子宮頸癌の発生に関与する癌関連遺伝子の同定とその臨床応用(1 子宮頸癌の発生と進展 : その制御を目指して)

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It is well established that infection of oncogenic HPV is the initial step for cervical carcinogenesis. However, it is not known when neoplastic growth starts after infection of high risk HPV. In addition, genetic alterations, including activation of proto-oncogenes and inactivation of tumor suppressor genes involved in cervical carcinogenesis have not been well characterized yet. In the present study, patterns of X-chromosome inactivation were evaluated in cases of cervical intraepithelial neoplasia to determine the presence of potentially premalignant neoplastic versus polyclonal benign cell populations. Monoclonal composition was demonstrated in all 20 cases of CIN3 (100%), 13 of 19 cases of CIN2 (68%) and 10 of 20 cases of CIN1 (50%). In one uterine cervix, in which dysplastic lesions were present in 6 blocks, the pattern of X-chromosome inactivation was the same in all lesions, suggesting that these individual lesions were derived from a single cell, with intraepithelial extension within the cervical mucosa. By contrast, another uterus contained 2 discontinuous dysplastic foci with different patterns of X-chromosome inactivation, indicating that the two lesions developed independently from each other. Twenty-two of 27 (80%) CINs which were monoclonal in composition were either progressed or persisted. By contrast, 7 of 10 (70%) CINs which were polyclonal in composition were regressed. All 10 cases of CINs which progressed were positive for high risk HPV infection and monoclonal in composition. Clonal status and infection of high risk HPV were thus significantly associated with clinical outcome in CIN1 and 2. Inactivation of the tumor suppressor genes, p53 p16^<INK4a>, p14^<ARF> and FHIT, and activation of the K-ras proto-oncogene, were analyzed. Inactivation of STK11, the gene responsible for Peutz-Jeghars syndrome, and activation of TSC403, which has been isolated from 3q27 where chromosomal gain is frequently observed in cervical carcinoma, were also studied. Inactivation of p53 was rare irrespective of the presence or absence of HPV infection (2/29 versus 0/7). In contrast, expression of p16^<INK4a> and p14^<ARF> transcripts was significantly associated with the presence of HPV infection (p = 0.0018 and 0.000555, respectively). Impaired expression of the FHIT gene product due to loss of normal FHIT transcript was detected in 13 of 30 (43%) invasive carcinoma of the uterine cervix but not in any 22 CINs, suggesting that inactivation of FHIT occurs as a late event in cervical carcinogenesis. Mutation in STK11 was detected in 6 of 11(55%) MDAs, not known to be associated with PJS, and 1 of 19 (5%) mucinous adenocarcinomas but not in 4 endometrioid adenocarcinomas or 15 squamous cell carcinomas. MDAs with STK11 mutation had significantly poorer prognosis than MDAs without STK11 mutation. Activation of K-ras by point mutation in codon 12 or 13 was detected in 17 of 57 (31%) endometrial carcinomas but only in 4 of 23 (4%) cervical carcinomas, suggesting that K-ras activation plays little role in cervical carcinogenesis. Overexpression of TSC403 mRNA was significantly higher in cervical carcinomas (10/20, 50%), especially in squamous cell carcinomas (56%), compared with endometrial carcinomas (3/29, 10%) or ovarian carcinomas (3/33, 9%). Cervical carcinomas which showed TSC403 overexpression had significantly poorer prognosis than those with normal level of TSC403 expression. The cervical carcinoma cell line, TCS, and NIH3T3, both expressed low revel of TSC 403 mRNA, acquired invasion activity in vitro significantly by induction of TSC403. The present study demonstrate that 1) Not only CIN3 but a majority of CIN1 and 2 are composed of a clonal neoplastic population of cells and such monoclonal CINs infected with high risk HPV are more likely to progress or persist compared with polyclonal CINs infected with low risk HPV, 2) inactivation of p16^<INK4a> -RB and p53-p14^<ARF> pathways, inactiv
社団法人日本産科婦人科学会の論文
2002-08-01

子宮頸癌の発生に関与する癌関連遺伝子の同定とその臨床応用(1 子宮頸癌の発生と進展 : その制御を目指して)

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