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One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed 10 principles that could be translated to controlling cancers: (i) prevent onset, (ii) monitor continuously, (iii) identify thresholds below which there will be no intervention, (iv) change interventions in response to burden, (v) preferentially select nonchemical control methods, (vi) use target-specific drugs, (vii) use the lowest effective dose, (viii) reduce cross-resistance, (ix) evaluate success based on long-term management, and (x) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design., (©2024 The Authors; Published by the American Association for Cancer Research.)

Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto's paradox) and somatic mutation rate but decreases with gestation time. The relationship between adult mass and malignancy prevalence was only apparent when we controlled for gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%), the black-footed penguin (<0.4%), ferrets (63%), and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer. Significance: Evolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records, we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes., (©2024 The Authors; Published by the American Association for Cancer Research.)

Hershey and colleagues recently showed how clones in a triple-negative breast cancer cell line cooperate for their mutual fitness benefit. In this system, clones exchange soluble metabolites to increase their in vitro growth rate at low population densities, therefore mitigating the documented growth barrier that reduces individual fitness in small tumor cell populations (Allee effect). Such cooperation could aid important transitions in cancer progression in which cancer cell populations are small, like invasion or metastasis. Using orthotopic transplantation, the authors demonstrate that this cooperation is functional in one such transition in vivo, increasing the metastatic load and number of metastases, which are usually polyclonal. Together, these findings highlight the need to consider ecologic interactions to properly understand tumor growth dynamics, and how they complement the standing evolutionary model of cancer progression in our quest to understand and treat cancer., (©2023 American Association for Cancer Research.)

Increasing evidence shows that tumor clonal architectures are often the consequence of a complex branching process, yet little is known about the expected dynamics and extent to which these divergent subclonal expansions occur. Here, we develop and implement more than 88,000 instances of a stochastic evolutionary model simulating genetic drift and neoplastic progression. Under different combinations of population genetic parameter values, including those estimated for colorectal cancer and glioblastoma multiforme, the distribution of sizes of subclones carrying driver mutations had a heavy right tail at the time of tumor detection, with only 1 to 4 dominant clones present at ≥10% frequency. In contrast, the vast majority of subclones were present at <10% frequency, many of which had higher fitness than currently dominant clones. The number of dominant clones (≥10% frequency) in a tumor correlated strongly with the number of subclones (<10% of the tumor). Overall, these subclones were frequently below current standard detection thresholds, frequently harbored treatment-resistant mutations, and were more common in slow-growing tumors. Significance: The model presented in this paper addresses tumor heterogeneity by framing expectations for the number of resistant subclones in a tumor, with implications for future studies of the evolution of therapeutic resistance. Cancer Res; 78(3); 830-9. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Cancer genomic instability contributes to the phenomenon of intratumoral genetic heterogeneity, provides the genetic diversity required for natural selection, and enables the extensive phenotypic diversity that is frequently observed among patients. Genomic instability has previously been associated with poor prognosis. However, we have evidence that for solid tumors of epithelial origin, extreme levels of genomic instability, where more than 75% of the genome is subject to somatic copy number alterations, are associated with a potentially better prognosis compared with intermediate levels under this threshold. This has been observed in clonal subpopulations of larger size, especially when genomic instability is shared among a limited number of clones. We hypothesize that cancers with extreme levels of genomic instability may be teetering on the brink of a threshold where so much of their genome is adversely altered that cells rarely replicate successfully. Another possibility is that tumors with high levels of genomic instability are more immunogenic than other cancers with a less extensive burden of genetic aberrations. Regardless of the exact mechanism, but hinging on our ability to quantify how a tumor's burden of genetic aberrations is distributed among coexisting clones, genomic instability has important therapeutic implications. Herein, we explore the possibility that a high genomic instability could be the basis for a tumor's sensitivity to DNA-damaging therapies. We primarily focus on studies of epithelial-derived solid tumors. Cancer Res; 77(9); 2179-85. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Cancers detected at a late stage are often refractory to treatments and ultimately lethal. Early detection can significantly increase survival probability, but attempts to reduce mortality by early detection have frequently increased overdiagnosis of indolent conditions that do not progress over a lifetime. Study designs that incorporate biomarker trajectories in time and space are needed to distinguish patients who progress to an early cancer from those who follow an indolent course. Esophageal adenocarcinoma is characterized by evolution of punctuated and catastrophic somatic chromosomal alterations and high levels of overall mutations but few recurrently mutated genes aside from TP53. Endoscopic surveillance of Barrett's esophagus for early cancer detection provides an opportunity for assessment of alterations for cancer risk in patients who progress to esophageal adenocarcinoma compared with nonprogressors. We investigated 1,272 longitudinally collected esophageal biopsies in a 248 Barrett's patient case-cohort study with 20,425 person-months of follow-up, including 79 who progressed to early-stage esophageal adenocarcinoma. Cancer progression risk was assessed for total chromosomal alterations, diversity, and chromosomal region-specific alterations measured with single-nucleotide polymorphism arrays in biopsies obtained over esophageal space and time. A model using 29 chromosomal features was developed for cancer risk prediction (area under receiver operator curve, 0.94). The model prediction performance was robust in two independent esophageal adenocarcinoma sets and outperformed TP53 mutation, flow cytometric DNA content, and histopathologic diagnosis of dysplasia. This study offers a strategy to reduce overdiagnosis in Barrett's esophagus and improve early detection of esophageal adenocarcinoma and potentially other cancers characterized by punctuated and catastrophic chromosomal evolution., (©2015 American Association for Cancer Research.)

All cancers are believed to arise by dynamic, stochastic somatic genomic evolution with genome instability, generation of diversity, and selection of genomic alterations that underlie multistage progression to cancer. Advanced esophageal adenocarcinomas have high levels of somatic copy number alterations. Barrett's esophagus is a risk factor for developing esophageal adenocarcinoma, and somatic chromosomal alterations (SCA) are known to occur in Barrett's esophagus. The vast majority (∼95%) of individuals with Barrett's esophagus do not progress to esophageal adenocarcinoma during their lifetimes, but a small subset develop esophageal adenocarcinoma, many of which arise rapidly even in carefully monitored patients without visible endoscopic abnormalities at the index endoscopy. Using a well-designed, longitudinal case-cohort study, we characterized SCA as assessed by single-nucleotide polymorphism arrays over space and time in 79 "progressors" with Barrett's esophagus as they approach the diagnosis of cancer and 169 "nonprogressors" with Barrett's esophagus who did not progress to esophageal adenocarcinoma over more than 20,425 person-months of follow-up. The genomes of nonprogressors typically had small localized deletions involving fragile sites and 9p loss/copy neutral LOH that generate little genetic diversity and remained relatively stable over prolonged follow-up. As progressors approach the diagnosis of cancer, their genomes developed chromosome instability with initial gains and losses, genomic diversity, and selection of SCAs followed by catastrophic genome doublings. Our results support a model of differential disease dynamics in which nonprogressor genomes largely remain stable over prolonged periods, whereas progressor genomes evolve significantly increased SCA and diversity within four years of esophageal adenocarcinoma diagnosis, suggesting a window of opportunity for early detection., (©2013 AACR.)

Here, we apply the theoretical framework of dispersal evolution to understand the emergence of invasive and metastatic cells. We investigate whether the dysregulated metabolism characteristic of cancer cells may play a causal role in selection for cell motility, and thus to the tissue invasion and metastasis that define cancer. With an agent-based computational model, we show that cells with higher metabolism evolve to have higher rates of movement and that "neoplastic" cells with higher metabolism rates are able to persist in a population of "normal" cells with low metabolic rates, but only if increased metabolism is accompanied by increased motility. This is true even when the cost of motility is high. These findings suggest that higher rates of cell metabolism lead to selection for motile cells in premalignant neoplasms, which may preadapt cells for subsequent invasion and metastasis. This has important implications for understanding the progression of cancer from less invasive to more invasive cell types., (©2011 AACR.)

The canonical route from normal tissue to cancer occurs through sequential acquisition of somatic mutations. Many studies have constructed a linear genetic model for tumorigenesis using the genetic alterations associated with samples at different stages of neoplastic progression from cross-sectional data. The common interpretation of these models is that they reflect the temporal order within any given tumor. Linear genetic methods implicitly neglect genetic heterogeneity within a neoplasm; each neoplasm is assumed to consist of one dominant clone. We modeled neoplastic progression of colorectal cancer using an agent-based model of a colon crypt and found clonal heterogeneity within our simulated neoplasms, as observed in vivo. Just 7.3% of cells within neoplasms acquired mutations in the same order as the linear model. In 41% of the simulated neoplasms, no cells acquired mutations in the same order as the linear model. We obtained similarly poor results when comparing the temporal order with oncogenetic tree models inferred from cross-sectional data. However, when we reconstructed the cell lineage of mutations within a neoplasm using several biopsies, we found that 99.7% cells within neoplasms acquired their mutations in an order consistent with the cell lineage mutational order. Thus, we find that using cross-sectional data to infer mutational order is misleading, whereas phylogenetic methods based on sampling intratumor heterogeneity accurately reconstructs the evolutionary history of tumors. In addition, we find evidence that disruption of differentiation is likely the first lesion in progression for most cancers and should be one of the few regularities of neoplastic progression across cancers.

Neoplastic progression is an evolutionary process driven by the generation of clonal diversity and natural selection on that diversity within a neoplasm. We hypothesized that clonal diversity is associated with risk of progression to cancer. We obtained molecular data from a cohort of 239 participants with Barrett's esophagus, including microsatellite shifts and loss of heterozygosity, DNA content tetraploidy and aneuploidy, methylation, and sequence mutations. Using these data, we tested all major diversity measurement methods, including genetic divergence and entropy-based measures, to determine which measures are correlated with risk of progression to esophageal adenocarcinoma. We also tested whether the use of different sets of loci and alterations to define clones (e.g., selectively advantageous versus evolutionarily neutral) improved the predictive value of the diversity indices. All diversity measures were strong and highly significant predictors of progression (Cox proportional hazards model, P < 0.001). The type of alterations evaluated had little effect on the predictive value of most of the diversity measures. In summary, diversity measures are robust predictors of progression to cancer in this cohort., (©2010 AACR.)

Barrett's esophagus (BE) is a premalignant intermediate to esophageal adenocarcinoma, which develops in the context of chronic inflammation and exposure to bile and acid. We asked whether there might be common genomic alterations that could be identified as potential clinical biomarker(s) for BE by whole genome profiling. We detected copy number alterations and/or loss of heterozygosity at 56 fragile sites in 20 patients with premalignant BE. Chromosomal fragile sites are particularly sensitive to DNA breaks and are frequent sites of rearrangement or loss in many human cancers. Seventy-eight percent of all genomic alterations detected by array-CGH were associated with fragile sites. Copy number losses in early BE were observed at particularly high frequency at FRA3B (81%), FRA9A/C (71.4%), FRA5E (52.4%), and FRA 4D (52.4%), and at lower frequencies in other fragile sites, including FRA1K (42.9%), FRAXC (42.9%), FRA 12B (33.3%), and FRA16D (33.3%). Due to the consistency of the region of copy number loss, we were able to verify these results by quantitative PCR, which detected the loss of FRA3B and FRA16D, in 83% and 40% of early molecular stage BE patients, respectively. Loss of heterozygosity in these cases was confirmed through pyrosequencing at FRA3B and FRA16D (75% and 70%, respectively). Deletion and genomic instability at FRA3B and other fragile sites could thus be a biomarker of genetic damage in BE patients and a potential biomarker of cancer risk.

Chromosome copy gain, loss, and loss of heterozygosity (LOH) involving most chromosomes have been reported in many cancers; however, less is known about chromosome instability in premalignant conditions. 17p LOH and DNA content abnormalities have been previously reported to predict progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA). Here, we evaluated genome-wide chromosomal instability in multiple stages of BE and EA in whole biopsies. Forty-two patients were selected to represent different stages of progression from BE to EA. Whole BE or EA biopsies were minced, and aliquots were processed for flow cytometry and genotyped with a paired constitutive control for each patient using 33,423 single nucleotide polymorphisms (SNP). Copy gains, losses, and LOH increased in frequency and size between early- and late-stage BE (P < 0.001), with SNP abnormalities increasing from <2% to >30% in early and late stages, respectively. A set of statistically significant events was unique to either early or late, or both, stages, including previously reported and novel abnormalities. The total number of SNP alterations was highly correlated with DNA content aneuploidy and was sensitive and specific to identify patients with concurrent EA (empirical receiver operating characteristic area under the curve = 0.91). With the exception of 9p LOH, most copy gains, losses, and LOH detected in early stages of BE were smaller than those detected in later stages, and few chromosomal events were common in all stages of progression. Measures of chromosomal instability can be quantified in whole biopsies using SNP-based genotyping and have potential to be an integrated platform for cancer risk stratification in BE.

Background: Defects in DNA damage recognition and repair have been associated with a wide variety of cancers. We conducted a prospective study to determine whether mutagen sensitivity, as determined by an in vitro assay, was associated with the future development of cancer in patients with Barrett's esophagus, which is associated with increased risk of progression to esophageal adenocarcinoma., Methods: We measured sensitivity to bleomycin in peripheral blood lymphocytes in a cohort of 220 patients with Barrett's esophagus. We followed these patients for 1,230 person-years (range, 3 months to 10.1 years; median, 6.4 years), using development of cancer and aneuploidy as end points. A subset of these patients was evaluated for inactivation of tumor-suppressor genes CDKN2A/p16 and TP53 [by mutation and loss of heterozygosity (LOH)] in their Barrett's segments at the time of, or before, the bleomycin test, and the patients were stratified by CDKN2A/p16 and TP53 status in an analysis of mutagen sensitivity and progression., Results: Bleomycin-sensitive patients were found to be at significantly greater risk of developing aneuploidy (adjusted hazard ratio, 3.71; 95% confidence interval, 1.44-9.53) and nonsignificantly greater risk of cancer (adjusted hazard ratio, 1.63; 95% confidence interval, 0.71-3.75). Among patients with detectable LOH at the TP53 locus (on chromosome 17p), increasing bleomycin sensitivity was associated with increased risk of developing cancer (P(trend) < 0.001) and aneuploidy (P(trend) = 0.005)., Conclusions: This study supports the hypothesis that sensitivity to mutagens increases the risk of neoplastic progression in persons with Barrett's esophagus, particularly those with 17p LOH including TP53.

Background and Aims: 17p (TP53) loss of heterozygosity (LOH) has been reported to be predictive of progression from Barrett's esophagus to esophageal adenocarcinoma, but the mechanism by which TP53 LOH develops is unknown. It could be (a) DNA deletion, (b) LOH without copy number change, or (c) tetraploidy followed by genetic loss. If an alternative biomarker assay, such as fluorescence in situ hybridization (FISH), provided equivalent results, then translation to the clinic might be accelerated, because LOH genotyping is presently limited to research centers., Methods: We evaluated mechanisms of TP53 LOH to determine if FISH and TP53 LOH provided equivalent results on the same flow-sorted samples (n = 43) representing established stages of clonal progression (diploid, diploid with TP53 LOH, aneuploid) in 19 esophagectomy specimens., Results: LOH developed by all three mechanisms: 32% had DNA deletions, 32% had no copy number change, and 37% had FISH patterns consistent with a tetraploid intermediate followed by genetic loss. Thus, FISH and LOH are not equivalent (P < 0.000001)., Conclusions: LOH develops by multiple chromosome mechanisms in Barrett's esophagus, all of which can be detected by genotyping. FISH cannot detect LOH without copy number change, and dual-probe FISH is required to detect the complex genetic changes associated with a tetraploid intermediate. Alternative biomarker assay development should be guided by appreciation and evaluation of the biological mechanisms generating the biomarker abnormality to detect potential sources of discordance. FISH will require validation in adequately powered longitudinal studies before implementation as a clinical diagnostic for esophageal adenocarcinoma risk prediction.

There is debate in the literature over the relative importance of genetic instability and clonal expansion during progression to cancer. Barrett's esophagus is a uniquely suited model to investigate neoplastic progression prospectively because periodic endoscopic biopsy surveillance is recommended for early detection of esophageal adenocarcinoma. We hypothesized that expansion of clones with genetic instability would predict progression to esophageal adenocarcinoma. We measured p16 (CDKN2A/INK4A) lesions (loss of heterozygosity, mutations, and CpG island methylation), p53 (TP53) lesions (loss of heterozygosity, mutation) and ploidy abnormalities (aneuploidy, tetraploidy) within each Barrett's esophagus segment of a cohort of 267 research participants, who were followed prospectively with cancer as an outcome. We defined the size of a lesion as the fraction of cells with the lesion multiplied by the length of the Barrett's esophagus segment. A Cox proportional hazards regression indicates that the sizes of clones with p53 loss of heterozygosity (relative risk = 1.27(x) for an x cm clone; 95% confidence interval, 1.07-1.50) or ploidy abnormalities (relative risk = 1.31(x) for an x cm clone; 95% confidence interval, 1.07-1.60) predict progression to esophageal adenocarcinoma better than the mere presence of such clones (likelihood ratio test, P < 0.01). Controlling for length of the Barrett's esophagus segment had little effect. The size of a clone with a p16 lesion is not a significant predictor of esophageal adenocarcinoma when we controlled for p53 loss of heterozygosity status. The combination of clonal expansion and genetic instability is a better predictor of cancer outcome than either alone. This implies that interventions that limit expansion of genetically unstable clones may reduce risk of progression to cancer.

Cells in neoplasms evolve by natural selection. Traditional cytotoxic chemotherapies add further selection pressure to the evolution of neoplastic cells, thereby selecting for cells resistant to the therapies. An alternative proposal is a benign cell booster. Rather than trying to kill the highly dysplastic or malignant cells directly, a benign cell booster increases the fitness of the more benign cells, which may be either normal or benign clones, so that they may outcompete more advanced or malignant cells in a neoplasm. In silico simulations of benign cell boosters in neoplasms with evolving clones show benign cell boosters to be effective at destroying advanced or malignant cells and preventing relapse even when applied late in progression. These results are conditional on the benign cell boosters giving a competitive advantage to the benign cells in the neoplasm. Furthermore, the benign cell boosters must be applied over a long period of time in order for the benign cells to drive the dysplastic cells to extinction or near extinction. Most importantly, benign cell boosters based on this strategy must target a characteristic of the benign cells that is causally related to the benign state to avoid relapse. Another promising strategy is to boost cells that are sensitive to a cytotoxin, thereby selecting for chemosensitive cells, and then apply the toxin. Effective therapeutic and prevention strategies will have to alter the competitive dynamics of a neoplasm to counter progression toward invasion, metastasis, and death.

Neoplastic progression is an evolutionary process characterized by genomic instability and waves of clonal expansions carrying genetic and epigenetic lesions to fixation (100% of the cell population). However, an evolutionarily neutral lesion may also reach fixation if it spreads as a hitchhiker on a selective sweep. We sought to distinguish advantageous lesions from hitchhikers in the premalignant condition Barrett's esophagus. Patients (211) had biopsies taken at 2-cm intervals in their Barrett's segments. Purified epithelial cells were assayed for loss of heterozygosity and microsatellite shifts on chromosomes 9 and 17, sequence mutations in CDKN2A/MTS1/INK4a (p16) and TP53 (p53), and methylation of the p16 promoter. We measured the expanse of a lesion in a Barrett's segment as the proportion of proliferating cells that carried a lesion in that locus. We then selected the lesion having expanses >90% in the greatest number of patients as our first putative advantageous lesion. We filtered out hitchhikers by removing all expanses of other lesions that did not occur independent of the advantageous lesion. The entire process was repeated on the remaining expanses to identify additional advantageous lesions. p16 loss of heterozygosity, promoter methylation, and sequence mutations have strong, independent, advantageous effects on Barrett's cells early in progression. Second lesions in p16 and p53 are associated with later selective sweeps. Virtually all of the other lesion expansions, including microsatellite shifts, could be explained as hitchhikers on p16 lesion clonal expansions. These techniques can be applied to any neoplasm.