Association Of A Specific Innate Immune Response To Dna Damage With Dna Repair Deficient Colorectal Cancers

3035 Background: We previously described a molecular subtype of tumors that presents an innate immune response to intrinsic DNA damage. The associated gene expression pattern is mediated by the STING viral response pathway within the cancer cell and is defined by up-regulation of cytokines that drive lymphocytic infiltration and up-regulation of immune checkpoint such as PD-L1 and IDO1. We have developed a 44-gene signature, the DNA damage response deficient (DDRD) assay that can prospectively identify this molecular subtype (Mulligan et al 2014). We now apply this assay to colorectal cancer (CRC) to look for associations with DNA repair deficiency. Methods: We applied the DDRD assay to 72 stage I, 448 stage II, 836 stage III and 90 stage IV CRC patients with gene expression and exome sequencing data from the TCGA, Marisa and PETACC3 datasets (Kucherlapati et al., 2012, Marisa et al., 2012, Bosman et al., 2009). The association between DDRD positivity and MSI (microsatellite instability) status was tested using Chi-squared testing. A further analysis was performed within the TCGA cohort to determine if DDRD positivity is associated to general mutational burden in CRC, including evaluation of mutations in known DNA repair genes. Results: Approximately 35% of CRC were DDRD positive. Consistent with a loss of DNA repair capacity, the mean mutational burden was significantly higher in high DDRD score samples (Spearman’s correlation P = 0.0008). A strong association was found between MSI and DDRD positivity in all datasets (T-test P < 0.001) where around 80% of tumors known to be MSI positive were DDRD positive. Significantly 25% of MSS (microsatellite stable) tumors were DDRD-positive. Gene mutations associated with the MSS DDRD positive group included ATM, ATR, BRCA1/2 and other components of the Fanconi Anemia(FA)/BRCA pathway (P < 0.001 ). Conclusions: The DDRD assay is detected in patients with DNA repair deficiencies, particularly MSI or mutations in components of the FA/BRCA pathway. As this molecular subgroup is defined by an innate immune response and activation of immune checkpoint genes such as PD-L1, we hypothesize that DDRD positive CRC patients may benefit from therapies that specifically target immune biology.