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In another group of 80 fPTC kindreds a familial nonmedullary thyroid cancer susceptibility gene referred to as FNMTC has been mapped to the long arm of chromosome 2 (2q21). The maximum multipoint LOD score in all families was 3.07, and this increased to 4.17, when the 17 pedigrees with the follicular variant of PTC were analyzed alone [21]. As with the previous linkage analysis, the susceptibility gene at this locus has not been identified.

Our studies identified the familial association of PTC and papillary renal neopla-sia PRN (both adenomas and carcinomas) in a large kindred. This disorder, which is designated fPTC/PRN (OMIM #605642), has been mapped to the long arm of chromosome 1 (1q21) with a multipoint single kindred LOD score of 3.58 [22]. Therefore, this syndrome is both clinically and genetically distinct from other fPTC disorders. There are a number of other neoplasms in this large kindred including benign thyroid adenomas, germ cell neoplasms premenopausal breast carcinomas and renal oncocytoma that occur in subjects that carry the affected allele. Unfortunately there are not enough genetically affected individuals to determine if these non-PTC neoplasms are components of the f PTC/PRN syndrome with low penetrance, or if they are just sporadic events in a large kindred. In this regard, it is of interest that epidemiology studies have identified an increased incidence of premenopausal breast carcinoma in PTC subjects [23]. One interpretation of this finding is that the use of I-131 in thyroid carcinoma subjects predisposes to breast carcinoma. Alternatively, our results support the hypothesis that an inherited susceptibility is responsible for this association. It may be that the fPTC/PRN gene predisposes to other malignancies.

Frequently sporadic tumors and familial tumors may be caused by mutations of the same susceptibility genes. For example, activating RET mutations are inherited in multiple endocrine neoplasia type 2 and develop spontaneously in sporadic medullary thyroid carcinoma. We have reviewed of the gene abnormalities of sporadic PTC to determine if these occur in genes that map to the linkage regions of the familial PTC syndromes. The neurotrophic tyrosine kinase receptor type 1 (NTRK1; TRK; TRKA) that is located at 1q23.1and RET that is located at 10q11.2 are both rearranged in sporadic PTC. These rearrangements effect illicit expression of these tyrosine kinases in the thyroid follicular cell. Activating BRAF (7q34) mutations also occur in sporadic PTC

[24] and activating mutations of hRAS occur in sporadic follicular thyroid neoplasms

[25]. Other genes contributing to the pathogenesis of follicular neoplasms include PTEN(10q23.31), PAX8 (2q13), and PPARG1 (3p25). Of these seven genes, PAX8, hRAS and TRK are potential candidates for fPTC based upon their chromosomal location. The sequence analysis of PAX8 in the FNMTC kindreds that map to 2q21 has not been reported. Completion of the human genome project indicates that TRK is telomeric to the fPTC/PRNlocus. Therefore, it is not the fPTC /PRN susceptibility gene. Sequence analysis of hRAS in fPTC/PRN indicates that the known activating mutation of hRAS does not cause this disorder [26]. Interestingly LOH, normally a rare event in PTC, has been observed in about 10 percent of sporadic PTC in the region near 1q21 [27]. This finding suggests that there may be a tumor suppressor gene for

PTC at the fPTC/PRN locus at 1q21. In summary, the genes causing sporadic PTC are not located within the fPTC loci, suggesting that the fPTC genes are distinct from the genes that cause sporadic PTC.

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