A functional germline variant in GLI1 implicates hedgehog signaling in clinical outcome of stage II and III colon carcinoma patients.
OBJECTIVE
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.


METHODS
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.


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 = 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.


CONCLUSIONS
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.
Authors' Affiliations: Division of Clinical Oncology, Department of Medicine; Research Unit: Genetic Epidemiology and Pharmacogenetics, Division of Clinical Oncology; Institute of Pathology; Clinical Institute of Medical and Laboratory Diagnostics, Medical University of Graz; Department of Pathology, General Hospital Graz West, Graz; Department of Pathology, General Hospital of Leoben, Leoben, Austria; and Department of Medical Oncology, University Hospital Zuerich, Zuerich, Switzerland.
Joanna
J
Szkandera
Martin
M
Pichler
Gudrun
G
Absenger
Michael
M
Stotz
Melanie
M
Weissmueller
Hellmut
H
Samonigg
Martin
M
Asslaber
Sigurd
S
Lax
Gerhard
G
Leitner
Thomas
T
Winder
Wilfried
W
Renner
Armin
A
Gerger
D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D005838:Genotype; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics*; D000071676:Zinc Finger Protein GLI1
D014408:Biomarkers, Tumor; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1