Hirschsprung's disease (HSCR) is a common condition (1 in 5,000 live births) resulting in intestinal obstruction in neonates and megacolon in infants and adults. This disease has been ascribed to the absence of autonomic ganglion cells, which are derived from the neural crest, in the terminal hindgut. Segregation analyses have suggested incompletely penetrant dominant inheritance in familial HSCR. Recently, a gene for HSCR has been mapped to chromosome 10q11.2. No recombination was observed between the disease locus and the locus for the RET proto-oncogene, a protein tyrosine kinase gene expressed in the cells derived from the neural crest. Here we report on nonsense and missense mutations in the extracellular domain of the RET protein (exons 2, 3, 5 and 6) in 6 unrelated probands and show that the mutant genotypes segregate with the disease in HSCR families. Mutations of RET have been previously reported in multiple endocrine neoplasia type 2A (MEN 2A). Thus, germ-line mutations of the RET gene may contribute either to developmental anomalies in HSCR or to inherited predisposition to cancer in MEN 2A.
Prophylactic oophorectomy is chosen by some women at high risk of ovarian cancer due to inherited predisposition. Unfortunately, this surgery is not 100% effective in preventing intra-abdominal carcinomatosis that histologically resembles ovarian cancer. To determine the incidence of post-oophorectomy carcinomatosis and to quantify the effectiveness of preventive surgery, a multicenter study is ongoing between the National Cancer Institute (NCI), Creighton University, and the United Kingdom. The prospective incidence of malignancy, especially of tissues derived from coelomic epithelium (primarily ovary, fallopian tube, and peritoneum), was compared between women of similar genetic risk who have or have not undergone oophorectomy. Analysis of 12 NCI families has been completed. Prospective observation ran from the date of family ascertainment until the date of cancer incidence, death, or December 31, 1992. Approximately 1600 person-years of observation occurred among 346 first-degree relatives of a breast or ovarian cancer case patient for women who had not undergone oophorectomy. Eight ovarian cancers occurred, compared with two carcinomatosis cases during 460 person-years of observation among 44 oophorectomized women. Compared with Connecticut Tumor Registry data adjusted for age, race, and birth cohort, there was an approximately 24-fold excess of ovarian cancer among non-oophorectomized women and a 13-fold excess of "ovarian" cancer among oophorectomized women, though this difference was not statistically significant. The confidence intervals around these numbers were large, and a collaborative analysis will be required to determine whether this apparent protective effect is real.
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