Editors’ Selections from Relevant Scientific Publications

Immune Response Pathways in FAP during cancer formation (by Esplin et al. via Nat Cancer)Multi-omic analysis of colon tissue specimens from people with familial adenomatous polyposis (FAP) has identified pathways that can potentially be targeted to prevent colorectal cancer (CRC). Individuals with FAP are near-certain to develop CRC. Esplin and colleagues performed extensive molecular analysis of healthy mucosa, benign polyps, and dysplastic polyps from six donors with FAP. These experiments revealed extensive metabolic, immunological, and other changes that contribute to precancer formation and progression to malignancy. For example, production of the pro-inflammatory lipid arachidonic acid was notably increased in polyp-forming mucosa, consistent with clinical data showing that non-steroidal anti-inflammatory drugs can help prevent tumorigenesis in FAP. While tumors from non-FAP-related CRC may differ in important ways, the authors believe that some mechanisms identified in this study could offer generalizable targets for preventing these malignancies.Esplin ED, … Snyder MP. Nat Cancer. 2024 Nov;5(11):1737–1753.Human lung cells (by E.P. Ewing/Centers for Disease Control and Prevention via Picryl)A recent study demonstrated that aging suppresses lung cancer initiation and progression by impairing the stemness of the originating alveolar cell. By inducing the expression of oncogenic KrasG12D and deletion of Tp53 in lung alveolar type 2 (AT2) stem cells in physiologically aged mice, Zhuang and colleagues showed that aging reduced tumorigenesis and delayed lung tumor progression, which was linked to an age-related decline in AT2 cell stemness. Further investigation revealed that ageing-associated DNA hypomethylation at specific enhancer sites increased expression of Nupr1 and its downstream target Lcn2, resulting in iron insufficiency and resistance to ferroptosis. Genetic inactivation of Nupr1 or iron supplementation restored the stemness and tumorigenic potential of aged AT2 cells. These findings suggest a role for cellular iron homeostasis in cancer development and highlight the importance of directing cancer prevention efforts to young individuals when stem cells are most susceptible to transformation.Zhuang X, … Tammela T. Nature. 2024 Dec 4.Fetus (by Raman Oza via Wikimedia Commons)The circulating cell-free DNA (cfDNA) tests used to detect chromosomal abnormalities during fetal development can also offer early warning of cancer. However, recognizing which results are associated with malignancy remains a challenge. Turriff and colleagues set out to answer this question by performing cancer screening in 107 pregnant people with irregular cfDNA findings. They subsequently made a cancer diagnosis in 52 study participants; 29 of these cases were asymptomatic, and another 13 experienced symptoms that they initially attributed to pregnancy. Notably, 92.2% of these cancer cases were linked with cfDNA tests revealing gains or losses in the copy number of multiple chromosomes or chromosome segments. These results suggest that pregnant people receiving such cfDNA results should undergo whole-body magnetic resonance imaging (MRI) as a follow-up diagnostic step.Turriff AE, … Bianchi DW. N Engl J Med. 2024;391:2123–2132.Prostate cancer (by Mikael Häggström via Wikimedia Commons)A new study investigated the predictive relationship between a multi-ancestry polygenic risk score (PRS) and the risk of developing or upgrading prostate cancer (PCa) in patients under active surveillance. In a prospective study of 1,220 patients, Goss and colleagues found that 470 patients upgraded at a rate of 17.7% over 2 years and 33.3% over 5 years. Each 1-standard deviation unit increase in the risk variants PRS-451 were associated with a 23% increase and risk variants PRS-400 were associated with a 27% increased hazard risk of upgrading at any point in time during follow-up. Associations with other outcomes were similar or stronger for PRS-400, except for prostate specific antigen (PSA) measurements. Higher PRS-400 scores were associated with smaller prostate volume, a higher percentage of biopsies with confirmed cancer, and higher PSA density. Overall, these findings indicate that PRS could inform surveillance strategies for patients with low-risk PCa, potentially reducing the burden of active surveillance for those with a lower risk of upgrading.Goss LB, … Darst BF. JAMA Oncol. 2024 Dec 12.