Evidence for predictive role of BRCA1 and bTUBIII in gastric cancer
Vladimir M Moiseyenko1, Nikita M Volkov, Evgeny N Suspistin
1NN Petrov Institute of Oncology, Pesochny-2, St. Petersburg 197758, Russia.
Abstract:
Sensitivity of gastric cancer (GC) to conventional cytotoxic therapy may be at least in part attributed to molecular features of the tumor cells. We analyzed all patients with metastatic GC treated in the N.N. Petrov Institute of Oncology (St. Petersburg) within years 1999-2010 and identified 65 cases with evaluable treatment response and available biological material. Two of 65 patients (3 %) carried germ-line BRCA1 5382insC mutation and demonstrated particularly pronounced response to the treatment; both of their tumors showed loss of the remaining BRCA1 allele, thus confirming the causative role of BRCA1 heterozygosity in GC predisposition. RNA expression of TS, DPD, BRCA1, ERCC, TOP2A and bTUBIII was analyzed in the remaining 63 tumors. Low BRCA1 expression was associated with increased response rate [6/9 (67 %) vs. 17/54 (32 %), p = 0.04]. Low bTUBIII level correlated with the improved probability of tumor response [21/49 (43 %) vs. 1/13 (8 %), p = 0.02] and prolonged overall survival (10.5 vs. 7.1 months, p = 0.02); this trend was maintained both for taxane-containing and for taxane-free drug combinations. We conclude that GC should be considered as a part of BRCA1-related hereditary cancer syndrome. Tumors with BRCA1 inactivation and low bTUBIII expression demonstrate improved response to cytotoxic therapy.
Insights
Gastric cancer (GC) sensitivity to chemotherapy is linked to BRCA1 gene mutations and expression levels. Tumors with BRCA1 inactivation and low beta-tubulin III (bTUBIII) expression show better responses to cytotoxic therapy.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Gastric cancer (GC) treatment response varies significantly.
- Tumor molecular features influence sensitivity to cytotoxic therapy.
Purpose of the Study:
- To investigate the role of BRCA1 mutations and gene expression in GC treatment response.
- To identify molecular markers predicting response to chemotherapy in metastatic GC.
Main Methods:
- Analysis of 65 metastatic GC patients treated between 1999-2010.
- Germline BRCA1 mutation screening (5382insC).
- RNA expression analysis of TS, DPD, BRCA1, ERCC, TOP2A, and bTUBIII.
Main Results:
- 3% of patients had germline BRCA1 5382insC mutation with pronounced treatment response.
- Low BRCA1 expression correlated with increased response rate (67% vs. 32%, p=0.04).
- Low bTUBIII expression correlated with improved tumor response (43% vs. 8%, p=0.02) and prolonged survival (10.5 vs. 7.1 months, p=0.02).
Conclusions:
- Gastric cancer should be considered within BRCA1-related hereditary cancer syndromes.
- Tumors with BRCA1 inactivation and low bTUBIII expression exhibit enhanced sensitivity to cytotoxic therapy.
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