Biomedical subjects

Carlo C Maley

Publications and source records attributed to Carlo C Maley.

14 recordsLinked to original sources

PubMed2025

Applying multilevel selection to understand cancer evolution and progression.

Natural selection occurs at multiple levels of organization in cancer. At an organismal level, natural selection has led to the evolution of diverse tumor suppression mechanisms, while at a cellular level, it favors traits that promote cellular proliferation, survival and cancer. Natural selection also occurs at a subcellular level, among collections of cells and even among collections of organisms; selection at these levels could influence the evolution of cancer and cancer suppression mechanisms, affecting cancer risk and treatment strategies. There may also be cancer-like processes happening at different levels of organization, in which uncontrolled proliferation at lower levels may disrupt a higher level of organization. This Essay examines how selection operates across levels, highlighting how we might leverage this understanding to improve cancer research, prevention and treatment.

Animals↗

PubMed2006

Cancer as an evolutionary and ecological process.

Neoplasms are microcosms of evolution. Within a neoplasm, a mosaic of mutant cells compete for space and resources, evade predation by the immune system and can even cooperate to disperse and colonize new organs. The evolution of neoplastic cells explains both why we get cancer and why it has been so difficult to cure. The tools of evolutionary biology and ecology are providing new insights into neoplastic progression and the clinical control of cancer.

Animals↗

PubMed2006

Progress in chemoprevention drug development: the promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer--a plan to move forward.

This article reviews progress in chemopreventive drug development, especially data and concepts that are new since the 2002 AACR report on treatment and prevention of intraepithelial neoplasia. Molecular biomarker expressions involved in mechanisms of carcinogenesis and genetic progression models of intraepithelial neoplasia are discussed and analyzed for how they can inform mechanism-based, molecularly targeted drug development as well as risk stratification, cohort selection, and end-point selection for clinical trials. We outline the concept of augmenting the risk, mechanistic, and disease data from histopathologic intraepithelial neoplasia assessments with molecular biomarker data. Updates of work in 10 clinical target organ sites include new data on molecular progression, significant completed trials, new agents of interest, and promising directions for future clinical studies. This overview concludes with strategies for accelerating chemopreventive drug development, such as integrating the best science into chemopreventive strategies and regulatory policy, providing incentives for industry to accelerate preventive drugs, fostering multisector cooperation in sharing clinical samples and data, and creating public-private partnerships to foster new regulatory policies and public education.

Biomarkers, Tumor↗

PubMed2006

Multistage carcinogenesis in Barrett's esophagus.

The multistage carcinogenesis of esophageal adenocarcinoma is a process of clonal evolution within Barrett's esophagus neoplasms. The initiating event for Barrett's esophagus is unknown, but is associated with chronic gastric reflux which probably also promotes progression. Inactivation of both alleles of CDKN2A appear to be early events causing clonal expansion. Clones with TP53 inactivated expand if they have already inactivated CDKN2A. After TP53 has been inactivated, tetraploid and aneuploid clones tend to develop. The final events that lead to invasion and metastasis are unknown. Evolutionary biology provides important tools to understand clonal evolution in progression and cancer prevention.

Barrett Esophagus↗

PubMed2006

Genetic clonal diversity predicts progression to esophageal adenocarcinoma.

Neoplasms are thought to progress to cancer through genetic instability generating cellular diversity and clonal expansions driven by selection for mutations in cancer genes. Despite advances in the study of molecular biology of cancer genes, relatively little is known about evolutionary mechanisms that drive neoplastic progression. It is unknown, for example, which may be more predictive of future progression of a neoplasm: genetic homogenization of the neoplasm, possibly caused by a clonal expansion, or the accumulation of clonal diversity. Here, in a prospective study, we show that clonal diversity measures adapted from ecology and evolution can predict progression to adenocarcinoma in the premalignant condition known as Barrett's esophagus, even when controlling for established genetic risk factors, including lesions in TP53 (p53; ref. 6) and ploidy abnormalities. Progression to cancer through accumulation of clonal diversity, on which natural selection acts, may be a fundamental principle of neoplasia with important clinical implications.

Adenocarcinoma↗

PubMed2006

Genetic mechanisms of TP53 loss of heterozygosity in Barrett's esophagus: implications for biomarker validation.

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.

Adenocarcinoma↗

PubMed2006

Mutagen sensitivity and neoplastic progression in patients with Barrett's esophagus: a prospective analysis.

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.

Adenocarcinoma↗

PubMed2006

Barrett's esophagus and its progression to adenocarcinoma.

Barrett's esophagus (BE) is the only known precursor for esophageal adenocarcinoma (EA). Therefore, the presence of BE identifies a high-risk group of patients who may be followed-up for early detection of EA and treated to reduce the risk for its progression. The initiating event for BE is unknown, although it is associated with chronic gastric reflux. Many of the genetic lesions involved in BE neoplastic progression are known, including loss of CDKN2A (p16) and TP53 (p53) and the development of tetraploidy and aneuploidy. Intensive endoscopic surveillance has been shown to improve survival although it can be difficult to implement in practice. Several exposures may be altered to reduce the risk for progression, including weight, diet, and the use of nonsteroidal anti-inflammatory drugs. However, most of these results should be confirmed in additional cohorts before they are used to change clinical practice.

Adenocarcinoma↗

PubMed2005

Natural selection in neoplastic progression of Barrett's esophagus.

Neoplasms progress to cancer through a process of natural selection. The rate of evolution, and thus progression is determined by three parameters: mutation rate, population size of the evolving neoplastic cells, and intensity of selection or rate of clonal expansion. All three parameters are reviewed in the context of Barrett's esophagus, a pre-malignant neoplasm. Although Barrett's esophagus is an ideal model for the study of neoplastic clonal evolution, similar studies may be carried out in a wide variety of human neoplasms. Evolutionary analyses provide insights for clinical management, including rates of progression to cancer and emergence of resistance to interventions.

Barrett Esophagus↗

PubMed2005

Biologic properties of columnar epithelium underneath reepithelialized squamous mucosa in Barrett's esophagus.

Chronic proton pump inhibitor (PPI) therapy may lead to partial regression of Barrett's esophagus (BE), resulting in the development of reepithelialized islands of squamous mucosa that may cover the underlying BE. The purpose of this study was to evaluate the clinical, histologic, and biologic characteristics of BE that is situated underneath squamous islands (BUSI). A total of 97 mucosal biopsies from 44 BE patients with BUSI were evaluated for a variety of histologic features (eg, type of epithelium, anatomic relationship of the underlying glands to the luminal surface, presence of adjacent mucosal glands or ducts, and the presence and degree of dysplasia), and immunostained for Ki-67, cyclin D1, and p53. BUSI was compared with adjacent areas of BE for all parameters. A clinical control group consisting of 50 BE patients without microscopic evidence of BUSI was selected for comparison of clinical and endoscopic features. The study group (34 males, 10 females; mean age, 67 years; mean length of BE, 5.5 cm) consisted of 27 (61%) and 12 (27%) patients on low- and high-dose PPI, respectively. On endoscopy, visible islands of squamous mucosa were noted in only 43% of study group patients (despite the presence of BUSI microscopically in all cases); one island was noted in 2%, multiple islands in 27%, and extensive islands in 14% of patients. The extent of squamous islands was unrelated to PPI dose. The study group was significantly more likely to have endoscopic evidence of extensive squamous islands compared with the control group (P = 0.009). Histologically, 89% of biopsies with BUSI showed intestinal-type, and 11% showed cardia-type, epithelium. Low- and high-grade dysplasia was noted in 4 (4%) and 5 (5%) biopsies, respectively. All patients with dysplasia in BUSI also showed dysplasia in other areas of the esophagus as well. Interestingly, BUSI reached the mucosal surface either by penetrating directly through, or by wrapping around, islands of squamous epithelium, in 68% of biopsies. Twenty-one percent of biopsies showed BUSI adjacent to submucosal glands or ducts. BUSI showed a significantly lower Ki-67 proliferation rate (29% vs. 49%, P < 0.001), and a lower, albeit nonsignificant, degree of cyclin D1 (16% vs. 29%) and p53 (4% vs. 17%) positivity in comparison to adjacent areas of BE. Furthermore, significantly lower proliferation rates were observed in BUSI that did not reveal an opening to the mucosal surface in comparison to foci that did. BUSI is phenotypically similar to typical surface BE but shows less severe proliferative abnormalities, particularly in buried glands that have no detectable connection to the esophageal lumen. Reduced proliferation may be due either to decreased exposure to luminal contents or to disruption of sloughing of surface epithelial cells into the crypt lumen. Prospective studies of large numbers of patients with BUSI will be required to determine the magnitude of its risk of progression to cancer.

Aged↗

PubMed2004

The combination of genetic instability and clonal expansion predicts progression to esophageal adenocarcinoma.

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.

Adenocarcinoma↗

PubMed2004

Selectively advantageous mutations and hitchhikers in neoplasms: p16 lesions are selected in Barrett's esophagus.

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.

Barrett Esophagus↗

PubMed2004

Cancer prevention strategies that address the evolutionary dynamics of neoplastic cells: simulating benign cell boosters and selection for chemosensitivity.

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.

Antineoplastic Agents↗

PubMed2003

Selective instability: maternal effort and the evolution of gene activation and deactivation rates.

We previously used simulations of gene expression to demonstrate that rapid activation and deactivation rates stabilized outcomes in stochastic systems. We hypothesized that transient single allele inactivation of an autosomal gene during gametogenesis or very early embryogenesis could have a selective advantage if it permits the functional sampling of each allele and precludes committing maternal effort to an embryo with a deleterious mutation. To test this hypothesis, we simulated the evolution of gene expression activation and deactivation rates and imposed two different selective pressures on the populations: (a). late selection against individuals that cannot maintain a threshold level of gene product that occurs after the investment of maternal effort (i.e., after birth); or (b). early selection: in addition to late selection, maintenance of the gene product above a threshold level was necessary for early development prior to commitment of maternal effort. We found that the opportunity to save reproductive effort from early selection caused the evolution of higher deactivation rates and lower activation rates than in the late selection condition. Thus, we predict that in the special case where early selection can save maternal investment in non-viable offspring, gene expression activation rates and deactivation rates might be selected to permit sampling of the product from each allele.

Evolution, Molecular↗