2A gene. We have identified missense mutations of the RET proto-oncogene in 20 of 23 apparently distinct MEN 2A families, but not in 23 normal controls. Further, 19 of these 20 mutations affect the same conserved cysteine residue at the boundary of the RET extracellular and transmembrane domains.