UZH-Logo

Maintenance Infos

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


Szkandera, J; Pichler, M; Absenger, G; Stotz, M; Weissmueller, M; Samonigg, H; Asslaber, M; Lax, S; Leitner, G; Winder, T; Renner, W; Gerger, A (2014). A functional germline variant in GLI1 implicates Hedgehog signaling in clinical outcome of stage II and III colon carcinoma patients. Clinical Cancer Research, 20(6):1687-1697.

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'-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.
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.

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'-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.
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.

Citations

9 citations in Web of Science®
9 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

20 downloads since deposited on 19 Feb 2015
16 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:15 March 2014
Deposited On:19 Feb 2015 16:00
Last Modified:05 Apr 2016 18:57
Publisher:American Association for Cancer Research
ISSN:1078-0432
Publisher DOI:https://doi.org/10.1158/1078-0432.CCR-13-1517
PubMed ID:24470513
Permanent URL: https://doi.org/10.5167/uzh-106843

Download

[img]
Content: Published Version
Filetype: PDF - Registered users only
Size: 1MB
View at publisher
[img]
Preview
Content: Accepted Version
Language: English
Filetype: PDF
Size: 625kB

TrendTerms

TrendTerms displays relevant terms of the abstract of this publication and related documents on a map. The terms and their relations were extracted from ZORA using word statistics. Their timelines are taken from ZORA as well. The bubble size of a term is proportional to the number of documents where the term occurs. Red, orange, yellow and green colors are used for terms that occur in the current document; red indicates high interlinkedness of a term with other terms, orange, yellow and green decreasing interlinkedness. Blue is used for terms that have a relation with the terms in this document, but occur in other documents.
You can navigate and zoom the map. Mouse-hovering a term displays its timeline, clicking it yields the associated documents.

Author Collaborations