Medizinische Universität Graz - Research portal
Selected Publication:
Gerger, AF.
Predictive and prognostic effects of germline polymorphisms in angiogenesis
and cancer stem cell pathway genes and colorectal cancer
[ Dissertation ] Medical University of Graz; 2012. pp. 61
[OPEN ACCESS]
FullText
- Authors Med Uni Graz:
- Gerger Armin
- Advisor:
- Renner Wilfried
- Samonigg Hellmut
- Speicher Michael
- Altmetrics:
- Abstract:
- There is substantial germline genetic variability within angiogenesis and cancer stem cell (CSC) pathway genes, thereby causing inter-individual differences in angiogenic capacity and resistance to anti-angiogenesis therapy and tumor-recurrence capacity. In this study we investigated (a) germline polymorphisms in genes involved in VEGF-dependent and -independent angiogenesis pathways to predict clinical outcome and tumor response in metastatic colorectal cancer patients (mCRC) treated with bevacizumab (BV) and oxaliplatin-based chemotherapy and (b) germline polymorphisms in a comprehensive panel of CSC genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II colon cancer. A total of 132 patients with mCRC treated with first-line BV and FOLFOX or XELOX and a total of 234 patients in adjuvant setting treated with 5-fluorouracil-based chemotherapy were included in this study. Whole blood samples were analyzed for germline polymorphisms in angiogenesis and CSC genes by PCR-RFLP or direct DNA-sequencing. In the metastatic setting the minor alleles of EGF rs444903 A>G and IGF-1 rs6220 A>G were associated with increased overall survival (OS) and remained significant in multivariate COX regression analysis (HR 0.52; 95%CI 0.31-0.87; adjusted-P=0.012 and HR 0.60; 95%CI 0.36-0.99; adjusted-P=0.046, respectively). CXCR1 rs2234671 G>C, CXCR2 rs2230054 T>C, EGFR rs2227983 G>A and VEGFR-2 rs2305948 C>T predicted tumor response, with CXCR1 rs2234671 G>C remaining significant in multiple testing (Pact=0.003). In the adjuvant setting the minor alleles of CD44 rs8193 C>T, ALCAM rs1157 G>A and LGR5 rs17109924 T>C were significantly associated with increased TTR (9.4 vs 5.4 years; HR, 0.51; 95%CI, 0.35-0.93; P=0.022; 11.3 vs 5.7 years; HR, 0.56; 95%CI, 0.33-0.94; P=0.024 and 10.7 vs 5.7 years; HR, 0.33; 95%CI, 0.12-0.90; P=0.023, respectively) and remained significant in the multivariate analysis stratified by ethnicity. In recursive partitioning, a specific gene variant profile including LGR5 rs17109924, CD44 rs8193 and ALDH1A1 rs1342024 represented a high-risk subgroup with a median TTR of 1.7 years (HR, 6.71, 95%CI, 2.71-16.63, P<0.001). In this study we identified common germline variants in VEGF-dependent and -independent angiogenesis genes predicting clinical outcome and tumor response in patients with mCRC receiving first-line BV and oxaliplatin-based chemotherapy. Furthermore, we identified common germline variants in colon CSC genes as independent prognostic markers for stage III and high-risk stage II colon cancer patients.