the relationship between k-ras gene mutation, some degree of ...

RESEARCH

Management in health XVIII/4/2014; pp. 26-29

THE RELATIONSHIP BETWEEN K K--RAS GENE MUTATION, SOME DEGREE OF DIFFERENTIATION AND TUMOR MARKERS IN ADVANCED COLORECTAL CANCER Iurii MUNTEANU1, MD, Bogdan MASTALIER2,5, MD, Mihaela Luminița MUNTEANU3, MD, Carmen CRIHANA4, MD, MD, Mirela Prof. Mircea CIUREA5, 6 PETRESCU ,Student 1

Department of General Surgery, Hospital CF-2, Bucharest, Romania.. 2 General Surgery Clinical Hospital Colentina, Bucharest, Romania. 3 Medical Center "Pop Basesti", Bucharest, Romania.. 4 Department of Clinical Oncology, Hospital CF-2, Bucharest, Romania. 5 University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania. 6 University "Titu Maiorescu", Faculty of Medicine, Bucharest, Romania

I

NTRODUCTION K-ras gene mutation

K-ras gene mutation is common in non-hereditary colorectal cancer. Although the role as a predictive biomarker to anti-EGFR therapy is well defined, its role as a prognostic marker is uncertain. We studied the relationship between the incidence of k-ras gene mutation, the degree of differentiation and the status of tumor markers in patients with advanced colorectal cancer resistant to complex cancer treatment. METHOD: Multicenter, retrospective study done in three oncology clinics in Bucharest from 2010 to 2014. The study included 71 stage III and IV colorectal cancer patients, which underwent surgery and adjuvant polychemotherapy. Under treatment they had an unfavourable evolution, the disease evolved worst in the first year of treatment. We analysed the K-ras gene status, the degree of tumor differentiation and the CEA and CA19-9 tumor markers, in all these patients. RESULTS: Of the 71 studied patients, 27 (38%) had the K-ras mutation. From this, 20 (74.1%) had high levels of CEA, and 16 (59.3%) had significant increases of CA19-9. By comparison, the 44 patients (62%) who had the "wild" gene, had elevated CEA in 28 (63.6%) of the cases and in 23 (52.3%) of the cases the CA19-9 was elevated. The G1 degree of differentiation was present in 28 patients; 11 (39%) were k-ras(+) and 17 (6%) k- ras(–), G2 was present in 36 patients; 14(39%) k- ras(+) and 22 (61%) k- ras(–), and the G3 was present in 7 patients; 2 (29%) k- ras(+) and 5 (71%) k- ras(–). CONCLUSION: K-ras gene mutations in patients with advanced colorectal cancer are not associated with increased prognostic tumor markers values or with the degree of tumor differentiation. The incidence does not differ significantly from that of the patients without the mutation.

Ras gene mutations have been reported in 40-50-% of the non-hereditary colorectal cancers (CRC) [1]. Ras oncogenes produce triggering signals for cell proliferation, being intimately involved in the cell cycle, which is believed to be an early event in coloKeywords: colorectal cancer, genetic mutation, K-ras, tumor markers. rectal tumorgenesis [2]. Cancer cells having a faster growth rate than normal cells release a growth factor while it became the most studied and widely used tumor called VEGF. It is responsible for the emergence of neo marker in human colorectal cancer. [6] High ACE values vessels. The negative evolution of colorectal cancers is in patients with colorectal cancer depend on the presence closely related to this factor. To survive, cancer cells need of peritumoral blood vessels, the immune inflammatory blood supply. If the intake is stopped, they can no longer response to the tumor cells and liver Kupffer cells state develop. K-ras oncogenes are the following steps in the which have receptors capable of binding the glycoprotein signal transduction pathway of the EGFR. Inhibition of the and to facilitate the clearance from the circulation [7].The EGFR by anti-EGFR monoclonal antibodies, reduce this lack of specificity and sensitivity made ACE not to be growthing. The effect is little on tumors with mutations in used as a screening tool in the detection of colorectal canthe k-ras gene. K-ras mutations have been studied for their cer, but was found to have a role in assessing the prognorole in the predictability of the response to chemotherapy; sis. Increased serum levels of ACE, more than 5 ng / ml at so according to some authors, in patients with colorectal the time of presentation is an independent negative progtumors that had k-ras mutations it was revealed a worse nostic indicator for both tumor recurrence and survival response to adjuvant treatment with 5-FU compared with [8]. ACE is a very useful tool for monitoring patients with groups of patients who did not have this mutation [3,4,5]. resection for colorectal cancer, increased serum levels being an indicator of local or distant cancer recurrence. Its usefulness lies in the fact that the cost-benefit ratio is CEA and CA 19-9 tumor markers finacially favorable for the determination of ACE versus Of the many studied tumor markers, carcinoembryonic other methods of postoperative follow-up. Despite the antigen (CEA) and CA 19-9 are most often associated with discovery of other tumor markers with a prognostic role the prognosis of CRC. ACE is an oncofetal glycoprotein in colorectal cancer, CEA remains the standard of comdiscovered in 1965 by Gold and Freedman. Meanparison. ACE association with other markers (CA19-9).

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Table 1 - The patients distribution according to degree of tumor differentiation and prognostic markers Ras status

Positive K-ras, 27 patients (38%)

Negative k-ras, 44 patients i (62%)

Tumoral markers

High CEA

Normal CEA

High Ca19-9

Normal Ca19-9

High CEA

Normal CEA

High Ca19-9

Normal Ca19-9

Number of patients

20 (74,1%)

7 (25,9%)

16 (59,3%)

11 (40,7%)

28 (63,6%)

16 (36,4%)

23 (52,3%)

21 (47,7%)

Grading

Positive K-ras

17 (38.6%) Normal CEA

High Ca19-9

Normal Ca199

5 (29,5%)

8 (47%)

9 (53%)

G1

Negative k-ras

Patients Markers

11 (40,7%) High CEA Normal CEA

High Ca19-9

Normal Ca19-9

Patients

9 (81,8%)

9 (81,8%)

2 (18,2%)

2 (18,2%)

High CEA 12 (70.5%)

Patients Total 14 (51,9%) G2

Total , 22 (50%)

Markers

High CEA

Normal CEA

High Ca19-9

Normal Ca19-9

High CEA

Normal CEA

High Ca19-9

Normal Ca199

Patients

10 (71,4%)

4 (28,6%)

9 (64,3%)

5 (35,7%)

14 (63.6%)

8 (26,4%)

13 (59,1%)

9 (40,9%)

Patients Total= 2 patients (7,4%) G3

Total = 5 patients (11.4%)

Markers

High CEA

Normal CEA

High Ca19-9

Normal Ca19-9

High CEA

Normal CEA

High Ca19-9

Normal Ca199

Patients

1 (50%)

1 (50%)

1 (50%)

1 (50%)

3 (60%)

2 (40%)

2 (40%)

3 (60%)

Note:To check the statistical assumptions we used the chi-square test. The chi-square test is used in the case of categorical variables (nominal or ordinal) and it provides information about the relationship between two variables. The test is based on the frequencies of values of the variables, presented as a table, having on the columns, the values of one variable and on the lines the values of the other variable. The fi values represent the observed frequencies of occurrences, on which after a certain calculus algorithm, a theoretical frequency for each observed frequency is determined. It follows that each cell will contain an obχ2 = ∑

( f i − fti ) 2 fti

served fi frequency and a theoretical fti one. Chi-square value is calculated as: Chi-square statistical value, determined by the above formula is compared with the critical value predetermined in statistical tables based on the significance threshold and on the df degrees of freedom. Based on this information the software determines the p significance threshold. If p 0.05efor χ2 = 0.33 and df = 1. In these circumstances we accept the null hypothesis that between K RAS and CA 19-9 tumor marker there is no significant statistical association. Phi coefficient equal to 0.07 shows a very small association between the two variables. Since χ2 test indicates a p-value> 0.05 it results that between the observed frequencies and the estimated ones there are no sig28 nificant statistical differences. Parameters Chi square df P Phi

Values 0.33 1 0.57 0.07

C

ONCLUSIONS :

CEA and CA 19-9 tumor markers have an independent predictive value. Patients with stage III-IV colorectal cancer, which evolved unfavorable under treatment, had their level not influenced by the k-ras genetic status. In addition the degree of tumor differentiation was not associated with this mutation. In our study we did not found interrelationship between K-ras mutation and prognosis of patients with advanced CRC. Incidence of this mutations in our grup of patiens does not differ significantly from that of all the patients with CRC in the same stage. To all intents and purposes the CRC is the genetical disease. We hope the new genetical studies will be helpful in the early diagnosis and for the efficient treatament of this kind of patients.

RESEARCH


Note: Materiality value for chi-square equal to 0.296 Parameters Values and 2 degrees of freedom is p Chi square 0.296 = 0.863. As p> 0.05 we condf 2 P 0.863 clude that there is a significant association between kras types and the degree of tumor differentiation.

Table 4 - The association between k-ras type and degree of differentiation Test results Gradding

Values Observed Theoretical Chi square contribution % Observed Theoretical Chi square contribution % Observed Theoretical Chi square contribution %

G1

G2

G3 Total on lines

K-ras Pozitive Negative 11 17 10.65 17.35 0.01 0.01 39% 61% 14 22 13.69 22.31 0.01 0.00 39% 61% 2 5 2.66 4.34 0.16 0.10 29% 71% 27 44

Lines total 28.00 28.00 0.02 100% 36.00 36.00 0.01 100% 7.00 7.00 0.27 100% 71

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