Abstract
An individual’s inherited genetic variation may contribute to the ‘angiogenic switch’, which is essential for blood supply and tumor growth of microscopic and macroscopic tumors. Polymorphisms in angiogenesis-related genes potentially predispose to colorectal cancer (CRC) or affect the survival of CRC patients. We investigated the association of 392 single nucleotide polymorphisms (SNPs) in 33 angiogenesis-related genes with CRC risk and survival of CRC patients in 1754 CRC cases and 1781 healthy controls within DACHS (Darmkrebs: Chancen der Verhütung durch Screening), a German population-based case-control study. Odds ratios and 95% confidence intervals (CI) were estimated from unconditional logistic regression to test for genetic associations with CRC risk. The Cox proportional hazard model was used to estimate hazard ratios (HR) and 95% CIs for survival. Multiple testing was adjusted for by a false discovery rate. No variant was associated with CRC risk. Variants in EFNB2, MMP2 and JAG1 were significantly associated with overall survival. The association of the EFNB2 tagging SNP rs9520090 (p < 0.0001) was confirmed in two validation datasets (p-values: 0.01 and 0.05). The associations of the tagging SNPs rs6040062 in JAG1 (p-value 0.0003) and rs2241145 in MMP2 (p-value 0.0005) showed the same direction of association with overall survival in the first and second validation sets, respectively, although they did not reach significance (p-values: 0.09 and 0.25, respectively). EFNB2, MMP2 and JAG1 are known for their functional role in angiogenesis and the present study points to novel evidence for the impact of angiogenesis-related genetic variants on the CRC outcome.
Highlights
Colorectal cancer (CRC) is the second most common cancer and the second leading cause of cancer death among men and women throughout the world asserting major public health problems [1]
Genetic variation may contribute to an ‘angiogenic switch’, which is essential for blood supply and tumor growth in microscopic and macroscopic tumors
We investigated the association of polymorphisms in angiogenesis-related genes with the risk of colorectal cancer as well as with overall survival and recurrence-free survival of colorectal cancer patients in the DACHS population-based case-control study using 1754 CRC cases and 1781 controls
Summary
Colorectal cancer (CRC) is the second most common cancer and the second leading cause of cancer death among men and women throughout the world asserting major public health problems [1]. There is a genetic component to the disease, which is estimated to explain up to 35% of the heritability in colorectal cancer risk [5,6]. Some studies point to genetic associations with the CRC outcome [7,8,9]. Angiogenesis, the generation of new blood vessels from pre-existing vessels, is crucial for tumor growth, progression and metastasis as it provides nutrients and oxygen to the growing tumor [10]. Angiogenesis is tightly controlled and only transiently turned on, in carcinogenic progression an ‘angiogenic switch’ perpetuates the formation of new blood vessels [11]
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