A FREQUENT MUTATION POLYMORPHISM IN TUMOR-SUPPRESSOR GENE INK4B (MTS-2) IN PAPILLARY AND MEDULLARY-THYROID CANCER/

Background. Structural genetic changes of tumors suppressor genes MTS- 1/INK4A and MTS-2/INK4B were demonstrated in a variety of human cancer s but not in thyroid cancer until now. Methods. Because MTS-2 encodes the tumor suppressor p15, a protein related to the transforming growth factor-beta inhibition of many epithelial cells such a thyrocytes, we investigated MTS-1 and MTS-2 genes in 87 thyroid cancers (29 papillar y, 26 follicular, 31 medullary, and 1 anaplastic), 8 goiters, and 38 c ontrol DNAs by using a semiquantitative polymerase chain reaction tech nique. Results. We failed to demonstrate homozygous deletions of MTS-1 and MTS-2 in thyroid tumors, but we demonstrated a highly frequent ba se pair exchange of the MTS-2 gene 27 condons upstream the 5' end of e xon 2. This genetic change formerly described as polymorphism was foun d to a lesser degree (15%), in control DNA when compared with papillar y thyroid cancer and medullary thyroid cancer (35% and 32%, respective ly), and it paralleled a higher prevalence of extensive lymph node met astases in thyroid cancer (p < 0.01). In addition, we could demonstrat e that genetic changes at site 27 upstream the 5' end of exon 2 were h arbored as somatic mutations in 2 of 10 thyroid cancers with simultane ously investigated corresponding control tissue. Conclusions. We concl ude that base pair exchange at this site most likely has biologic impo rtance for the tumor suppressor p15 and may contribute to tumorigenesi s and lymphatic spread of differentiated and medullary thyroid cancer.