Surface Ki-67 Expression Improves Reproducibility of Dysplasia Diagnosis in Barrett’s Esophagus

Yousaf, Hira; Hayat, Umar; Manivel, J. Carlos; Iwamoto, Carlos; Peltola, Justin; Hanson, Brian; Larson, Wendy; Dachel, Susan; Gravely, Amy; Mesa, Hector

doi:10.1093/ajcp/aqaa004

Cited by 9 publications

(5 citation statements)

References 22 publications

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“…The present smaller study reports similar findings, with p53 highly specific (94%) and Ki-67 highly sensitive (100%) for further dysplasia. Ki-67 expression has been reported to predict the future risk of high-grade dysplasia and EAC in patients with BE [13,31,32] and none of the patients with negative Ki-67 expression at the index endoscopy had dysplasia on follow-up endoscopy. Previous studies have reported that abnormal p53 expression predicts progression to high-grade dysplasia or EAC in patients with BE [33,34].…”

Section: Discussionmentioning

confidence: 99%

Variation in proliferative and cell cycle markers in Barrett’s esophagus in relation to circumferential and axial location in the esophagus

Umar,

Alleyne,

Cheung

et al. 2024

European Journal of Gastroenterology &Amp; Hepatology

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Background Adenocarcinoma in Barrett’s esophagus (BE) occurs more frequently between 12 and 3 o’clock at the gastroesophageal junction (GEJ). Methods BE patients were prospectively recruited from December 2013 to July 2016. Expression of p53, Ki-67, cyclin-D1, COX-2 and p21 was assessed in quadrantic biopsies from the proximal and distal margins of the BE segments. Cell cycle marker association with current or subsequent dysplasia or adenocarcinoma was examined. Results 110 patients: median age 64 (IQR, 56–71) years; median BE segment length C4M6; and a median follow-up of 4.7 (IQR, 3.6–5.7) years. In total 13 (11.8%) had evidence of dysplasia or neoplasia (2.7% indefinite for dysplasia, 5.5% low grade, 1.8% high grade and 1.8% adenocarcinoma) at index endoscopy. Six (7%) developed dysplasia or neoplasia (1 low grade, 2 high grade and 3 adenocarcinoma) during follow-up. Ki-67 expression was highest at 3 o’clock, and overall was 49.6% higher in the 12-6 o’clock position compared to 6-12 o’clock [odds ratio (OR), 1.42 (95% confidence interval (CI), 1.00–2.12)]. A similar pattern was found with p21 [1.82 (1.00–3.47)]. There was increased expression of several markers in distal BE biopsies; cyclin-D1 [1.74 (1.29–2.34)]; Cyclo-oxygenase 2 [2.03 (1.48–2.78]) and p21 [2.06 (1.16–3.68)]. Expression of Ki-67 was lower in distal compared to proximal biopsies [0.58 (0.43–0.78)]. P53 expression had high specificity (93.8%) for subsequent low-grade dysplasia, high-grade dysplasia or adenocarcinoma. Conclusion Increased cellular proliferation was seen at 12-6 o’clock at the GEJ. Cell-cycle marker expression was increased at the GEJ compared to the proximal BE segment. These findings mirror reflux esophagitis and suggest ongoing reflux contributes to the progression of dysplasia and malignancy in BE.

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Section: Discussionmentioning

confidence: 99%

Variation in proliferative and cell cycle markers in Barrett’s esophagus in relation to circumferential and axial location in the esophagus

Umar,

Alleyne,

Cheung

et al. 2024

European Journal of Gastroenterology &Amp; Hepatology

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“…The estimated percentage of positive cells was ranked as 0 (negative‐10%), 1 (10%–25%), 2 (26%–50%), 3 (51%–75%) and 4 (>75%) in each tissue. Five views were taken per tissue 39,40 …”

Section: Methodsmentioning

confidence: 99%

“…Five views were taken per tissue. 39,40 For IHC of ESCC tissues, tissues were subjected to immunostaining using antibodies FAM135B. These retrospective ESCC specimens from patients after platinumbased neoadjuvant therapy were obtained from the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.…”

Section: Immunohistochemistry and Staining Scorementioning

confidence: 99%

FAM135B sustains the reservoir of Tip60‐ATM assembly to promote DNA damage response

Zhang

Liu

et al. 2022

Clinical & Translational Med

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Background Recently, the mechanism by which cells adapt to intrinsic and extrinsic stresses has received considerable attention. Tat‐interactive protein 60‐kDa/ataxia–telangiectasia‐mutated (TIP60/ATM) axis‐mediated DNA damage response (DDR) is vital for maintaining genomic integrity. Methods Protein levels were detected by western blot, protein colocalisation was examined by immunofluorescence (IF) and protein interactions were measured by co‐immunoprecipitation, proximity ligation assay and GST pull‐down assays. Flow cytometry, comet assay and IF assays were used to explore the biological functions of sequence similarity 135 family member B (FAM135B) in DDR. Xenograft tumour, FAM135B transgenic mouse models and immunohistochemistry were utilised to confirm in vitro observations. Results We identified a novel DDR regulator FAM135B which could protect cancer cells from genotoxic stress in vitro and in vivo. The overexpression of FAM135B promoted the removal of γH2AX and 53BP1 foci, whereas the elimination of FAM135B attenuated these effects. Consistently, our findings revealed that FAM135B could promote homologous recombination and non‐homologous end‐joining repairs. Further study demonstrated that FAM135B physically bound to the chromodomain of TIP60 and improved its histone acetyltransferase activity. Moreover, FAM135B enhanced the interactions between TIP60 and ATM under resting conditions. Intriguingly, the protein levels of FAM135B dramatically decreased following DNA damage stress but gradually increased during the DNA repair period. Thus, we proposed a potential DDR mechanism where FAM135B sustains a reservoir of pre‐existing TIP60‐ATM assemblies under resting conditions. Once cancer cells suffer DNA damage, FAM135B is released from TIP60, and the functioning pre‐assembled TIP60‐ATM complex participates in DDR. Conclusions : We characterised FAM135B as a novel DDR regulator and further elucidated the role of the TIP60‐ATM axis in response to DNA damage, which suggests that targeting FAM135B in combination with radiation therapy or chemotherapy could be a potentially effective approach for cancer treatment.

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“…LGD: occasionally (+) with cytoplasmic and membranous; HGD: often (+) with cytoplasmic and membranous [118,192,193] Ki67 BE: (+) nuclear at the base of the crypt Dysplasia: (+) diffused nuclear [119] P53 BE: (−)…”

Section: Imp3mentioning

confidence: 99%

Diagnostic Challenges during Inflammation and Cancer: Current Biomarkers and Future Perspectives in Navigating through the Minefield of Reactive versus Dysplastic and Cancerous Lesions in the Digestive System

Pateras,

Igea,

Nikas

et al. 2024

IJMS

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In the setting of pronounced inflammation, changes in the epithelium may overlap with neoplasia, often rendering it impossible to establish a diagnosis with certainty in daily clinical practice. Here, we discuss the underlying molecular mechanisms driving tissue response during persistent inflammatory signaling along with the potential association with cancer in the gastrointestinal tract, pancreas, extrahepatic bile ducts, and liver. We highlight the histopathological challenges encountered in the diagnosis of chronic inflammation in routine practice and pinpoint tissue-based biomarkers that could complement morphology to differentiate reactive from dysplastic or cancerous lesions. We refer to the advantages and limitations of existing biomarkers employing immunohistochemistry and point to promising new markers, including the generation of novel antibodies targeting mutant proteins, miRNAs, and array assays. Advancements in experimental models, including mouse and 3D models, have improved our understanding of tissue response. The integration of digital pathology along with artificial intelligence may also complement routine visual inspections. Navigating through tissue responses in various chronic inflammatory contexts will help us develop novel and reliable biomarkers that will improve diagnostic decisions and ultimately patient treatment.

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Surface Ki-67 Expression Improves Reproducibility of Dysplasia Diagnosis in Barrett’s Esophagus

Cited by 9 publications

References 22 publications

Variation in proliferative and cell cycle markers in Barrett’s esophagus in relation to circumferential and axial location in the esophagus

Variation in proliferative and cell cycle markers in Barrett’s esophagus in relation to circumferential and axial location in the esophagus

FAM135B sustains the reservoir of Tip60‐ATM assembly to promote DNA damage response

Diagnostic Challenges during Inflammation and Cancer: Current Biomarkers and Future Perspectives in Navigating through the Minefield of Reactive versus Dysplastic and Cancerous Lesions in the Digestive System

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