Circulating and genetic factors in colorectal cancer : Potential factors for establishing prognosis?

Sammanfattning: Surgery is the main treatment option of colorectal cancer (CRC) and a survival rate of < 10 % is estimated if distant metastases have developed. It is therefore it of importance to find factors that may be useful together with tumour, node, metastasis (TNM) stage to establish early CRC diagnosis, prognosis and follow-up of CRC patients. The aim of this thesis was to study the possible association of CD93, PLA2G4C, PDGF-D and inflammatory cytokines previously described in other cancers with CRC disease progression.Using a prospective study approach in paper I and II genotyping of single nucleotide polymorphisms (SNPs) of CD93 and PLA2G4C revealed both a genotype and an allele type of potential importance in CRC prognosis. The T/T genotype of CD93 was shown to be associated with an increased CD93 expression in CRC tissue. Further, CRC patients carrying this genotype were associated with disseminated CRC at diagnosis and a lower recurrence-free survival after surgery. The A allele of a SNP of PLA2G4C was associated with worse outcome in CRC and was a stronger predictor for CRC-specific mortality than the conventional risk factors used in the clinic for selection of stage II patients for adjuvant treatment. This may indicate that the T/T genotype of CD93 and the A allele of PLA2G4C may be potential genetic factors related to severe tumour disease, spread and for distinguishing CRC patients that may benefit from a more comprehensive follow-up and adjuvant treatment.To study the putative involvement of PDGF-D in CRC the effects of PDGF-D signalling was studied in vitro in paper III. PDGF-D signalling altered the expression of genes of importance in CRC carcinogenesis and proliferation which was blocked by imatinib, a tyrosine kinase inhibitor. This indicates that PDGF-D signalling may be an important pathway in CRC progression and a potential target in CRC treatment.In paper IV analysis of various inflammatory cytokines in plasma at diagnosis were performed using Luminex. For most of the cytokines an association between higher levels and increased total- or CRC-specific mortality appeared two years after surgery. High levels of the inflammatory cytokines CCL1 and CCL24 was strongly correlated with a worse CRC prognosis and may be of interest for further evaluation.In conclusion, this thesis present circulating and genetic factors such as CD93, PLA2G4C, PDGF-D, CC1 and CCL24 that may be of importance in establishing CRC progression and may be of support together with TNM stage in establishing prognosis.