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The fhit (fragile histidine triad) gene on chromosome 3p14.2 is a candidate tumour-suppressor gene; its abnormal transcripts are detected in several human cancers. To define the role of the fhit gene in the development of endometrial cancer, we examined 39 endometrial carcinomas for the presence of fhit gene alterations. fhit transcripts were analyzed by RT-PCR and direct sequencing. Loss of fhit transcript was observed in 6/39 (15%) tumours. Aberrant fhit transcripts, with deletions and/or insertions, were observed in 7/39 (18%) tumours but not in any normal endometrium. Allelic losses at D3S1300 and D3S4103, both located within intron 5 of fhit, were detected in 6/25 (24%) and 5/22 (23%) informative cases respectively. Expression of fhit protein was detected by immunohistochemistry; fhit protein was strongly expressed in 8/8 proliferative phase and 5/5 secretory phase endometria, also in 5/5 atrophic endometria; and it was strongly expressed in 6/6 simple hyperplasias without atypia, 6/6 complex hyperplasias without atypia, and 11/11 complex hyperplasias with atypia. In contrast, loss or reduced expression of fhit protein was observed in 13/27 (48%) endometrial adenocarcinomas. The impaired expression of the fhit protein was significantly correlated with the histological grade of the tumours. The present data suggest that inactivation of the fhit gene is an important genetic event associated with the genesis of endometrial carcinoma, especially with tumours of higher histological grade, which are believed to emerge directly from an atrophic endometrium. Int. J. Cancer 85:306–312, 2000. ©2000 Wiley-Liss, Inc.

We have reported a significant frequency of an alteration of the fragile histidine triad (fhit) gene in squamous-cell carcinoma of the uterine cervix (series 1). To further define the role of fhit alteration in the development of cervical carcinoma, we surveyed 36 normal cervical epithelium, 22 cervical intra-epithelial neoplasias (CINs) and 20 additional cases of invasive cervical carcinomas (series 2). fhit transcripts were analyzed using reverse-transcription-polymerase-chain-reaction amplification and sequencing. Loss of expression of fhit was observed in 14 of 48 (29%) invasive carcinomas (8/28, series 1; 6/20, series 2) but not in any normal squamous epithelia or CINs analyzed. Abnormal fhit transcripts, including deletions and/or insertions, were observed in 12 of 48 (25%) invasive carcinomas (9/28, series 1; 3/20, series 2), 6 of 22 (27%) CINs, and 10 of 40 (25%) normal squamous epithelia (0/4, series 1; 10/36, series 2). Point mutation was detected in 9 of 48 (19%) cervical carcinomas (8/28, series 1; 1/20, series 2). Inactivation in both alleles was observed in 18 of 48 cervical carcinomas (38%), but not in any of 22 CINs or 40 normal squamous epithelia. Loss or impaired expression of the fhit-gene product was detected in 13 of 30 (43%) cervical carcinomas by immunohistochemistry, whereas all 6 normal cervical epithelia, or 22 CINs, expressed fhit protein. There was a strong association of impaired fhit protein expression with the disruption of normal fhit transcript in cervical carcinoma. No apparent correlation was observed between fhit inactivation and HPV infection. Our results suggest that fhit-gene inactivation occurs, not as an initiating event, but rather as a later event in cervical carcinogenesis, when the cervical tumor has acquired an invasive character. Int. J. Cancer 85:6–12, 2000. © 2000 Wiley-Liss, Inc.

We have examined the roles of 2 putative tumor-suppressor genes, the p16 and p15 inhibitor-of-cyclin-dependent-kinase genes, in the most commonly occurring epithelial tumors of the human ovary. Expression of p16 mRNA, examined by RT-PCR, was significantly reduced in 15 of the 48 tumors. Aberrant expression of p16 protein, detected by immunohistochemistry, occurred in 22 of 60 tumors, more frequently in low-grade tumors, and had significant correlation with low p16 mRNA expression. Hypermethylation of a site within the 5'-CpG island of the p16 gene was significantly associated with loss of p16 mRNA and protein expression. Homozygous gene deletion, evaluated by differential PCR analysis, was found in 2 tumors for the p16 gene and in 1 tumor for the p15 gene among 70 ovarian tumors examined. PCR-SSCP analysis detected point mutations in p16 in 4 tumors and in p15 in 1 tumor. One was a 38-bp deletion, from codons 48 to 60, in a mucinous tumor of low malignant potential; another was a non-sense mutation in codon 60 in a mucinous adenocarcinoma. The remaining 2 mutations were mis-sense mutations, one in codon 58 and the other in codon 60, in 2 endometrioid adenocarcinomas. We conclude that inactivation of p16, by loss of p16 mRNA and protein expression as a consequence of hypermethylation of the 5'-CpG island, rather than by gene deletion or point mutation, may play an important role in the genesis of human ovarian epithelial tumors. Int. J. Cancer 74:148-155, 1997. © 1997 Wiley-Liss, Inc.

The fragile histidine triad (FHIT) tumor suppressor gene at 3p14.2 has abnormalities in several types of human cancers. To investigate the potential role of FHIT in cervical cancer, which exhibits frequent loss of heterozygosity of 3p, we have examined primary cervical cancer samples from 28 patients for alterations of the FHIT gene. Abnormal FHIT transcripts were detected using reverse transcription-polymerase chain reaction (PCR) and subsequently by sequencing. Of 28 primary cervical carcinomas analyzed, 12 tumors (43%) showed abnormal FHIT transcripts, including deletion, insertion and point mutation. Loss of a FHIT transcript was observed in 2 cases (7%). Allelic loss of the FHIT gene was detected in 16 of 27 informative cases (59%). Oncogenic human papillomavirus (HPV) type 16, 18, 33, 35, 58 and 59 were not only present but were expressed in 24 of 28 cases (85%) by consensus PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) analysis for the HPV E6 and E7 genes. Our data indicate that alteration of the FHIT gene is an important genetic event associated with cervical cancer and oncogenic HPV integration. Int. J. Cancer 76:176–181, 1998.© 1998 Wiley-Liss, Inc.