Co-occurring mutations in the POLE exonuclease and non-exonuclease domains define a unique subset of highly mutagenic tumors

SomaticPOLEmutations in the exonuclease domain (ExoD) are prevalent in colorectal cancer (CRC), endometrial cancer (EC), and others and typically lead to dramatically increased tumor mutation burden (TMB). To understand whether non-ExoD mutations also play a role in mutagenesis, we assessed TMB in 447/14541POLE-mutated CRCs, ECs, and ovarian cancers (OC) based on classification TMB-High (TMB-H) or TMB-Low (TMB-L). TMB-H tumors were segregated as ‘POLEExoD driver’, ‘POLEExoD driver plusPOLEVariant’, and ‘POLEVariant TMB-H’. Intriguingly, TMB was highest in tumors bearing ‘POLEExoD driver plusPOLEVariant’ (pPOLEvariants categorize a unique subset ofPOLE-driven tumors defined by ultra-high TMB, which has implications for abundance of tumor neoantigens, therapeutic response, and patient outcomes.SignificanceSomaticPOLEExoD driver mutations cause proofreading deficiency that induces high tumor mutation burden (TMB). This study defines a novel modifier role for non-ExoD mutations inPOLEExoD-driven tumors, associated with ultra-high TMB. These data may inform acquisition of tumor neoantigens, tumor classification, therapeutic response, and patient outcomes.