NF-κB2 and RELB offer prognostic information in colorectal cancer and NFKB2 rs7897947 represents a genetic risk factor for disease development.

The Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) family of transcription factors plays an important role in immune responses and cancer development and progression. We have focused on NF-κB2 and RELB of the alternative pathway of NF-κB, which remains largely underexplored in colorectal cancer (CRC). We found that NF-κB2 and RELB protein levels were upregulated in tumour and surrounding stromal tissue compared to distant non-neoplastic tissue (NN) and associated stroma (p<0.001 in all associations). Moreover, low RELB protein expression was associated with decreased overall survival (p = 0.032). Lower RELB gene expression levels were observed in tumour compared to NN tissue (p = 0.003) and were associated with shorter time to progression (TTP) (p = 0.025). NF-κB2 gene expression levels were similar in tumour and NN tissue, but higher tumour levels were prognostic for improved survival (p = 0.038) and TTP (p<0.001). We also assessed the significance of two NF-κB2 genetic polymorphisms, rs12769316 and rs7897947. Both polymorphisms were associated with lymph node infiltration (p = 0.045 and p = 0.009, respectively). In addition, rs12769316 AA homozygotes relapsed less often compared to G allele carriers (p = 0.029). Moreover, rs7897947 allele frequencies differed significantly between CRC patients and healthy controls (p<0.001) and the minor allele (G) was associated with reduced risk for developing CRC (p<0.001, OR: 0.527, 95% CI: 0.387-0.717). In conclusion, the alternative NF-κB pathway appears deregulated in CRC. Moreover, NF-κB2 and RELB expression levels seem to be significant for the clinical outcome of CRC patients and rs7897947 appears to be a risk factor for CRC development.