Chromosome 3p tumor-suppressor gene alterations in cervical carcinomas. Mol Carcinog 2001 Mar;30(3):159-68
Date
04/13/2001Pubmed ID
11301476DOI
10.1002/mc.1024Scopus ID
2-s2.0-0035063353 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
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 identified. The region of 3p14.2-pter encompasses a region of frequent loss and contains at least three tumor-suppressor genes: fragile histidine triad (FHIT), transforming growth factor-beta receptor II (T beta R-II), and Von Hippel-Lindau. To identify those loci within 3p14.2-pter that are important in cervical cancer, invasive tumors were first subjected to high-density LOH analysis. With 25 microsatellite markers, LOH was detected in seven of 15 cervical carcinomas (47%). Losses always included markers mapping to 3p22, and markers at this location were exclusively lost in two tumors, implicating this as a site of a cervical tumor-suppressor gene. Because it is a known tumor-suppressor gene located at 3p22 and thus a potential target for inactivation in these tumors, the T beta R-II gene was subsequently screened for mutation and altered expression levels. Whereas no tumor-derived mutations were detected in any of the tumors, six of ten tumors showed T beta R-II transcript levels reduced by > or = 50% when compared with normal cervical epithelium. Nine of 15 (60%) tumors exhibited LOH at 3p22 or reduced expression of T beta R-II, suggesting that reduced T beta R-II levels contribute to cervical tumorigenesis. Two cases exhibited silent germline polymorphisms of T beta R-II: one corresponding to a C1167T transversion and the other to an A1266G transition. The FHIT gene, which is located at 3p14.2, 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. However, aberrantly short transcripts of the FHIT gene were evident in six of nine (67%) tumors. Only one of these also displayed LOH, indicating that this gene was altered in at least 10 of 15 (67%) tumors. These results provide evidence that the inactivation of two known tumor-suppressor genes, TbetaR-II and FHIT, on chromosome 3p is involved in cervical carcinogenesis. Mol. Carcinog. 30:159--168, 2001.
Author List
Herzog CR, Crist KA, Sabourin CL, Kelloff GJ, Boone CW, Stoner GD, You MMESH terms used to index this publication - Major topics in bold
Acid Anhydride HydrolasesAdenocarcinoma
Carcinoma, Squamous Cell
Chromosomes, Human, Pair 3
Female
Genes, Tumor Suppressor
Humans
Loss of Heterozygosity
Mutation
Neoplasm Proteins
Polymorphism, Single-Stranded Conformational
Proteins
RNA, Messenger
Receptors, Transforming Growth Factor beta
Uterine Cervical Neoplasms