Detection of Mutations in Barrett’s Esophagus Before Progression to High-Grade Dysplasia or Adenocarcinoma

Stachler, Matthew D.; Camarda, Nicholas D.; Deitrick, Christopher; Kim, Anthony; Agoston, Agoston T.; Odze, Robert D.; Hornick, Jason L.; Nag, Anwesha; Thorner, Aaron R.; Ducar, Matthew D.; Noffsinger, Amy; Lash, Richard H.; Redston, Mark; Carter, Scott L.; Davison, Jon M.; Bass, Adam J.

doi:10.1053/j.gastro.2018.03.047

Cited by 124 publications

(147 citation statements)

References 47 publications

(74 reference statements)

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“…In contrast to a previous NGS study, the high‐resolution SNP arrays used in our study permit highly sensitive detection of copy number alterations in small genomic regions, at exon resolution, and in small cellular subpopulations in each tested sample. The most frequent SCNAs in nondysplastic BE involved FHIT exon 5 and/or CDKN2A/B , and their combined alterations were significantly more prevalent in preprogression‐BE (88%) than in both NvDBE cohorts (24%).…”

Section: Discussionsupporting

confidence: 93%

“…Our data are consistent with previous studies showing frequent CDKN2A /p16 inactivation in EAC, preneoplastic BE and dysplastic precursor lesions . CDKN2A /p16 is a member of the INK4 family of cyclin‐dependent kinase inhibitor proteins (p16 INK4a , p15 INK4b , p18 INK4c and p19 INK4d ) that negatively regulate progression through the G1 phase of the cell cycle by binding to and inhibiting cyclin D/cdk4–6 complexes .…”

Section: Discussionsupporting

confidence: 93%

“…Furthermore, p16 nuclear expression was lower in IM of progressors with somatic loss of CDKN2A/B than in IM of progressors without somatic loss of CDKN2A/B , albeit it did not reach statistical significance ( p = 0.053). In addition to the somatic structural genetic alterations identified in our study, inactivating mutations and epigenetic mechanisms such as CpG hypermethylation can contribute to reduced p16 expression in some BE cases.…”

Section: Discussionmentioning

confidence: 78%

“…A number of recent studies reported a spectrum of genomic alterations in nondysplastic BE and in dysplastic precancer and EAC lesions . However, most studies were cross‐sectional and there are limited data from preprogression longitudinal samples reporting genome‐wide alterations in BE . Furthermore, our study is the first to study genome‐wide copy number alterations from longitudinal BE samples characterized histologically as negative for dysplasia, which is possible because we performed high‐resolution SNP arrays from FFPE, in contrast to previous studies that tested separate fresh tissue samples, or used a limited 243 gene next‐generation sequencing (NGS) panel …”

Section: Discussionmentioning

confidence: 99%

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High‐resolution genomic alterations in Barrett's metaplasia of patients who progress to esophageal dysplasia and adenocarcinoma

Sepulveda

Komissarova

Kongkarnka

et al. 2019

Intl Journal of Cancer

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The main risk factor for esophageal dysplasia and adenocarcinoma (DAC) is Barrett's esophagus (BE), characterized by intestinal metaplasia. The critical genomic mechanisms that lead to progression of nondysplastic BE to DAC remain poorly understood and require analyses of longitudinal patient cohorts and high‐resolution assays. We tested BE tissues from 74 patients, including 42 nonprogressors from two separate groups of 21 patients each and 32 progressors (16 in a longitudinal cohort before DAC/preprogression‐BE and 16 with temporally concurrent but spatially separate DAC/concurrent‐BE). We interrogated genome‐wide somatic copy number alterations (SCNAs) at the exon level with high‐resolution SNP arrays in DNA from formalin‐fixed samples histologically confirmed as nondysplastic BE. The most frequent abnormalities were SCNAs involving FHIT exon 5, CDKN2A/B or both in 88% longitudinal BE progressors to DAC vs. 24% in both nonprogressor groups (p = 0.0004). Deletions in other genomic regions were found in 56% of preprogression‐BE but only in one nonprogressor‐BE (p = 0.0004). SCNAs involving FHIT exon 5 and CDKN2A/B were also frequently detected in BE temporally concurrent with DAC. TP53 losses were detected in concurrent‐BE but not earlier in preprogression‐BE tissues of patients who developed DAC. CDKN2A/p16 immunohistochemistry showed significant loss of expression in BE of progressors vs. nonprogressors, supporting the genomic data. Our data suggest a role for CDKN2A/B and FHIT in early progression of BE to dysplasia and adenocarcinoma that warrants future mechanistic research. Alterations in CDKN2A/B and FHIT by high‐resolution assays may serve as biomarkers of increased risk of progression to DAC when detected in BE tissues.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

High‐resolution genomic alterations in Barrett's metaplasia of patients who progress to esophageal dysplasia and adenocarcinoma

Sepulveda

Komissarova

Kongkarnka

et al. 2019

Intl Journal of Cancer

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“…BE is one of the precursors for EAC and has been extensively studied to identify early events of carcinogenesis and differences between the progressing and nonprogressing types of BEs. Some of these studies identified different mutation, DNA methylation, and SCNA patterns among the progressing and nonprogressing types of BE suggesting a window of opportunity for early detection with multiomics approach . A couple of recent reports using molecular biomarker‐based nonendoscopic method (Table ) enables an efficient, well‐tolerated, sensitive, and specific method of screening at‐risk populations for BE .…”

Section: Future Perspectivesmentioning

confidence: 99%

Molecular landscape of esophageal cancer: implications for early detection and personalized therapy

Talukdar

Pietro

Secrier

et al. 2018

Annals of the New York Academy of Sciences

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Esophageal cancer (EC) is one of the most lethal cancers and a public health concern worldwide, owing to late diagnosis and lack of efficient treatment. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are main histopathological subtypes of EC that show striking differences in geographical distribution, possibly due to differences in exposure to risk factors and lifestyles. ESCC and EAC are distinct diseases in terms of cell of origin, epidemiology, and molecular architecture of tumor cells. Past efforts aimed at translating potential molecular candidates into clinical practice proved to be challenging, underscoring the need for identifying novel candidates for early diagnosis and therapy of EC. Several major international efforts have brought about important advances in identifying molecular landscapes of ESCC and EAC toward understanding molecular mechanisms and critical molecular events driving the progression and pathological features of the disease. In our review, we summarize recent advances in the areas of genomics and epigenomics of ESCC and EAC, their mutational signatures and immunotherapy. We also discuss implications of recent advances in characterizing the genome and epigenome of EC for the discovery of diagnostic/prognostic biomarkers and development of new targets for personalized treatment and prevention.

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Barrett's esophagus: The pathomorphological and molecular genetic keystones of neoplastic progression

et al. 2021

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Barrett's esophagus is a widespread chronically progressing disease of heterogeneous nature. A life threatening complication of this condition is neoplastic transformation, which is often overlooked due to lack of standardized approaches in diagnosis, preventative measures and treatment. In this essay, we aim to stratify existing data to show specific associations between neoplastic transformation and the underlying processes which predate cancerous transition. We discuss pathomorphological, genetic, epigenetic, molecular and immunohistochemical methods related to neoplasia detection on the basis of Barrett's esophagus. Our review sheds light on pathways of such neoplastic progression in the distal esophagus, providing valuable insight into progression assessment, preventative targets and treatment modalities. Our results suggest that molecular, genetic and epigenetic alterations in the esophagus arise earlier than cancerous transformation, meaning the discussed targets can help form preventative strategies in at-risk patient groups.

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Detection of Mutations in Barrett’s Esophagus Before Progression to High-Grade Dysplasia or Adenocarcinoma

Cited by 124 publications

References 47 publications

High‐resolution genomic alterations in Barrett's metaplasia of patients who progress to esophageal dysplasia and adenocarcinoma

High‐resolution genomic alterations in Barrett's metaplasia of patients who progress to esophageal dysplasia and adenocarcinoma

Molecular landscape of esophageal cancer: implications for early detection and personalized therapy

Barrett's esophagus: The pathomorphological and molecular genetic keystones of neoplastic progression

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