Chromosome 3p tumor-suppressor gene alterations in cervical carcinomas

Loss of heterozygosity (LOH) on chromosome 3p is a common event in cervical cancer and typically occurs in a dispersed pattern involving several loci. This implies that more than one resident tumor-suppressor gene is involved in the genesis of these tumors; however, specific targets remain to be ide ntified. The region of 3p 14.2-pter encompasses a region of frequent loss a nd contains at least three tumor-suppressor genes: fragile histidine triad (FHIT), transforming growth factor-beta receptor II (T betaR-II), and Von H ippel-Lindau. To identify those loci within 3p 14.2-pter that are important in cervical cancer, invasive tumors were first subjected to high-density L OH analysis. With 25 microsatellite markers, LOH was detected in seven of 1 5 cervical carcinomas (47%). Losses always included markers mapping to 3p22 , and markers at this location were exclusively lost in two tumors, implica ting this as a site of a cervical tumor-suppressor gene. Because it is a kn own tumor-suppressor gene located at 3p22 and thus a potential target for i nactivation in these tumors, the T betaR-II gene was subsequently screened for mutation and altered expression levels. Whereas no tumor-derived mutati ons were detected in any of the tumors, six of ten tumors showed T betaR-II transcript levels reduced by greater than or equal to 50% when compared wi th normal cervical epithelium. Nine of 15 (60%) tumors exhibited LOH at 3p2 2 or reduced expression of T betaR-II, suggesting that reduced T betaR-II l evels contribute to cervical tumorigenesis. Two cases exhibited silent germ line polymorphisms of T betaR-II: one corresponding to a C1167T transversio n and the other to an A1266G transition. The FHIT gene, which is located at 3p 14.2, also frequently incurred LOH and abnormal transcription in these tumors. LOH of FHIT was observed in five of the 15 tumors analyzed. Neither mutations nor homozygous deletions of FHIT were detected in the tumors. Ho wever, aberrantly short transcripts of the FHIT gene were evident in six of nine (67%) tumors. Only one of these also displayed LOH, indicating that t his gene was altered in at least 10 of 15 (67%) tumors. These results provi de evidence that the inactivation of two known tumor-suppressor genes, T be taR-II and FHIT, on chromosome 3p is involved in cervical carcinogenesis. ( C) 2001 Wiley-Liss, Inc.