TY - JOUR
T1 - Abnormalities of fragile histidine triad genomic and complementary DNAs in cervical cancer
T2 - Association with human papillomavirus type
AU - Muller, Carolyn Y.
AU - O'Boyle, John D.
AU - Fong, Kwun M.
AU - Wistuba, Ignacio I.
AU - Biesterveld, Eric
AU - Ahmadian, Mohsen
AU - Miller, David S.
AU - Gazdar, Adi F.
AU - Minna, John D.
N1 - Funding Information:
Supported by Public Health Service grant HD00849 from the National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. C. Y. Muller is an AAOGF-NIHCD Fellow of the Reproductive Scientist Development Program. J. D. Minna is supported in part by Texas ARP grant 003660-080.
PY - 1998/3/18
Y1 - 1998/3/18
N2 - Background: Chromosome 3p14.2 contains FRA3B, the most active chromosome breakage site in the human genome. The fragile histidine triad (FHIT) gene, a putative tumor suppressor gene, overlaps FRA3B. Human papillomavirus (HPV), a known cofactor in cervical carcinogenesis, can integrate into FRA3B. We examined abnormalities in FHIT and its RNA transcripts in cervical cancer cell lines and tumors. We also investigated the relationship between loss of heterozygosity (LOH) in FHIT/FRA3B and the presence of oncogenic HPV types. Methods: Eleven cell lines, 40 tumors (20 fresh and 20 archival), and 10 normal cervical epithelia were examined. Two intragenic polymorphic markers (D3S1300 and D3S4103) and the polymerase chain reaction (PCR) were used to examine FHIT LOH. Reverse transcription-PCR (RT-PCR) analysis and single- strand conformation polymorphism analysis of RT-PCR products were used to characterize FHIT transcripts. Oncogenic HPV types were identified by PCR, using general and type-specific primers. Results: All normal epithelia, 19 of 20 fresh tumors and nine of 11 cell lines expressed wild-type and, occasionally, exon 8-deleted FHIT transcripts. Additional aberrant FHIT transcripts were seen in nine of 20 fresh tumors and in seven of 11 cell lines. DNA sequencing of the aberrant transcripts revealed a variety of insertions and deletions but no point mutations. Three cell lines also had homozygous FHIT deletions. Oncogenic HPV types (i.e., 16, 18, 31, and 33) were detected in 18 of 20 archival tumors, and, in these tumors, LOH within FHIT was identified in nine of 16 informative cases. HPV 16 was found to be associated with LOH in the FHIT/FRA3B region (P = .041). Conclusion: FHIT/FRA3B is frequently altered in cervical cancer, demonstrating LOH, occasional homozygous deletions, and frequent aberrant transcripts not found in normal epithelia. However, the presence of wild-type transcripts and the lack of protein-altering point mutations raise questions about FHIT's function as a classic tumor suppressor gene in cervical tissue.
AB - Background: Chromosome 3p14.2 contains FRA3B, the most active chromosome breakage site in the human genome. The fragile histidine triad (FHIT) gene, a putative tumor suppressor gene, overlaps FRA3B. Human papillomavirus (HPV), a known cofactor in cervical carcinogenesis, can integrate into FRA3B. We examined abnormalities in FHIT and its RNA transcripts in cervical cancer cell lines and tumors. We also investigated the relationship between loss of heterozygosity (LOH) in FHIT/FRA3B and the presence of oncogenic HPV types. Methods: Eleven cell lines, 40 tumors (20 fresh and 20 archival), and 10 normal cervical epithelia were examined. Two intragenic polymorphic markers (D3S1300 and D3S4103) and the polymerase chain reaction (PCR) were used to examine FHIT LOH. Reverse transcription-PCR (RT-PCR) analysis and single- strand conformation polymorphism analysis of RT-PCR products were used to characterize FHIT transcripts. Oncogenic HPV types were identified by PCR, using general and type-specific primers. Results: All normal epithelia, 19 of 20 fresh tumors and nine of 11 cell lines expressed wild-type and, occasionally, exon 8-deleted FHIT transcripts. Additional aberrant FHIT transcripts were seen in nine of 20 fresh tumors and in seven of 11 cell lines. DNA sequencing of the aberrant transcripts revealed a variety of insertions and deletions but no point mutations. Three cell lines also had homozygous FHIT deletions. Oncogenic HPV types (i.e., 16, 18, 31, and 33) were detected in 18 of 20 archival tumors, and, in these tumors, LOH within FHIT was identified in nine of 16 informative cases. HPV 16 was found to be associated with LOH in the FHIT/FRA3B region (P = .041). Conclusion: FHIT/FRA3B is frequently altered in cervical cancer, demonstrating LOH, occasional homozygous deletions, and frequent aberrant transcripts not found in normal epithelia. However, the presence of wild-type transcripts and the lack of protein-altering point mutations raise questions about FHIT's function as a classic tumor suppressor gene in cervical tissue.
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U2 - 10.1093/jnci/90.6.433
DO - 10.1093/jnci/90.6.433
M3 - Article
C2 - 9521167
AN - SCOPUS:0032542697
SN - 0027-8874
VL - 90
SP - 433
EP - 439
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 6
ER -