Personalization of treatment for patients with stomach cancer using molecular genetic markers
Authors: I. Bykov, M. Mikerova, M. Nemtsova, T. Kchorobryh
Journal: Annals of Oncology (2018)

Introduction: Surgical treatment is the most effective method of treatment of gastric cancer, however this method gives good results only at early stage of the disease. One way to improve the results of a gastric cancer patient's treatment is the strategy of personalization based on implication of gastric cancer molecular genetic markers. Methods: The research was conducted in the Clinic of faculty surgery of N.N. Burdenko of Sechenov University. The study period ran from 2006 through 2017. Participants included 156 patients – 106 patients with gastric cancer (group of the research) and 50 patients with cholelithiasis (control). All 106 patients with cancer of the stomach underwent standard examination which included laboratory and instrumental (electrocardiography, external respiration function testing, ultrasonography of abdominal organs, esophagogastroduodenoscopy, X-ray examination, multislice computed tomography of organs of the thorax and abdominal cavity with intravenous contrasting) methods and consultations of profile experts. For the study, biopsies were performed during esophagogastroduodenoscopy, and samples for histological and cytological examination were taken. Samples of 53 patients received at biopsy were examined on molecular genetic markers. All 50 patients from the cholelithiasis group underwent preoperative examination including the esophagogastroduodenoscopy with biopsy, and molecular genetic markers were analyzed. All 106 patients with gastric cancer underwent surgical treatment: gastrectomy – 42 patients (40%) or resections – 64 patients (60%) with a lymph node dissection D1 – 9 patients (8%), D2 – 85 patients (87%), D3 – 13 patients (12%). In all the cases tumor cells were found in the samples, taken from a tumor. In all biopsy samples from edges of a resection tumor cells were found to be absent, atrophic gastritis in combination with an intestinal metaplasia and/or a dysplasia of various degree was found. Results of a postoperative histological examination of the stages of neoplastic process showed the following: T1N0M0 – 16 (15%), T1N1M0-T2N0M0 – 20 (18,9%), T1N2M0-T3N0M0 – 26 (24,6%), T2N2M0-T4N0M0 – 20 (18,9%), T3N2M0-T4N1M0 – 10 (9,4%%), T4N2M0-T4N2M1 – 14 (13,2%). High-grade differentiated adenocarcinoma was found in 16 cases (15%), moderately differentiated adenocarcinoma – 34 (32%), low-grade differentiated adenocarcinoma - 32 (30,2%), signet ring cell carcinoma – 22 (20,8%), undifferentiated cancer – 2 (2%). Cholecystectomia was performed in all 50 patients from group of comparison. In all biopsy samples from patients with cholelithiasis tumor cells were found to be absent, and atrophic gastritis without intestinal metaplasia and epithelial dysplasia were found. Results: The methylation of genes RASSF1A, MLH1, the expression of genes of MMP7, hTERT, BIRC5 and telomerase activity in combination with other methods of examination can be used for diagnostics of gastric carcinoma at early stages (p < 0,01). High level of CDH1, N33, DAPK methylation in morphologically normal tissue, boundary with tumoral, indicates high probability of involvement of this tissue in pretumor transformation (p < 0,01) that needs additional control for patients in the postoperative period with the aim of early diagnostics of a recurrence of the disease. The samples received endoscopically could be used for presurgical evaluation of gastric cancer molecular genetic markers (p < 0,01). Conclusion: In our research we showed the possibility of introducing a system of molecular markers in clinical practice. The methylation of genes RASSF1A, MLH1, the expression of genes of MMP7, hTERT, BIRC5 and telomerase activity helps to improve diagnostics of a gastric carcinoma and to concretize tactics of management with a patient. As we continue our search for markers, it has to include evaluation of methylation genes CDH1, N33, RUNX3 as recurrence disease predictors. Also, the search for predictors of effective use of 5-fluorouracil and platinum based chemotherapeutic schemes continues. By preliminary estimate definition of polymorphic options of a gene TYMS (R2/R3, G>C, del 6 bp) and ТР53 (Arg>Pro, ins 16 bp) is capable to influence individual choice of chemotherapy regimen.