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The development and progression of early-stage lung adenocarcinoma (LUAD) is associated with marked alterations in the surrounding tissue, including changes in seemingly healthy cells. Sinjab et al. used single-cell RNA-seq to analyze five LUAD specimens as well as histologically normal cells from 14 specific locations relative to those tumors, generating detailed molecular maps of the tumor microenvironment. They observe considerable intratumoral heterogeneity, with LUAD specimens harboring normal cells and malignancy-associated alterations observed within non-tumor sites, providing new insights into tumor evolution. These profiles also showed how the immunological environment surrounding LUAD facilitates progression, revealing potential opportunities to develop optimized interventions for early-stage disease.

Sinjab A, … Kadara H. Cancer Discov. 2021 Oct;11:2506–23.

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The metaplastic condition known as Barrett's esophagus (BE) has been identified as a potential precursor to esophageal adenocarcinoma (EAC), but it remains unclear whether this is a necessary step in EAC pathogenesis. To resolve this, researchers must determine which cell populations give rise to BE, and Nowicki-Osuch et al. have now identified these progenitors through extensive single-cell analysis of healthy and diseased donor tissue. They found that BE arises in the cardia, the stomach tissue adjacent to the gastroesophageal junction, and that the cells that develop BE are also the likely starting point for EAC—highlighting a common point of origin that could be targeted for early diagnosis or treatment.

Nowicki-Osuch K, … Fitzgerald RC. Science. 2021 Aug 13;373:760–7.

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New technologies have been developed to analyze tumor-derived cell free DNA in (cfDNA) in liquid biopsies. In one study, Mathios et al. utilized machine learning to examine blood samples from 365 individuals (symptomatic patients at high risk for lung cancer and asymptomatic subjects with a completed imaging procedure) plus an independent validation cohort (46 lung cancer patients and 385 non-cancer subjects). The samples were used to produce cfDNA fragmentation profiles, then compared to individual clinical outcomes. These “fragmentomes” could be used to prescreen for lung cancer and reduce unnecessary or invasive procedures, which could potentially improve lung cancer screening practices, particularly in populations considered low risk for lung cancer. In another study, Siejka-Zielińska et al. developed a breakthrough TET-assisted pyridine borane sequencing (TAPS) technique to characterize epigenetic and genetic information of cfDNA. The investigators used the TAPS technique to analyze cfDNA from 85 hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) samples along with noncancer controls. Multimodal genetic and epigenetic profiles were generated from only 10 ng of cfDNA, including copy number variations, DNA methylation patterns, tissue of origin, and DNA fragmentation. Further research into this technique will improve noninvasive methods for early detection of PDAC and HCC.

Mathios D, … Velculescu VE. Nat Commun. 2021 Aug 20;12:5060.

Siejka-Zielińska P, … Song CX. Sci Adv. 2021 Sep 3;7:eabh0534.

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Screening for prostate cancer using a combination of methods could produce more accurate results than one method alone. The widely-used prostate specific antigen (PSA) test effectively detects early signs of prostate cancer and is associated with better outcomes, but is prone to false positives and can result in unnecessary treatments. Nordström et al. collected data from men thought to be at risk of prostate cancer as determined by the PSA test or a new screening test, Stockholm3, which combines plasma protein measurements with clinical information and a genetic test. The researchers randomly assigned one group of men to receive either systematic prostate biopsies or biparametric MRI followed by MRI-targeted and systematic biopsy in MRI-positive men. The Stockholm3 test resulted in 36% fewer MRIs and 8% fewer biopsies than the PSA-based screening. Combining the Stockholm3 test and an MRI-targeted biopsy approach reduced the rate of false diagnoses by 69%, while as sensitive as the traditional PSA-based diagnostic strategy in detecting clinically significant prostate cancer.

Nordström T, … STHLM3 study group. Lancet Oncol. 2021 Sep;22:1240–9.

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A mouse study shows that a vaccine derived from mutant proteins can prevent certain tumors caused by genetic mutations. Tumors associated with Lynch syndrome occur because of mismatch repair deficiencies and microsatellite instability, which leads to the accumulation of frameshift DNA mutations and creation of specific, nonfunctional peptide neoantigens. Gebert et al. used computational analysis of the mouse genome to identify places where such frameshift mutations frequently occur. The researchers isolated four shared frameshift peptides that were able to trigger the immune system into attacking tumor cells, made a vaccine from these peptides, and injected it into a mouse model of Lynch syndrome. The vaccine reduced intestinal tumors and prolonged the animals' lives, suggesting that neoantigen vaccination could be a promising avenue for immunoprevention of intestinal tumors in patients with Lynch Syndrome.

Gebert J, … Kloor M. Gastroenterology. 2021 Oct;161:1288–302.e13.