Abstract 2188: Genetic variation in angiogenesis-related genes is associated with colorectal cancer risk and prognosis
Authors: Scherer Dominique , Balavarca Yesilda , Habermann Nina , Buck Katharina , Seibold Petra , Kap Lisanne , Butterbach Katja , Pfütze Katrin , Benner Axel , Hoffmeister Michael , Brenner Hermann , Burwinkel Barbara , Chang-Claude Jenny , Ulrich Cornelia M. 
Published: May 2015

Introduction

Angiogenesis, the generation of new blood vessels, is crucial in tumor growth, progression, and metastasis. The process involves a variety of factors including signaling, adhesion and chemotactic molecules, ECM (extracellular matrix) proteins, proteinases, transcription factors, growth factors and receptors. Variation in genes encoding these factors potentially influence angiogenic processes. We thus evaluated the association between variants in angiogenesis-related genes and risk as well as prognosis of colorectal cancer (CRC).

Approach

In a candidate pathway approach, we investigated 437 variants in 36 angiogenesis-related genes for association with CRC risk and prognosis in ∼1800 patients and ∼1800 controls of the German DACHS/IMPACT study. Patients were aged 30 years or older and diagnosed between 2003 and 2007. CRC risk was estimated using conditional logistic regression based on the co-dominant inheritance model. In addition, we investigated the association between polymorphisms and overall survival using multivariable Cox regression. Correction for multiple testing was performed using false discovery rates (FDR).

Results

Risk

Several of the investigated variants in ANGTP1, ETS1, FLT4, MMP2, NOTCH4, PDGFRB, TGFB2 were associated with risk of CRC, and one variant in DLL1 (delta-like 1) remained significant after accounting for multiple testing. DLL1 rs9348307 was associated with decreased risk of CRC (ORGC 0.81, 95% CI 0.68-0.96; ORCC 0.62, 95% CI 0.36-1.06, p=0.02).

Survival

After a median follow up time of 5 years, variants in twelve genes (ANGPT1, EFNB2, ETS1, FLT4, JAG1, KDR, MMP2, MMP9, NRP1, NRP2, PDGFRB, TGFB2) were associated with overall survival in CRC patients. When accounting for multiple testing, variants in EFNB2, JAG1 and MMP2 remained significant.

Most of the EFNB2 variants were associated with poorer survival, while one variant in EFNB2 was associated with better survival (rs2391333: HRCT 0.88, 95% CI 0.74-1.05; HRTT 0.60, 95% CI 0.45-0.78, p&lt;0.001). Furthermore, two variants in JAG1 were associated with worse survival in CRC patients (rs3748480: HRTG 1.27, 95% CI 1.05-1.53; HRGG 1.79, 95% CI 1.02-3.13, p=0.02; rs6040062: HRGA 1.26, 95% CI 1.04-1.52; HRAA 1.78, 95% CI 1.02-3.12, p=0.02). Finally, three variants in MMP2 (rs11639960, rs1561219, rs17301608) were associated with poorer survival, while one MMP2 variant was associated with improved survival in CRC patients (rs243847: HRTC 0.87, 95% CI 0.73-1.04, HRCC 0.60, 95% CI 0.46-0.78, p&lt;0.001).

Conclusion

Variants in angiogenesis-related genes were associated with CRC risk and overall survival in CRC patients. Two of the identified genes (DLL1 and JAG1) are involved in NOTCH signaling, which is crucial to cell differentiation, proliferation, apoptosis and angiogenesis, underlining the importance of this oncogenic pathway in colorectal carcinogenesis.

Citation Format: Dominique Scherer, Yesilda Balavarca, Nina Habermann, Katharina Buck, Petra Seibold, Lisanne Kap, Katja Butterbach, Katrin Pfütze, Axel Benner, Michael Hoffmeister, Hermann Brenner, Barbara Burwinkel, Jenny Chang-Claude, Cornelia M. Ulrich. Genetic variation in angiogenesis-related genes is associated with colorectal cancer risk and prognosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2188. doi:10.1158/1538-7445.AM2014-2188