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Single Nucleotide Polymorphisms within Interferon Signaling Pathway Genes Are Associated with Colorectal Cancer Susceptibility and Survival.

Lu, S., Pardini, B., Cheng, B., Naccarati, A., Huhn, S., Vymetalkova, V., ... & Försti, A., 2014.

PloS one, 9(10), e111061

Paper summary

34 carefully selected SNPs, with potential links to colorectal cancer (CRC) risk and clinical outcome were analysed in 1327 CRC cases and 758 healthy controls in this blinded, hospital-based, case-control study. The 34 SNPs assayed were potentially functional genetic variants within Interferon signalling pathway genes. Genotyping was performed using KASP on an ABI real-time PCR machine, which delivered >99% accuracy and 97.0 – 99.5% call rate. As a result 7 SNPs associated with CRC susceptibility and two SNPs associated with CRC survival were identified.


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Highlights of the paper

  • Study conducted by a large consortium of high-profile research groups from Germany (DKFZ), Italy (HuGeF), Sweden and the Czech Republic.
  • Application of KASP genotyping in a blinded, hospital-based, case-control study
    • KASP genotyping used with >99% accuracy and concordance with duplicate sample quality controls.
    • Genotype call rate range between 97.0 – 99.5%
    • Example of KASP genotyping used to confirm positive association between patient genetic variation and CRC risk and survivability.
  • KASP genotyping performed on whole genome amplified DNA performed on the ABI PRISM 7900HT sequence detection system.

Commentary

Interferons (IFNs) are proteins produced and used by the human body to communicate between cells in order to trigger the protective defences of the immune system. They require a complex pathway of related proteins, including regulatory factors and receptors, in order to exert their effects. Inflammatory immune responses are known to play a role in colorectal carcinogenesis, and studies have already been undertaken which link SNPs in immune-related genes with CRC risk or prognosis.

The strongest findings of the study showed that SNPs in IFNAR1 and IFNGR1 (both IFN receptors) are associated with susceptibility to CRC, and SNPs in IFNA7 / IFNA14 (components of IFN signalling pathways) are associated with CRC patient survival. IFNAR1 and IFNGR1 are two genes which are already associated with CRC development and progression, as well as other diseases, and genetic pre-disposition. All together these results add to a growing body of work which indicates that genetic variation in the IFN signalling pathway genes plays a role in the etiology and survival of CRC.


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Colorectal cancer risk and patients’ survival: influence of polymorphisms in genes somatically mutated in colorectal tumors. Huhn, S., Bevier, M., Pardini, B., Naccarati, A., Vodickova, L., Novotny, J., ... & Försti, A. (2014). Cancer Causes & Control, 25(6), 759-769.

‘Following the identification of 209 candidate cancer genes in studies of CRC tumours, it was hypothesised for this case-control study that germline variants of these genes could influence CRC risk. After excluding well-established CRC genes, 35 SNPs were genotyped using KASP chemistry in 1399 CRC patient samples and 838 healthy controls to assess risk. In 406 cases, the influence of the SNPs on patient survival was also analysed.