DIFFERENTIAL LOSS OF HETEROZYGOSITY IN THE REGION OF THE COWDEN LOCUSWITHIN 10Q22-23 IN FOLLICULAR THYROID ADENOMAS AND CARCINOMAS

The susceptibility gene for Cowden disease (CD), an autosomal dominant inherited cancer syndrome, has recently been mapped to an approximate ly 6-cM interval on chromosome subband 10q22-23 between the markers D1 0S541 and D10S564, CD is characterized by hamartomas of many organ sys tems, including the thyroid, breast, skin, and gastrointestinal tract, as well as carcinoma of the thyroid and breast, Follicular thyroid ad enomas and carcinomas are significant component tumors in CD; thus, we sought to examine their sporadic counterpart tumors for loss of heter ozygosity (LOH) of microsatellite markers in the 20-cM region within a nd flanking the Cowden critical interval. In all, 38 sporadic thyroid tumors were analyzed, LOH within the CD interval was observed in 5 of 19 (26%) follicular thyroid adenomas and 1 of 9 (11%) Hurthle cell ade nomas, Furthermore, of these adenomas with LOH, 3 of 4 (75%) were atyp ical follicular adenomas, whereas 2 of 15 (13%) were typical follicula r adenomas, Surprisingly, no LOH was detected in this region in 10 fol licular carcinomas, The shortest region of overlap includes the marker s D10S1735 and D10S1739. If the LOH observed in these sporadic tumors is related to the CD gene, then the Cowden critical interval can be re vised to lie within the interval defined by D10S579 and D10S564. LOH i n this narrow interval implicates the CD gene, or another gene in that interval, in follicular thyroid tumorigenesis, However, this does not explain the lack of LOH in follicular carcinomas, Taken together, it may instead be evidence against a stepwise progression from atypical a denomas to carcinomas, Alternatively, sporadic thyroid adenoma formati on may be independent of that locus, but loss of this region could pre vent carcinoma formation, thus implying that the CD gene may be an onc ogene or growth promoter.