RESUMEN
Barrett's oesophagus (BE) is the premalignant condition associated with the development of oesophageal adenocarcinoma (OAC). Diagnostically, p53 immunohistochemistry remains the only biomarker recommended clinically to aid histopathological diagnosis. The emerging mutational profile of BE is one of highly heterogeneous lesions at the genomic level with many mutations already occurring in non-dysplastic tissue. As well as point mutations, larger scale copy-number changes appear to have a key role in the progression to OAC and clinically applicable assays for the reliable detection of aneuploidy will be important to incorporate into future clinical management of patients. For some patients, the transition to malignancy may occur rapidly through a genome-doubling event or chromosomal catastrophe, termed chromothripsis, and detecting these patients may prove especially difficult. Given the heterogeneous nature of this disease, sampling methods to overcome inherent bias from endoscopic biopsies coupled with the development of more objective biomarkers than the current reliance on histopathology will be required for risk stratification. The aim of this approach will be to spare low-risk patients unnecessary procedures, as well as to provide endoscopic therapy to the patients at highest risk, thereby avoiding the burden of incurable metastatic disease.
Asunto(s)
Adenocarcinoma/genética , Esófago de Barrett/genética , Variaciones en el Número de Copia de ADN/genética , Neoplasias Esofágicas/genética , Inestabilidad Genómica/genética , Mutación/genética , Lesiones Precancerosas/genética , Aneuploidia , Cromotripsis , Proteínas de Unión al ADN , Progresión de la Enfermedad , Humanos , Proteínas de la Membrana/genética , Miosinas/genética , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Semaforinas , Proteína Smad4/genética , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
BACKGROUND: There is need for the application of biomarkers in a clinical setting in order to improve patient care. Current surveillance methods are costly for health care systems and invasive for patients, and subjective methodology leads to frequent misdiagnosis. This review summarises the most advanced recent and relevant literature in the field of biomarker development in the context of Barrett's esophagus and comments on their potential application. Studies included roughly correlate with Early Detection Research Network phases three and four. RECENT FINDINGS: A number of individual candidate and panels of biomarkers have been investigated recently. These include: gene-specific mutations such as loss of heterozygosity, copy number alterations (in particular aneuploidy) methylation panels, altered gene expression, and glycosylation assayed by lectin binding, as well as genetic and clonal diversity measures. Immunostaining for p53 is the only candidate biomarker deemed "ready for prime time." This has been recommended for use clinically as an adjunct to histological diagnosis of dysplastic Barrett's esophagus in the 2014 British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's esophagus. CONCLUSIONS: Progress is being made but in many cases further prospective validation studies are required before clinical application can take place. Limitations to furthering these studies include the large patient cohorts required for prospective validation studies, costs associated with studies, and reproducibility of methods across laboratories. Continued research in this area is strongly recommended as, in the long run, biomarker application has the potential to significantly improve patient care.
Asunto(s)
Adenocarcinoma/genética , Esófago de Barrett/genética , Transformación Celular Neoplásica/genética , Neoplasias Esofágicas/genética , Vigilancia de la Población/métodos , Lesiones Precancerosas/genética , Adenocarcinoma/química , Adenocarcinoma/patología , Esófago de Barrett/metabolismo , Esófago de Barrett/patología , Biomarcadores/análisis , Transformación Celular Neoplásica/química , Transformación Celular Neoplásica/patología , Neoplasias Esofágicas/química , Neoplasias Esofágicas/patología , Expresión Génica , Humanos , Mutación , Lesiones Precancerosas/química , Lesiones Precancerosas/patología , Proteína p53 Supresora de Tumor/análisisRESUMEN
Recent studies show that aneuploidy and driver gene mutations precede cancer diagnosis by many years1-4. We assess whether these genomic signals can be used for early detection and pre-emptive cancer treatment using the neoplastic precursor lesion Barrett's esophagus as an exemplar5. Shallow whole-genome sequencing of 777 biopsies, sampled from 88 patients in Barrett's esophagus surveillance over a period of up to 15 years, shows that genomic signals can distinguish progressive from stable disease even 10 years before histopathological transformation. These findings are validated on two independent cohorts of 76 and 248 patients. These methods are low-cost and applicable to standard clinical biopsy samples. Compared with current management guidelines based on histopathology and clinical presentation, genomic classification enables earlier treatment for high-risk patients as well as reduction of unnecessary treatment and monitoring for patients who are unlikely to develop cancer.