A Functional Germline Variant in GLI1 Implicates Hedgehog Signaling in Clinical Outcome of Stage II and III Colon Carcinoma Patients

Abstract

Purpose: 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.Experimental Design: 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 0 -exonuclease assays. Results: 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 ¼ 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 ¼ 2.43; CI 95%, 1.52-3.87; P < 0.001). In subanalyses, the association was limited to patients with surgery alone (HR ¼ 3.21; CI 95%, 1.59-6.49; P ¼ 0.001), in contrast with patients with adjuvant chemotherapy (HR ¼ 0.82; CI 95%, 0.35-1.95; P ¼ 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.Conclusion: 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.

Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β Inactivation–Mediated Repression of the Hedgehog/Gli1 Pathway

“…DGT inhibits osteosarcoma growth and metastasis through repression of the HH/Gli1 pathway The protein Gli1 functions as a downstream transcription factor of HH signaling and plays a pivotal role in cellular growth and metastasis of many types of tumors (27)(28)(29). However, the function of Gli1 in osteosarcoma remains unclear.…”

The Prognostic Significance of the Hedgehog Signaling Pathway in Colorectal Cancer

“…53 Finally, Gli1 polymorphisms could predict for time to recurrence. 52 Nevertheless, in a number of studies these observations could either not be confirmed 32,43,54 or conflicting results were noticed. 50 One possible explanation for this might be differences in the populations studied.…”

“…In the reported studies where patients underwent resection for colon cancer, 32,[37][38][39]42,49,50,52,[38][39][40]43,50,[52][53][54] the administration of adjuvant chemotherapy was confirmed in only 3 of them. 43,52,54 Interestingly, pathway activation did not predict for survival in any of the studies in which patients received adjuvant chemotherapy. The small number of patients 32,50 and the evaluation of cytoplasmic rather than the nuclear expression of Gli1 43 could also contribute to these discrepancies.…”

“…In Table 2 the antibodies used for Gli1, Shh, Smo, and Ptch IHC and the positive and negative controls are summarized. 3,[22][23][24]32,33,[36][37][38][39][40][41]43,47,48,[51][52][53] Comparisons of the different antibodies is beyond the scope of this review but the effect of different antibody concentrations in the interpretation of results as been highlighted in the past. 66 In most cases the absence of primary antibody was used as a negative control but there were cases in which the primary antibody was replaced with phosphateor Tris-buffered saline.…”

“…Szkandera et al suggested that patients with the mutated C/C genotype had worse time to recurrence compared with patients with the nonmutated genotype. 52 The difference was observed in patients who underwent only resection and not in those having adjuvant 5-fluorouracil (FU) chemotherapy. Moreover, patients harboring the mutated genotype did not seem to get benefit from adjuvant 5-FU chemotherapy.…”