Prevalence of germline <i>MSH3</i> polymorphisms in ulcerative colitis and early-onset colorectal cancer patients that potentiates inflammation-to-cancer transformation

The DNA mismatch repair protein MSH3 reversibly shifts from nucleus to the cytosol upon IL-6 signaling, abrogating the repair function of the MSH3-MSH2 heterodimer in the nucleus and increases aggressiveness and metastasis potential of colorectal cancers. A polymorphism proximate to MSH3's nuclear localization signal (NLS), Δ27bpMSH3, alters NLS function such that IL-6 triggers Δ27bpMSH3 accumulation in the cytosol. Public databases indicate Δ27bpMSH3 is rare in the germline yet we previously identified its presence in half of colon cancer cell lines tested and 19% of ulcerative colitis (UC) tissue samples. Here in examining ~ 200 each of UC, early-onset (eo)CRC, and late-onset (lo)CRC patients, biallelic MSH3 NLS germline polymorphisms were exclusively present in 15% of controls but in 18% of UC and 17% of eoCRC patients and were higher among CRC stage 3/4 patients compared to stage 2 patients; these marginal increases could potentiate inflammation-to-cancer transformation and/or metastatic disease. Using cell models we demonstrate IL-6-induced binding of wild type and Δ27bpMSH3 to the NFκB activating complex NEMO/IKKγ which stabilizes MSH3 after disengaging from its nuclear partner MSH2, linking inflammation with DNA repair protein stability. Additional NLS modifications using MSH3-FLAG mimics cytosolic Δ27bpMSH3 retention to cause loss-of-function after inflammation.