Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Szkandera, J; Pichler, M; Absenger, G; Stotz, M; Weissmueller, M; Samonigg, H; Asslaber, M; Lax, S; Leitner, G; Winder, T; Renner, W; Gerger, A.
A functional germline variant in GLI1 implicates hedgehog signaling in clinical outcome of stage II and III colon carcinoma patients.
Clin Cancer Res. 2014; 20(6):1687-1697
Doi: 10.1158/1078-0432.CCR-13-1517
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- Leading authors Med Uni Graz
- Gerger Armin
- Szkandera Joanna
- Co-authors Med Uni Graz
- Absenger Gudrun
- Asslaber Martin
- Leitner Gerhard
- Pichler Martin
- Renner Wilfried
- Samonigg Hellmut
- Stotz Michael
- Weissmüller Melanie
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- Abstract:
- Cumulating evidence indicates that germline variants in the Wnt, Notch, and Hedgehog pathways are involved in colon carcinoma progression and metastasis. We investigated germline polymorphisms in a comprehensive panel of Wnt, Notch, and Hedgehog pathway genes to predict time to recurrence (TTR) and overall survival in patients with stage II and III colon carcinoma. A total of 742 consecutively collected patients with stage II and III colon carcinoma were included in this retrospective study. Genomic DNA was analyzed for 18 germline polymorphisms in Wnt, Notch, and Hedgehog pathway genes (SFRP, DKK 2 and 3, AXIN2, APC, MYC, TCF7L2, NOTCH2, and GLI1) by TaqMan 5'-exonuclease assays. In univariate analysis, the homozygous mutant variant of GLI1 rs2228226 G>C was significantly associated with decreased TTR in a recessive genetic model after adjustment for multiple testing [HR = 2.35; confidence interval (95% CI), 1.48-3.74; P < 0.001] and remained significant in multivariate analysis including clinical stage, lymphovascular-, vascular-, and perineural-invasion (HR = 2.43; CI 95%, 1.52-3.87; P < 0.001). In subanalyses, the association was limited to patients with surgery alone (HR = 3.21; CI 95%, 1.59-6.49; P = 0.001), in contrast with patients with adjuvant chemotherapy (HR = 0.82; CI 95%, 0.35-1.95; P = 0.657). When the subgroup of patients with "high-risk" GLI1 rs2228226 C/C genotype was analyzed, no benefit of adjuvant 5-fluorouracil-based chemotherapy could be found. This is the first study identifying GLI1 rs2228226 G>C as an independent prognostic marker in patients with stage II and III colon carcinoma. Prospective studies are warranted to validate our findings. ©2014 AACR.
- Find related publications in this database (using NLM MeSH Indexing)
- Adenocarcinoma - genetics Adenocarcinoma - mortality Adenocarcinoma - pathology
- Adult -
- Aged -
- Aged, 80 and over -
- Colonic Neoplasms - genetics Colonic Neoplasms - mortality Colonic Neoplasms - pathology
- Female -
- Genotype -
- Hedgehog Proteins - metabolism
- Humans -
- Immunohistochemistry -
- Kaplan-Meier Estimate -
- Male -
- Middle Aged -
- Neoplasm Staging -
- Polymorphism, Single Nucleotide -
- Prognosis -
- Proportional Hazards Models -
- Retrospective Studies -
- Signal Transduction - physiology
- Transcription Factors - genetics
- Tumor Markers, Biological - genetics