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In a cohort at average risk for colorectal cancer, a cell-free DNA blood-based test had 83% sensitivity for colorectal cancer, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions.

Introduction Advances in our understanding of the molecular genetics and epigenetics of colorectal cancer have led to novel insights into the pathogenesis of this common cancer. These advances have revealed that there are molecular subtypes of colon polyps and colon cancer and that these molecular subclasses have unique and discrete clinical and pathological features. Although the molecular characterization of these subgroups of colorectal polyps and cancer is only partially understood at this time, it does appear likely that classifying colon polyps and cancers based on their genomic instability and/or epigenomic instability status will eventually be useful for informing approaches for the prevention and early detection of colon polyps and colorectal cancer. Conclusions In this review, we will discuss our current understanding of the molecular pathogenesis of the polyp to cancer sequence and the potential to use this information to direct screening and prevention programs.

ObjectiveMutations in cell-free circulating DNA (cfDNA) have been studied for tracking disease relapse in colorectal cancer (CRC). This approach requires personalised assay design due to the lack of universally mutated genes. In contrast, early methylation alterations are restricted to defined genomic loci allowing comprehensive assay design for population studies. Our objective was to identify cancer-specific methylated biomarkers which could be measured longitudinally in cfDNA (liquid biopsy) to monitor therapeutic outcome in patients with metastatic CRC (mCRC).DesignGenome-wide methylation microarrays of CRC cell lines (n=149) identified five cancer-specific methylated loci (EYA4, GRIA4, ITGA4, MAP3K14-AS1, MSC). Digital PCR assays were employed to measure methylation of these genes in tumour tissue DNA (n=82) and cfDNA from patients with mCRC (n=182). Plasma longitudinal assessment was performed in a patient subset treated with chemotherapy or targeted therapy.ResultsMethylation in at least one marker was detected in all tumour tissue samples and in 156 mCRC patient cfDNA samples (85.7%). Plasma marker prevalence was 71.4% for EYA4, 68.5% for GRIA4, 69.7% for ITGA4, 69.1% for MAP3K14-AS1% and 65.1% for MSC. Dynamics of methylation markers was not affected by treatment type and correlated with objective tumour response and progression-free survival.ConclusionThis five-gene methylation panel can be used to circumvent the absence of patient-specific mutations for monitoring tumour burden dynamics in liquid biopsy under different therapeutic regimens. This method might be proposed for assessing pharmacodynamics in clinical trials or when conventional imaging has limitations.

The risk of colorectal cancer (CRC) varies between people, and the cellular mechanisms mediating the differences in risk are largely unknown. Senescence has been implicated as a causative cellular mechanism for many diseases, including cancer, and may affect the risk for CRC. Senescent fibroblasts that accumulate in tissues secondary to aging and oxidative stress have been shown to promote cancer formation via a senescence‐associated secretory phenotype (SASP). In this study, we assessed the role of senescence and the SASP in CRC formation. Using primary human colon tissue, we found an accumulation of senescent fibroblasts in normal tissues from individuals with advanced adenomas or carcinomas in comparison with individuals with no polyps or CRC. In in vitro and ex vivo model systems, we induced senescence using oxidative stress in colon fibroblasts and demonstrated that the senescent fibroblasts secrete GDF15 as an essential SASP factor that promotes cell proliferation, migration, and invasion in colon adenoma and CRC cell lines as well as primary colon organoids via the MAPK and PI3K signaling pathways. In addition, we observed increased mRNA expression of GDF15 in primary normal colon tissue from people at increased risk for CRC in comparison with average risk individuals. These findings implicate the importance of a senescence‐associated tissue microenvironment and the secretory factor GDF15 in promoting CRC formation. The accumulation of senescent fibroblasts in colon tissue secrete GDF‐15 as a driver SASP factor that promotes cell proliferation in normal colon cells as well as migration and invasion in adenoma and cancer cell lines, thus creating a pro‐tumorigenic microenvironment.

Colorectal cancer had a low incidence several decades ago. However, it has become a predominant cancer and now accounts for approximately 10% of cancer-related mortality in western countries. The ‘rise’ of colorectal cancer in developed countries can be attributed to the increasingly ageing population, unfavourable modern dietary habits and an increase in risk factors, such as smoking, low physical exercise and obesity. New treatments for primary and metastatic colorectal cancer have emerged, providing additional options for patients; these treatments include laparoscopic surgery for primary disease, more-aggressive resection of metastatic disease (such as liver and pulmonary metastases), radiotherapy for rectal cancer, and neoadjuvant and palliative chemotherapies. However, these new treatment options have had limited impact on cure rates and long-term survival. For these reasons, and the recognition that colorectal cancer is long preceded by a polypoid precursor, screening programmes have gained momentum. This Primer provides an overview of the current state of the art of knowledge on the epidemiology and mechanisms of colorectal cancer, as well as on diagnosis and treatment. Colorectal cancer is a common cancer globally; its increased incidence over the past 60 years is associated with red meat consumption, smoking, alcohol intake and an ageing population. Here, Kuipers et al . describe the biology and treatment of colorectal cancers, and discuss the impact that screening will have on outcomes.

A hypermutated subtype of advanced prostate cancer was recently described, but prevalence and mechanisms have not been well-characterized. Here we find that 12% (7 of 60) of advanced prostate cancers are hypermutated, and that all hypermutated cancers have mismatch repair gene mutations and microsatellite instability (MSI). Mutations are frequently complex MSH2 or MSH6 structural rearrangements rather than MLH1 epigenetic silencing. Our findings identify parallels and differences in the mechanisms of hypermutation in prostate cancer compared with other MSI-associated cancers. Several patients with metastatic prostate cancer have been shown to harbour tumours with markedly high mutation rates. Here, the authors characterise hypermutation in advanced prostate cancer samples and show that these samples have somatic mismatch repair gene mutations and microsatellite instability.

In randomized trial involving 171 adults with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with combination therapy with eflornithine (an inhibitor of ornithine decarboxylase) and sulindac (an NSAID) than with either drug alone.

The gut microbiome is implicated in the pathogenesis of colorectal cancer (CRC), but the full scope of this dialogue is unknown. Here we aimed to define the scale and membership of the body of CRC- and health-associated gut bacteria in global populations. We performed a microbiome-CRC correlation analysis of published ultra-deep shotgun metagenomic sequencing data from global microbiome surveys, utilizing a de novo (reference-agnostic) gene-level clustering approach to identify protein-coding co-abundant gene (CAGs) clusters. We link an unprecedented ~ 23–40% of gut bacteria to CRC or health, split nearly evenly as CRC- or health-associated. These microbes encode 2319 CAGs encompassing 427,261 bacterial genes significantly enriched or depleted in CRC. We identified many microbes that had not previously been linked to CRC, thus expanding the scope of “known unknowns” of CRC-associated microbes. We performed an agnostic CAG-based screen of bacterial isolates and validated predicted effects of previously unimplicated bacteria in preclinical models, in which we observed differential induction of precancerous adenomas and field effects. Single-cell RNA sequencing disclosed microbiome-induced senescence-associated gene expression signatures in discrete colonic populations including fibroblasts. In organoid co-cultures, primary colon fibroblasts from mice with microbiomes promoted significantly greater growth than fibroblasts from microbiome-depleted mice. These results offer proof-of-principle for gene-level metagenomic analysis enabling discovery of microbiome links to health and demonstrate that the microbiome can drive precancer states, thereby potentially revealing novel cancer prevention opportunities.

Current cancer screening methods are effective for detecting early stage cancers and even preventing some cancers, but their effectiveness has only been demonstrated for a handful of cancers, and for many cancers, there are no screening tests clinically available. In addition, the majority of the screening methods are not ideal, resulting in suboptimal compliance and the occurrence of preventable cancers. A screening test that is convenient, safe, accurate and that can screen for multiple cancers is an ideal screening test that would address many of the shortcomings of the current tests. Multi-cancer detection tests (MCD) have the potential to meet these challenges and have engendered substantial enthusiasm in light of this. Using advances in DNA sequencing technology, cancer epigenetics and artificial intelligence, they are able to detect a large number of cancers predominantly via the patterns of methylated DNA alterations, DNA sequence alterations, and DNA fragment patterns of cell free DNA in the plasma and can accurately distinguish the cancer site of origin. Of note, some of the tests also combine circulating free DNA (cfDNA) with protein-based markers. However, for the majority of early stage cancers, the sensitivity is modest and below that of most of the current standard of care cancer screening tests. Furthermore, the clinical utility of screening for many of the cancers detectable by MCD tests remains to be proven. Here we describe the features of MCD tests, review the current data supporting their potential to be used in the clinic for cancer screening, and discuss the knowledge gaps surrounding understanding their clinical utility, with a focus on GI cancer screening.

Computational modeling of somatic evolution, a process shaped by ecology and impacting both host cells and microbial communities in the human body, can capture important dynamics driving carcinogenesis. Here we considered models for esophageal adenocarcinoma (EAC), a cancer that has dramatically increased in incidence over the past few decades in Western populations, with high case fatality rates due to late-stage diagnoses. Despite advancements in genomic analyses of the precursor Barrett’s esophagus (BE), prevention of late-stage EAC remains a significant clinical challenge. Previous microbiome studies in BE/EAC have focused on quantifying static microbial abundance differences rather than determining population dynamics. Using whole genome sequencing data from a total of 505 esophageal samples, we first applied a robust bioinformatics pipeline to extract non-host DNA reads, mapped these putative reads to microbial taxa, and retained those taxa with high genomic coverage. When applying mathematical models of demographic stochasticity to sequential stages of progression to EAC, we observed evidence of neutral dynamics in community assembly within normal esophageal tissue and BE, but not EAC. In a large case–control study of BE patients who progressed to EAC versus BE patients with non-cancer outcomes (NCO) during follow-up (mean = 10.5 years), we found that Helicobacter pylori deviated significantly from the neutral expectation in BE NCO only, suggesting that factors related to H. pylori or H. pylori infection itself may influence EAC risk. Additionally, stochastic simulations incorporating selection recapitulated non-neutral behaviors observed. Formally modeling dynamics during progression holds promise in clinical applications by offering a deeper understanding of microbial involvement in cancer development.