Absenger, Gudrun

Gerger, Armin

Lax, Sigurd

Leitner, Gerhard

Martin, Asslaber

Pichler, Martin

Renner, Wilfried

Stotz, Michael

Szkandera, Joanna

Weissmüller, Melanie

Winder, Thomas

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PD 0007 ACOMMONGENE VARIANT IN HEDGEHOG PATHWAYGENE GLI1 IDENTIFIES PATIENTS AT RISKOFRECURRENCE IN STAGE II COLON CANCERThomas Winder1, Joanna Szkandera2, Gudrun Absenger3, Melanie Weissmüller2,Martin Pichler4, Michael Stotz2, Sigurd Lax4, Gerhard Leitner4, Asslaber Martin4,Wilfried Renner5, Armin Gerger31University Hospital Zürich, Switzerland; Academic Teaching Hospital Feldkirch,Austria, 2Division of Clinical Oncology, Department of Internal Medicine, MedicalUniversity of Graz, Graz, Austria, 3Division of Oncology, Department of InternalMedicine, Medical University of Graz, Graz, Austria, 4Medical University Graz, Graz,Austria, 5Clinical Institute of Medical and Chemical Laboratory Diagnostics,Medical University of Graz, Graz, AustriaBackground: A paradigm shift is ongoing in how we approach and effectively managestage II and III colon cancer (CC) patients and it is now widely recognized that amultitude of factors contribute to the success (or failure) of CC treatment. Specifically, thepresence of significant heterogeneity among patients and their respective diseases mayhave a significant impact on the efficacy of treatment and overall disease prognosis. TheWnt, Notch and Hedgehog signaling pathways have recently been shown to play a centralrole in the development and progression of CC. Germline variants in these pathways mayresult in heterogeneity among patients by altered gene function and/or gene activity,thereby causing individual differences in tumor recurrence and chemoresistance. Weinvestigated a comprehensive panel of germline polymorphisms in Wnt, Notch andHedgehog signaling pathways to predict recurrence in stage II and III CC patients.Methods: A total of 815 patients with histopathologically confirmed stage II and IIICC treated at the Division of Clinical Oncology, Department of Medicine, MedicalUniversity of Graz were recruited in this retrospective analysis. Genomic DNAwasextracted from tissue samples using QIAamp DNA mini Kit (Qiagen) and analysed forpotential functional germline polymorphisms in SFRP, DKK2, DKK3, APC, MYC,TCF7L2, NOTCH-2 and GL1 genes by 5’-exonuclease assay (TaqMan).Results: Overall, the homozygous GG variant of GLI1 rs2228226 C > G wassignificantly associated with shorter DFS in univariate (79 vs 122 months; HR 1.955,95%CI 1.236-3.092, p = 0.004) and multivariate Cox regression analysis adjusted forknown prognostic markers (HR 1.844, 95%CI 1.161-2.927, p = 0.009). Moreover, theAnnals of Oncology poster discussionsVolume 24 | Supplement 4 | June 2013 doi:10.1093/annonc/mdt202 | ivGLI1 rs2228226 GG variant was significantly associated with decreased OS inunivariate analysis (94 vs 129 months; HR 1.697, 95%CI 1.009-2.854, p = 0.046). Instage II patients, the homozygous GG variant of GLI1 rs2228226 remainedsignificantly associated with decreased DFS in univariate (70 vs 145 months; HR 3.035,95% CI 1.262-7.301, p = 0.013) and multivariate analysis (HR 3.874, 95% CI1.578-9.507, p = 0.003). In stage III patients, the GG genotype of rs2228226 showed atrend for decreased DFS in univariate analysis (71 vs 104 months; HR 1.650, 95% CI0.962-2.831, p = 0.069). In multivariate analysis, the GG variant was significantlyassociated with decreased DFS (HR 1.749, 95% CI 1.016-3.010, p = 0.044).Conclusion: This study provides the first evidence that the germline polymorphismrs2228226 in Hedgehog pathway gene GLI1 is an independent prognostic markerespecially for stage II CC patients. GLI rs2228226 may help to identify colon cancerpatients at high risk of recurrence who might benefit from adjuvant treatment.Prospective biomarker embedded trials are warranted to validate our findings.

PD-0007A COMMON GENE VARIANT IN HEDGEHOG PATHWAY GENE GLI1 IDENTIFIES PATIENTS AT RISK OF RECURRENCE IN STAGE II COLON CANCER

PD-0007A COMMON GENE VARIANT IN HEDGEHOG PATHWAY GENE GLI1 IDENTIFIES PATIENTS AT RISK OF RECURRENCE IN STAGE II COLON CANCER

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