A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage

Mutational signatures are imprints of pathophysiological processes arising through tumorigenesis. We generated isogenic CRISPR-Cas9 knockouts (Δ) of 43 genes in human induced pluripotent stem cells, cultured them in the absence of added DNA damage, and performed whole-genome sequencing of 173 subclones. ΔOGG1, ΔUNG, ΔEXO1, ΔRNF168, ΔMLH1, ΔMSH2, ΔMSH6, ΔPMS1, and ΔPMS2 produced marked mutational signatures indicative of being critical mitigators of endogenous DNA modifications. Detailed analyses revealed mutational mechanistic insights, including how 8-oxo-dG elimination is sequence-context-specific while uracil clearance is sequence-context-independent. Mismatch repair (MMR) deficiency signatures are engendered by oxidative damage (C>A transversions), differential misincorporation by replicative polymerases (T>C and C>T transitions), and we propose a 'reverse template slippage' model for T>A transversions. ΔMLH1, ΔMSH6, and ΔMSH2 signatures were similar to each other but distinct from ΔPMS2. Finally, we developed a classifier, MMRDetect, where application to 7,695 WGS cancers showed enhanced detection of MMR-deficient tumors, with implications for responsiveness to immunotherapies

The management of complicated colorectal cancer in older patients in a global perspective after COVID-19: the CO-OLDER WSES project

BACKGROUND: Colorectal (CRC) cancer is becoming a disease of the elderly. Ageing is the most significant risk factor for presenting CRC. Early diagnosis of CRC and management is the best way in achieving good outcomes and longer survival but patients aged ≥75 years are usually not screened for CRC. This group of patients is often required to be managed when they are symptomatic in the emergency setting with high morbidity and mortality rates. Our main aim is to provide clinical data about the management of elderly patients presenting complicated colorectal cancer who required emergency surgical management to improve their care. METHODS: The management of complicated COlorectal cancer in OLDER patients (CO-OLDER; ClinicalTrials.gov ID: NCT05788224; evaluated by the local ethical committee CPP EST III-France with the national number 2023-A01094-41) in the emergency setting project provides carrying out an observational multicenter international cohort study aimed to collect data about patients aged ≥75 years to assess modifiable risk factors for negative outcomes and mortality correlated to the emergency surgical management of this group of patients at risk admitted with a complicated (obstructed and perforated) CRC. The CO-OLDER protocol was approved by Institutional Review Board and released. Each CO-OLDER collaborator is asked to enroll ≥25 patients over a study period from 1st January 2018 to 30th October 2023. Data will be analyzed comparing two periods of study: before and after the COVID-19 pandemic. A sample size of 240 prospectively enrolled patients with obstructed colorectal cancer in a 5-month period was calculated. The secured database for entering anonymized data will be available for the period necessary to achieve the highest possible participation. RESULTS: One hundred eighty hospitals asked to be a CO-OLDER collaborator, with 36 potentially involved countries over the world. CONCLUSIONS: The CO-OLDER project aims to improve the management of elderly people presenting with a complicated colorectal cancer in the emergency setting. Our observational global study can provide valuable data on the effectiveness of different management strategies in improving primary assessment, management and outcomes for elderly patients with obstructed or perforated colorectal cancer in the emergency setting, guiding clinical decision-making. This information can help healthcare providers make informed decisions about the best course of action for these patients