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THE CiOUNCIL FOR TOBACCO RESEARCH-II.S.A.. INC. Memorandum To: Dr. J.F.Glenn and Staff From: D.H.Ford Re: Site visit with Dr. S.A.Wells, Washington University, St. Louis, MO. Oct.27,1990. Grant No. 2541R1 entitled "Gene mapping of multiple endocrine neoplasia Type I." Goal: To determine if there is a specific gene which codes for Multiple Endocrine Neoplasia Type I (MEN-I) which can be identified and characterized. This is a disease which is inherited as a Mendel- ian autosomal dominant trait which has full penetrance and is char- acterized by neoplasia of the parathyroid glands, pituitary gland and the pancreatic islet cells. He hopes to be able to clone the MEN-I gene, develop a screening protocol based on DNA polymorphism typing for risk assessment in kindred members, identify possible gene mutations and relate to possible differences in disease severity and to identify the biochemical function of the MEN-I gene product. Results: Inasmuch as Dr. Wells had to make an unexpected trip to Washington during the week when we were supposed to meet, I had the opportunity to meet with him for only a few minutes the previous Saturday. His quick review is well summarized in the Brief Progress Summary in his renewal application. Clearly, they have already screened a lot of subjects in three families (M,McD and S) and established many lymphoblastoid cell lines. The analysis of tissue from 11 tumors demonstrated a loss of either a part or of the whole of chromosome 11 in 10 of the 11 tumors, suggesting that the tumors are clonal. No other chromosome was consistently.lost. From work with a recombinant DNA library, the region of interest on chromosome 11 appears to be the segment llqll-11q13. The region which was most correlated with MEN-I mapped to 11q13 in 9 of 11 tumors. This has been reported in Cancer Research 50:6529-6533,1990;"Loss of hetero- zygosity on chromosome 11 in tumors from patients with Multiple Endocrine Neoplasia Syndrome Type 1," as well as in an absrract in The Amer.J.Human Genetics entitled "Isolation of three new markers located on 11q11-14 close to the MEN-1 gene." Comment: Although this investigation is in an area in which I would hesitate to register an objective evaluation, the work discussed by Dr. Wells seems well done and certainly pertinent to our interest in CTR in understanding the evolution of malignancy. Like so many others, MEN-I appears to be caused by a deletion of some chromosomal genetic message, possibly the loss'of a suppressor gene. This loss might then be interpreted to permit the expression of a constitutional mutation. Although Dr. Wells, as Chief of Surgery probably has little time himself to participate too actively in thetype of molecular study entailed by this program, the staff whichAhas ha-s assembled for this program appears more than capable to pursue his/their objectives. DHF