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DeGregori: Cells with cancer-associated mutations take over our normal tissues as we age #CancerEvoEco24

DeGregori: We should stop calling these mutations that show up with age "oncogenic" #CancerEvoEco24

DeGregori: Working with TraceRx, looking at samples from lobe that doesn't have cancer. Duplex sequence to 10K-20K depth in a 30 gene panel. #CancerEvoEco24

DeGregori: Also have samples from autopsies (PEACE study) and sample from patients with false positive that triggered a broncoscopy #CancerEvoEco24

DeGregori: Analyzed mutations relative to smoking status (never, former, current). See more selection for mutations (in the cancer gene panel) in smokers than never smokers #CancerEvoEco24

DeGregori: See clear selection for KRAS and EGFR mutations in this normal tissue. But most of the specific point mutations are not the ones seen in lung cancers #CancerEvoEco24

DeGregori: Particularly in the never smokers, saw mutations in KRAS and EGFR, but not the ones that show up in the cancers #CancerEvoEco24

DeGregori: The mutations that promote clonal expansion are not the mutations observed in cancer (even if you only look at COSMIC annotated mutations) #CancerEvoEco24

DeGregori: A mutation can be adaptive in a normal tissue but not contribute to malignancies (as was seen in a lot of other studies of normal tissues) #CancerEvoEco24

DeGregori: Faiz Jabbar combined dN/dS with variant allele frequency as both signals of selection. TP53, Notch1, NF1, and ERBB4 were the top selected genes in the normal lung tissue - in smokers #CancerEvoEco24

DeGregori: Smokers have a higher fraction of lung tissue (9%) occupied by the mutations in the panel gene, compared to the never smokers (2%) #CancerEvoEco24

DeGregori: Got up to 30 different small pieces of lung tissue from the PEACE autopsies. Saw different mutations in the same gene in different locations within the same individual. #CancerEvoEco24

DeGregori: Saw patient specific mutations in particular genes (may be due to individual differences in tissue level selection or to exposures) #CancerEvoEco24

DeGregori: Can treat mice with cigarette smoke (used CRISPR to inactivate particular genes in a few cells). Smoking increased the frequency of the mutant clones. Looks like knocking out NF1 led to more progenitor cells (though not sure if they are protenitors yet) #CancerEvoEco24

DeGregori: Some evidence that clones with NF1 mutation make the lung more permeable to carcinogens #CancerEvoEco24

DeGregori: Age and smoking perturb tissue leading to harmful clonal expansions that further perturb the tissue... vicious cycle #CancerEvoEco24

DeGregori: This is not just a problem for cancers, but for many other disease as well #CancerEvoEco24

I'm going to try to migrate to Bluesky as much as possible. Please follow me there at Carlo Maley.bsky.social

We are excited to announce that a 10 year project to gather and analyze veterinary necropsy data to discover cancer prevalence across (292) vertebrate species has finally been published open access in Cancer Discovery @aacr bit.ly/40nCqmH #componc #cancer

We just published a review of lessons farmers have learned for how to control pesticide resistance from evolving, and how to apply those to oncology to prevent cancers from evolving therapeutic resistance: bit.ly/48OfFdX