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KMID : 0350519930460041579
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Journal of Catholic Medical College
1993 Volume.46 No. 4 p.1579 ~ p.1592
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Detection of c-K-ras Oncogene Point Mutations in Ovarian Cancers
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Abstract
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It has been well established that specific alterations in members of the ras gene family, H-ras, K-ras and N-rad, can convert them into active oncogenes. These alterations are either point mutations occuring in either codon 12, 13 or 61 or
alternatively, a 5-to 50-fold amplification of the wild-type gene. Activated ras oncogenes have been found in a significant proportion of ail tumors but the incidence varies considerably with the tumor type : it is relatively frequent(20-40 %) in
colorectal cancer and acute myeloid leukemia, but absent or present only rarely in, for example, breast and stomach cancer. But the role of c-K-ras point mutation in the development of ovarian carcinomas has not been studied extensively yet.
Polymerase chain reaction followed by gel electrophoresis was performed using wild-type normal and specific point mutation primes(GGT→GAT, GGT→AGT, GGT→TGT and GGT→GGT) to detect point mutation of codon 12 of c-K-ras oncogene.
The ras oncogene point mutation was confirmed by Southern blot hybridization using synthetic oligonucleotide probes 3´-end labelled with digoxigenin-Dutp. With this method, the frequency of point mutations on codon 12 of c-K-ras oncogene was
examined in
37 cases of ovarian cancer tissues.
The relationship between the presence of a c-K-ras point mutation and clinical or histopathological features of the ovarian carcinoma were also analysed.
@ES The results were as follows :
@EN 1. The incidence of four point mutations on codon 12 in 37 ovarian cancer cases was 45.9 %(17/37) and distribution were 43.2 %(16/37), 2.7 %(1/37), 0 %(0/37) and 0 %(0/37) in GGT→GAT, GGT→AGT, GGT→TGT, and GGT→GTT.
2. The incidence of four point mutations on codon 12 among 37 patients with ovarian cancer according to histological type was 45.5 %(10/22) with sercus type cystadenocarcinoma, 57.1 %(4/7) with mucinous type cystadenocarcinoma, 100 %(1/1) with
endometrioid adenocarcinoma, 100 %(1/1) with granulosa cell tumor, and 100 %(1/1) with endodermal sinus tumor But we were unable to detect point mutation in two dysgerminomas, one Sertoli Leydig cell tumor and two undifferentiated carcinomas.
3. Comparing the positive rate of point mutations of codon 12 among 37 patients with ovarian cancer with the clinical stage, point mutation was detected in 28.5 %(2/7) with stageⅠ, 40.0 %(2/5) with stageⅡ, and 52.0 %(13/25) with stage Ⅲ/Ⅳ.
There
was no statistically significant increasement of point mutations with the advance of the clincal stage of ovarian cancer(P<0.05).
4. Comparing the positive rate of point mutations on codon 12 among 37 patients with ovarian cancer according to the histologic grade, point mutation was detected in 50.0 %(2/4) with gradeⅠ, 41.7 %(5/12) with gradeⅡand 47.6 %(10/21) with grade
Ⅲ(P>0.05).
5. The incidence of point mutations on codon 12 among 33 patients with ovarian cancer who underwent pelvic lymph node dissection was 57.1 %(12/21) of the patients with pelvic lymph node metastases and 16.7 %(2/12) of the patients without pelvic
lymph
node metastases. There was statistically significant difference between the positive rate of c-K-ras pont mutations and the pelvic lymph nodal status(P<0.05).
The activation of ras oncogene seems to be the one step in the multistep process of tumor fomation in ovarian cancer. Furthermore, the point mutation of c-K-ras gene could occur more frequently in the patients of ovarian cancer with pelvic lymph
node
metastases than in those without pelvic lymph node metastases, suggesting the role in tumor progression. More study will be necessary, but the detection of c-K-ras point mutation as the possibilty of biological tumor marker to predict clinical
outcome
may be utilized.
From these results, we concluded that the point mutation on codon 12 of c-K-ras oncogena are considered to be one of the important genetic change in the formation and progression of ovarian cancers.
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